Indian Rett Syndrome Foundation

Brain Plasticity and Disease: AMatter of Inhibition: A Review Article

2011-12-05T17:24:00.000+05:30

Interesting article by Laura Baroncelli and Colleagues.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

A role for glia in the progression of Rett’s syndrome

2011-12-05T17:23:00.000+05:30

Interesting article by Daniel T. Lioy.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

INSIDE THE MINDS OF MICE AND MEN

2011-12-05T17:21:00.002+05:30

Interesting article by MONYA BAKER.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

Subclinical myocardial dysfunction in Rett syndrome

2011-12-05T17:19:00.000+05:30

Interesting article by Claudio De Felice and colleagues.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

MeCP2 and Rett syndrome: reversibility and potential avenues for therapy: A Review Article

2011-12-05T17:18:00.000+05:30

Interesting article by Kamal K.E. GADALLA and colleagues.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

Folinic Acid supplementation in Rett syndrome patients does not influence the course of Disease: A Randomized Study

2011-12-05T17:16:00.000+05:30

Interesting article by Eveline E. O. Hagebeuk and colleagues.

Note: Please click on the title to read the full article.

Source: NCBI-PubMed

Movement Disorders Emergencies in Childhood

2011-12-05T17:09:00.001+05:30

A very Interesting article by F.J. Kirkham and Colleagues.

Note: Click on the title to read the full article.

Source:NCBI-Pubmed

Rett Syndrome: Exploring the Autism Link

2011-12-05T17:08:00.000+05:30

A very Interesting article by Dr. Alan K Percy.

Must read.

Note: Click on the title to read the full article.

Source:NCBI-Pubmed

Rett Syndrome Research Trust Launches Awareness Campaign in Iconic Times Square Location

2011-11-08T16:46:00.000+05:30

Trumbull, CT (PRWEB) November 03, 2011

The Rett Syndrome Research Trust is pleased to announce a campaign to boost awareness of Rett Syndrome in the most iconic of all advertising venues – Times Square in New York City. A newly created public service announcement will run an average of nine times an hour for three months starting November 1st on the colossal 6000 square foot Mediamesh display at the corner of 42nd Street and 8th Avenue. An estimated 1.5 million people are expected to view the PSA daily.

Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome is caused by mutations in a gene called MECP2.

The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders.

While Rett Syndrome has become a high-profile disorder in scientific circles, it is still fairly unknown in the lay and medical communities; thousands of girls and women remain un- or misdiagnosed. We welcome this unique opportunity to help raise the profile of this disease, which has been dramatically reversed in pre-clinical models.

“I am so thankful to Bill Koenigsberg, CEO and Founder of Horizon Media, who secured this spectacular advertising real estate; Garage Media, owner of the Port Authority Display; A2AMedia, who manages the screen, for giving us the opportunity to showcase our disorder; and Jon Denny, film and TV producer, for creating our PSA. When smart, talented, generous people come together for a good cause, amazing things can happen,” said Monica Coenraads, Executive Director of RSRT and parent of a teenaged daughter severely disabled by Rett Syndrome.

“We are thrilled to help RSRT get out their message for such a worthy cause,” said Bill Koenigsberg.

About the Rett Syndrome Research Trust
The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. Our goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With our experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high-level research. This puts RSRT in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects. To learn more about the Trust, please visit http://www.ReverseRett.org

Source: PRWEB

A Mid-Michigan Family Shares Their Experience With Rett Syndrome

2011-11-08T16:42:00.000+05:30

Source: WLNS.com

Note: Click on the title to read the full news.

Families Raise Awareness About Rett Syndrome

2011-11-08T16:35:00.000+05:30

By DAN MANNARINO Staff reporter

12:23 a.m. EDT, October 16, 2011
NEW YORK (PIX11)—
Imagine you have thoughts, hopes, and dreams but no way to actually express them. It's a rare disorder called Rett Syndrome that affects young girls. Worldwide, 20 girls are born every day with the disorder.

Dr. Sasha Djukic says the disorder doesn't begin right at birth. "Imagine you have a child who is 1 year old, happy and healthy, and then the disease starts, in a matter of a few months it drops the ability to speak, use her hands, walk," says Djukic.

Abby Diamond is now a beautiful, 8-year-old girl. At age 3, she was diagnosed with Rett Syndrome and stopped walking and communicating with her family.

The problem is, not many people know about the disease, so not many people donate money to research.

So today, under perfectly blue skies, families gathered on the steps of the Tweed Courthouse in Lower Manhattan and in other locations around the globe to raise awareness about Rett Syndrome.

"Climbing steps is a symbolic gesture, bringing you upward and forward," says Djurik.

In an inspiring sight to watch, the girls slowly but surely climbed the 30 steps. Joining them were members of the New York City Fire Department who, in some cases, carried these brave girls to the top.

"The girls are good girls, pure in nature, friendly and trapped inside these bodies," says Abby's father, Erick Diamond.

CAL artists support Rett Syndrome fundraiser

2011-11-08T16:30:00.000+05:30

A ray of hope for Indian Rett Angels and their families

2011-08-25T23:02:00.000+05:30

Renowned neuro-scientist, Dr Mriganka Sur is all set to collaborate with the All India Institute of Medical Sciences (AIIMS), New Delhi for a research on finding a cure for neuro development diseases like Autism, Rett syndrome, etc.

Speaking to the Chandigarh Newsline, Dr Sur, professor of Neurosciences and head, department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), USA, said, “We are planning to collaborate on a research programme on neuro development disorders. Despite the rarity of the disease, Rett syndrome which is found 95 per cent in girls due to their mutations, in India, the percentage of girls suffering from it is quite high. Even in USA, one in every 150 children is prone to Autism and in the United Kingdom, the chances of having autism are even higher, one in every 100. Though there are clinical trials and constant researches going on, there is no cure yet for most neuro development disorders.”

Dr Sur, who is the director of Simon’s Initiative on Autism, said, “Though some studies have established that Autism is mostly a genetic disease, yet gene therapy is no cure for this genetic disorder.”

Though there are no pre natal tests available to detect if the child could be born with autism, however, Dr Sur warns that autism in family history may be a sign. “If anyone in the family has a history of autism, chances are that the baby could be born with the disorder too. But instead of losing hope, would be parents should approach genetic counsellors or informed physicians.”

The available therapies for autism include applied behaviour analysis (ABA), developmental models, structured teaching, speech and language therapy, social skills therapy, and occupational therapy, he added.

The diseases

Autism spectrum disorder (ASD) is a range of complex neuro development disorders, characterised by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behaviour. Usually, the symptoms start showing before the child is three years old.

Rett syndrome is a childhood neuro developmental disorder that affects females almost exclusively. The child generally appears to grow and develop normally, before symptoms begin. Early symptoms may include loss of muscle tone, a slowing of development, problems crawling or walking, and diminished eye contact. As the syndrome progresses, a child will lose purposeful use of hands and the ability to speak. The inability to perform motor functions is perhaps the most severely disabling feature of Rett syndrome, interfering with body movement.

Source: Indian express.com

Note: To read the original post please click on the title of this news.

Fourth Annual Rett syndrome Meeting and Symposium: 23rd October 2011

2011-08-04T22:31:00.001+05:30

Dear All,

As October is "Rett syndrome Awareness Month", So Indian Rett Syndrome Foundation is going to organize the Fourth Annual Rett Syndrome Awareness Meet/Symposium with help of Department of Pediatrics, AIIMS, New Delhi.

This meeting will be joined by Parents from different parts of India and Healthcare professionals (Doctors, Therapists, Scientists and Researchers). This one day Meeting/symposium will include lectures on the basics of Rett syndrome and its management, Parent-Doctor interactive sessions and therapy sessions.

Come and Join us to educate yourself and raise awareness about Rett Syndrome, a neurodevelopmental disorder. which primarily affects girls known as "Silent Angels".

We are also looking forward for sponsorships for this event and donations for this cause. Your help and support can improve lives of these little Angels and their families.

Date of Event: 23rd October, 2011
Day: Sunday
Time: 9.30am
Venue: Conference Hall, First Floor, JLN Auditorium,
All India Institute of Medical Sciences
Ansari Nagar
New Delhi-110029

Please save the date in your calenders and let your family/friends know about this by spreading the word.

If you have any queries in regard of this event, please contact us at

info@rettsyndrome.in, info.rett@yahoo.com

Registration to this event is totally free but limited. For registration for this event, please contact

rkhajuria@rettsyndrome.in
admin@rettsyndrome.in

Regards,

Indian Rett Syndrome Foundation
12/1, sector –1, Pushp Vihar,
New Delhii -110017
INDIA
Website: www.rettsyndrome.in
E-mail: info@rettsyndrome.in, admin@rettsyndrome.in, info.rett@yahoo.com
Blog: www.rettsyndromeindia.blogspot.com
Ph# +919999343421

Please vote for International Rett Syndrome Foundation: Vivint Gives Back Project

2011-06-30T23:56:00.000+05:30

Ex Vivo Treatment with a Novel Synthetic Aminoglycoside NB54 in Primary Fibroblasts from Rett Syndrome Patients Suppresses MECP2 Nonsense Mutations

2011-06-28T00:45:00.000+05:30

A recent and very interesting article by Vecsler and colleagues

Abstract

BACKGROUND:

Nonsense mutations in the X-linked methyl CpG-binding protein 2 (MECP2) comprise a significant proportion of causative MECP2 mutations in Rett syndrome (RTT). Naturally occurring aminoglycosides, such as gentamicin, have been shown to enable partial suppression of nonsense mutations related to several human genetic disorders, however, their clinical applicability has been compromised by parallel findings of severe toxic effects. Recently developed synthetic NB aminoglycosides have demonstrated significantly improved effects compared to gentamicin evident in substantially higher suppression and reduced acute toxicity in vitro.

RESULTS:

We performed comparative study of suppression effects of the novel NB54 and gentamicin on three MECP2 nonsense mutations (R294X, R270X and R168X) common in RTT, using ex vivo treatment of primary fibroblasts from RTT patients harboring these mutations and testing for the C-terminal containing full-length MeCP2. We observed that NB54 induces dose-dependent suppression of MECP2 nonsense mutations more efficiently than gentamicin, which was evident at concentrations as low as 50 µg/ml. NB54 read-through activity was mutation specific, with maximal full-length MeCP2 recovery in R168X (38%), R270X (27%) and R294X (18%). In addition, the recovered MeCP2 was translocated to the cell nucleus and moreover led to parallel increase in one of the most important MeCP2 downstream effectors, the brain derived neurotrophic factor (BDNF).

CONCLUSION:

Our findings suggest that NB54 may induce restoration of the potentially functional MeCP2 in primary RTT fibroblasts and encourage further studies of NB54 and other rationally designed aminoglycoside derivatives as potential therapeutic agents for nonsense MECP2 mutations in RTT.

Note: Click on the title to read the full article

Source: NCBI-Pubmed

Physical and Mental Health of Mothers Caring for a Child With Rett Syndrome

2011-05-31T00:40:00.001+05:30

By

Crystal L. Laurvick, MPH, Michael E. Msall, MD,Sven Silburn, MS (ClinPsych) Carol Bower, PhD, Nicholas de Klerk, PhD,Helen Leonard, MBChB

ABSTRACT

OBJECTIVES. Our goal was to investigate the physical and mental health of mothers who care for a child with Rett syndrome.

METHODS.

We assessed maternal physical and mental health by using the SF-12 version 1 physical component summary and mental component summary scores as the outcome measures of interest. Mothers (n 135) of children with Rett syndrome completed the SF-12 measure as part of the Australian Rett Syndrome Study in 2002. The analysis investigated linear relationships between physical and mental health scores and maternal, family, and child characteristics.

RESULTS. Mothers ranged in age from 21 to 60 years and their children from 3 to 27years. Nearly half of these mothers (47.4%) indicated that they worked full-time or part-time outside the home, and 41% had a combined family (gross) income of 40 000 Australian dollars. The resultant model for physical health demonstrated that the following factors were positively associated with better maternal physical health: the mother working full-time or part-time outside the home, having some high school education, having private health insurance, the child not having breathing problems in the last 2 years, the child not having home-based structured therapy, and high scores on the Family Resource Scale (indicating adequacy of time resources for basic and family needs). The resultant model for mental health demonstrated that the following factors were positively associated with better maternal mental health: the mother working full-time or part-time outside the home, the child not having a fracture in the last 2 years, lesser reporting of facial stereotypes and involuntary facial movements, being in a well-adjusted marriage, and having low stress scores.

CONCLUSIONS. Our study suggests that the most important predictors of maternal physical and emotional health are child behavior, caregiver demands, and family function.

Note: Click on the title to read the full article.

Source: Pubmed

Daily tips for day to day living with Rett syndrome : Advice from the Internation Rett Syndrome Foundation Experts

2011-05-30T22:34:00.000+05:30

Bathing

If she does not sit without support, it may be hard to get her in and out of the tub and keep her stable and safe while you wash her.

There are a number of waterproof bath chairs available, ranging from mesh sling-back styles to rigid plastic benches and chairs.

A hand-held shower hose can be very useful in the tub, especially for hair washing.

Waterproof wheelchairs are available for use in roll-in showers.

A mesh table that hooks into the back of a roll-in shower provides a safe way to bathe without undue bending by the caregiver.

Lifting to Prevent Back Injuries

It is important to learn how to lift correctly, so that you place the least amount of strain on your body, particularly your back. It is a good idea to attend one of your daughter’s PT sessions to get suggestions for the best ways to care for her with the least lifting possible. The school district may even allow you to have special PT sessions for training purposes. Ask your school administrator or request it in her IEP. While good lifting techniques can prevent injuries, they will also make transfers safer and easier. A training session should include: transferring in and out of your car, in and out of the tub, in and out of sitting to stand position, placing the wheelchair in and out of the car, and any other situations which pull on your back. When lifting, widen the base of your stance and bend your legs while keeping your back straight. When transferring from bed to chair, lean your daughter forward into your shoulder. A sliding board is an inexpensive piece of equipment which can be used for safe transfers. If your daughter is able to learn to assist you, practice often so she can gain strength to help. There are a number of mechanical devices when lifting becomes too difficult. Ramps, platform lifts, stairway lifts, and elevators increase accessibility and decrease back strain. Bathtub and bedside lifts can be invaluable. When changing diapers, it is better to roll the girl on her side to place the diaper under her rather than to lift her hips. It may not seem like a lot of strain, but over time, lifting the wrong way can be harmful.

The general principles of lifting are:

* the force is against you
* lift from the waist
* add upper body weight
* watch your weight
* warm up before lifting

The causes of back injuries include:

* lifting from the waist, and twisting
* lifting overhead or away from you
* heavy, repetitive lifting
* awkward position
* unbalanced load
* sitting/standing in one position too long

Traveling

Vacation and Travel For Families with Special Needs Children:

Most families with children choose to vacation and travel during the summer months, and it may take some planning to have a successful vacation. Even more so for families with children who have special needs. There are many things to consider when planning a vacation: destination, transportation, hotel or other overnight arrangements, activities, adaptations, and general accessibility, to name a few.

Tips for Air Travel:

* Contact the airline as early as possible for special assistance, or use a travel agent who is familiar with making special reservations.
* If possible, ask for a non-stop flight to avoid airport shuffle.
* If you use a car seat, make sure it is certified for air travel.
* Make sure to label all equipment with your name, address, and phone number.
* If your child’s wheel chair is checked, remind the flight attendant before landing so she can make a radio inquiry to make sure the chair is delivered promptly.
* Make arrangements for special meals in advance. Do take along some of your child’s favorite snacks and drinks.
* Take your child to the toilet or change her diaper before the flight.
* Invest in a Walkman or DVD player and a good set of barrettes to anchor the headset.
* Offer your child something to eat or drink during descent.

Additional Travel Tips:

* Make advanced arrangements with car rental services.
* Before you leave home, get a disabled parking placard that can be used everywhere.
* Check with your hotel to be sure your room and facilities are handicap accessible.
* The following is a list of Web sites, which addresses those considerations. They contain information about vacation travel through articles, books, Internet links, and other resources.

1. A wonderful Directory of Summer Camps for Children with Disabilities was compiled by the National Information Center for Children and Youth with Disabilities (NICHCY). It contains disability-specific as well as general camp resources.
2. The Global Access Disabled Travel Network is a Web site containing personal travel experiences, as well as information on travel books, specific destinations, tips on planning, hotels and resorts, etc.
3. Travel with Kids offers information and links to cruise ship accessibility, tour operators and travel agents specializing in special needs, outdoor vacations for people with disabilities, and much more.
4. The Parenting Special Needs Web site has a section on Accessible Summer Recreation. It includes accessible travel, camps for special children, recreation and sport, adaptive equipment, and also just for fun activities for children with special needs.
5. The Enabled RVer hosts articles on topics related to RV travel, such as accessible RVs, the Handicapped Travel Club (HTC), travel guides, campgrounds and specific destinations, resources, and adaptive equipment.
6. Access-Able Travel Source contains information on travel with disabilities, mature travel, disability magazines, access guides, wheelchair travel, scooter rental, accessible transportation, world destinations, lists of travel professionals, links, and tips for the traveler with disabilities.
7. The Project ACTION Accessible Travelers' Database was created to assist tourists with disabilities to access mass transit systems while traveling to other cities. The database includes information on hotel/motel shuttles, accessible taxis, private bus/tour companies, van rentals, public transit operators, and national 800 numbers.
8. The Disability Travel and Recreation Resources web site includes information and links on topics such as travel planning, destinations, transportation, air travel, children, and books.
9. Emerging Horizons is a magazine, available online and in print, about accessible travel for people with mobility disabilities. It includes access information, resources, news and travel tips.
10. The Society for Accessible Travel & Hospitality (SATH) actively promotes awareness, respect, accessibility, and employment for persons with disabilities in the tourism industry. SATH contains disability-specific 'How To Travel' articles, as well as an extensive list of resources for the traveler with disabilities.
11. Accessible Recreation on Federal Lands provides a listing of government resources that manage federal recreation sites in the United States. It also includes the Accessibility Data Management System (ADMS), an online resource containing accessibility information about many federal facilities.
12. The National Center on Physical Activity and Disability web site contains a virtual library with an extensive list of resource directories, fact sheets, bibliographies, and monographs. Topics range from adaptive equipment, adapting activities in recreation programs, camping, hiking, fishing, scuba, and much more.

Although the sources listed above seem extensive, it is just the tip of the iceberg. Explore what will best fit you and your needs as a family

Source: International Rett Syndrome Foundation (www.rettsyndrome.org)

Longevity in Rett Syndrome: Analysis of the North American Database

2011-05-23T18:15:00.000+05:30

Interesting article by

Russell S. Kirby and colleagues

Source: NCBI-Pubmed

Note: Click on the title post to read the full article

Long-term follow-up of functioning after spinal surgery in patients with Rett syndrome

2011-05-23T18:13:00.000+05:30

Interesting article by

Eva-Lena Larsson and colleagues

Source: NCBI-Pubmed

Note: Click on the title post to read the full article

Autism Spectrum Disorders

2011-05-23T18:01:00.000+05:30

Judith H Miles, MD, PhD
Thompson Center for Autism and Neurodevelopmental Disorders & Department of Child Health
University of Missouri Hospitals and Clinics
Columbia, MO
milesjh@missouri.edu

Rebecca B McCathren, PhD
Early Childhood Special Education
College of Edicuation
University of Missouri
Columbia, MO
mccathrenr@missouri.edu

Janine Stichter, PhD
Thompson Center for Autism and Neurodevelopmental Disorders & Department of Special Education
University of Missouri
Columbia, MO
stichterj@missouri.edu

Marwan Shinawi, MD
Department of Pediatrics, Division of Genetics and Genomic Medicine
Washington University School of Medicine
St. Louis, MO
Shinawi_M@kids.wustl.edu

Summary

Disease characteristics. Autism comprises a clinically heterogeneous group of disorders – collectively referred to as “autism spectrum disorders” (ASD) – that share common features of impaired social relationships, impaired language and communication, and repetitive behaviors or a narrow range of interests. For most children with autism, symptoms develop gradually, although approximately 30% have a "regressive" onset usually between ages 18 and 24 months. About 50%-70% of children with autism are identified as intellectually disabled by nonverbal IQ testing and approximately 25% develop seizures. Autism can be considered complex (i.e., presence of dysmorphic features and/or microcephaly) or essential (i.e., absence of physical abnormalities and microcephaly). About 25% of children who fit the diagnostic criteria for ASD at age two to three years subsequently begin to talk and communicate, and by age six to seven years blend to varying degrees into the regular school population. The remaining 75% have lifelong disability requiring intensive parental, school, and social support.

Diagnosis/testing. The behavioral criteria presented in the American Psychiatric Association Manual of Psychiatric Diseases, 4th edition (DSM-IV) remain the standard for making an autism diagnosis in the US. Currently, three subgroups (autistic disorder, Asperger syndrome, and PDD-NOS) are recognized. To qualify for a diagnosis of autistic disorder (i.e., classic autism), a child must have shown abnormalities in social interaction and language used for social communication or symbolic/imaginative play and either stereotypic motor mannerisms or restricted patterns of interest before age three years. If the child does not meet criteria for autistic disorder, he or she may be given a diagnosis of Asperger syndrome (AS) or pervasive developmental disorder-not otherwise specified (PDD-NOS), the other two disorders included in ASD. Autism has many etiologies, a concept that was widely embraced following the discovery of the molecular basis of Rett syndrome in 2006. Since then autism has been documented in hundreds of neurologically based syndromes with multiple causes, outcomes, and treatment responses. Currently, an etiology can be identified for between 15% and 20% of individuals with autism; in the others the cause remains unknown.

Management. Treatment of manifestations: Management of autism involves educational, behavioral, and medical therapies to promote conversational language and social interactions while mitigating repetitive self-stimulatory behaviors, tantrums, aggression, and self-injurious behaviors. The mainstay of therapy is early individualized intensive training either in the school or home, where the environment must be predictable with planned transitions between activities and venues. Visual supports are helpful in promoting language acquisition. The Visually Cued Instruction and Schedules program uses graphic clues to aid communication, organizational skills, and self-management. The Picture Exchange Communication System provides a visual system in which to learn communication. Social Stories intervention increases appropriate behavior by explaining social situations in ways understandable to the student. Medications, especially atypical antipsychotics, can ameliorate specific symptoms such as aggressive or self-injurious behavior. Children treated early can usually be taught, to varying degrees, to communicate, recognize and respond to social interactions, develop imaginative play, and curb all-consuming repetitive self-stimulatory behaviors.

Prevention of secondary complications: Intensive behavioral intervention programs can prevent or at least mitigate aggressive behaviors (tantrums, aggression, and self injurious behaviors) that occur commonly in children with no communication skills or interest in social interactions.

Surveillance: At least annual surveillance for health, developmental progress, education milestones, behavioral and family functioning preferably at a multidisciplinary autism clinic is strongly recommended.

Testing of relatives at risk: Because sibs are at increased risk of developing autism or an ASD, their language, development, and behavior should be closely monitored for the first three years, preferably through an autism sib program.

Genetic counseling. For individuals with autism in whom the etiology is known, genetic counseling and risk assessment are based on the genetics of that specific diagnosis. For autism of unknown cause, the empiric aggregate risk to sibs is 5%-10% for autism and 10%-15% for milder conditions, including language, social, and psychiatric disorders. For families with two or more affected children, the recurrence risk approaches 35%. Male sibs (brothers) of a proband with essential autism have a 7% risk for autism and an additional 7% risk for milder ASD. Female sibs (sisters) of a proband with essential autism have a 1% risk for autism; the risk for a milder ASD is unknown. The recurrence risk to sibs of a proband with complex autism is 1% for autism and an additional 2% for a milder ASD.

Definition

Clinical Manifestations

Autism spectrum disorders (ASD) develop prior to age three years. Infants typically do not care to be held or cuddled and do not reach out to be picked up. Often they are "colicky" and hard to console, typically quieting more readily when left alone. They may avoid and fail to initiate eye contact or stare into space. Sleep disturbances and sensory issues may be noted in the first year. Despite early signs, children with ASD often do not come to medical attention until after the second year when language delays are obvious.

For most children, the onset of ASD symptoms is gradual; however, approximately 30% have a "regressive" onset. These children begin to speak and then, either gradually or precipitously, lose language and become distant. Within a matter of days, the child may refuse to make eye contact and stop responding to his/her name. Deafness is often suspected, although hearing tests are normal. Repetitive movements may develop immediately or not until the child is age three or four years. Though it has been debated whether these children are well and then become damaged by some exogenous exposure, the best evidence, including retrospective analysis of first birthday videotapes and neuropathologic studies, suggests their regressive course is genetically determined [Lord et al 2004, Volkmar et al 2005, Werner & Dawson 2005, Stefanatos 2008].

Approximately 25% of children who fit the diagnostic criteria for ASD at age two or three years subsequently begin to talk and communicate and by age six or seven years blend to varying degrees into the regular school population. Even for this group, social impairments generally continue. For the remaining 75%, most have some improvement with age but continue to require parent, school, and societal support. Excellent reviews of outcomes are provided by Howlin et al [2000], Howlin et al [2004], Seltzer et al [2004], and Farley et al [2009]. Some studies indicate that fewer than 5% of children with autism completely recover [Nordin & Gillberg 1998]; however, loosening of diagnostic criteria to include less impaired children appears to be increasing that number. A 20-year follow-up of adults between ages 22 and 46 years diagnosed with autism and average or near-average cognitive abilities in the 1980s found that half the individuals functioned quite well and half were employed in full-time or part-time paying jobs; however, only 12% lived independently and 56% lived with their parents [Farley et al 2009].

Autism spectrum disorders are defined completely on the basis of three areas of behavioral impairment:

*

Impairments in social interaction. Impairment in social interaction distinguishes individuals with autism from those around them. Children with classic autism are unable to "read" other people, ignoring them and often strenuously avoiding eye contact. Typically, they do not comfort others or seek comfort and do not share interests with others, such as bringing toys or pictures to their parents. Rather, they use their parents as objects, and may climb on them to get to a desired object, pull the parent by the hand, or place the parent's hand on the object, as if the child were using a tool. In clinic, the child who is content to turn pages of a magazine or spin the wheels of a car may become agitated when a simple examination is attempted. At home, the child with autism usually prefers to be by himself, engaging in his own, often repetitive, activities. The lack of functional or spontaneous make-believe play is characteristic. Toys are lined up, sorted, twirled, or hurled, but are not used for imaginative games or imitation of day-to-day activities, such as feeding the baby or washing the dishes. When play emerges later, it is stylized and not spontaneous. Children with autism fail to develop friendships with peers and siblings. In school, they often stand and watch other children from a distance. Some children respond to social overtures but take little social initiative, while others seek interaction but have little sense of how to proceed toward normal friendships.
*

Impairments in communication. Children with autism fail to develop reciprocal communication either by speech, gestures, or facial expressions. Characteristically, young children fail to use eye gaze or pointing to communicate and direct their parent’s attention. Early pragmatic skills are limited and are characterized by typical rates of requesting but substantially reduced rates of social interaction and establishing joint attention. Deficits in pragmatic skills are present throughout life and affect both language and social interaction. The young child appears unable to grasp the concept that speech can be used to name objects, to request a toy, or to engage others. In contrast to the child with nonspecific intellectual disability or a primary developmental language disorder who usually has better receptive than expressive language, the child with autism has impaired receptive language. When children with autism learn to talk, they display stereotypic speech that may involve echolalia, pronoun reversal, and unusual inflections and intonations. Unlike typically developing children who begin talking using one-word utterances, children with autism may begin talking in "chunks" composed of commercials, movies, or others' speech. These chunks often convey idiosyncratic meanings and the child with autism has no understanding of the conventional meaning of the individual words. Pragmatic difficulties including difficulties sustaining a conversation, turn taking, and allowing the conversational partners to introduce their topics, usually continue despite improvement in expressive speech. [Lord et al 2004].
*

Repetitive and stereotypic behaviors. Infants may stare or rock. Toddlers may have motor "stereotypies" such as movements of fingers, twirling strings, flicking pages of books, or licking. Repetitive whole body movements may include spinning and running back and forth. The repetitive behaviors often have a visual component such as holding the fingers to the side of the face and watching them with a sideways glance. Sometimes the movements become more complex with an individualized sequence of patting, rubbing, or twirling. These stereotypies may last for hours. Though the cause of the repetitive movements is unclear, they seem to have a calming effect and may (especially in the older child) surface in times of stress. This repetitiveness is reflected in a rigid need for sameness in daily routines. Children with autism can develop elaborate rituals in which the order of events, the exact words, and the arrangement of objects must be followed. Failure of parents/caretakers to follow the proscribed order of events results in inconsolable outbursts.

Other symptoms occurring in a substantial number of individuals with autism spectrum disorders:

*

Hyper- and hyposensitivities to sound and touch. Loud or high-pitched noises such as the vacuum cleaner cause great discomfort, causing the child to hold his hands over his ears. The feel of certain clothes or of being touched may be unbearable; conversely, truly painful stimuli like a burn or laceration are ignored.
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Odd behaviors around foods and their presentation, such as accepting a limited number of foods or only eating french fries that come from McDonalds®.
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Abnormal sleep patterns (60%), such as never sleeping through the night, trouble going to sleep, or getting up for the day at 2:00 am.
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Tantrums and/or self-injurious and aggressive behaviors brought on by a change in routine, an offending touch, being asked to do something they do not want to do, or for no apparent reason.
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Impaired motor development with toe walking early in life, hypotonia, general clumsiness, and inability to ride a two-wheel bicycle.
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Total disregard for danger, resulting in high risk of early death, commonly from drowning.

Evidence suggests that as many as 15% of adolescents or young adults with autism develop a catatonia syndrome associated with marked deterioration in movement with slowness and freezing in mid-movement, vocalizations, and regression of self-care skills.

Obesity is a common complication of unknow cause. Medication side-effects, inactive life style and difficulty withholding food from children with aggression may be implicated.

Delineation of ASD subgroups. In an attempt to sort out the clinical and etiologic heterogeneity within autism, researchers are increasingly emphasizing the identification of phenotypic features (endophenotypes or biomarkers) to delineate subgroups that could predict outcomes and direct treatment choices [Viding & Blakemore 2007]. The terms “endophenotypes” and “biomarkers” imply that these neurophysiologic, biochemical, endocrinologic, neuroanatomic, and cognitive features are more biologic and, thus, more proximally related to the underlying etiologic processes than the behavioral symptoms [Gottesman & Gould 2003].

The following phenotypes have been investigated:

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IQ scores in longitudinal studies strongly predict long-term outcomes and are directly associated with the degree of autistic psychopathology even in young children [Lord et al 2001, Howlin et al 2004, Chawarska & Bearss 2008]. Stevens et al [2000] reported that early normal or near-normal nonverbal IQ is the best predictor of adequate functioning by grade school; however, in the presence of significant language addition, uneven cognitive profiles typical of autism may make an average of widely discrepant scores meaningless [Klin et al 2005a]. That said, 50% to 70% of autistic children have historically been classified as intellectually disabled by nonverbal IQ testing [Fombonne 2005, Baird et al 2006]. An epidemiologic study from the Centers for Disease Control and Prevention reported 44.6% of the ASD population had intellectual disability. Lower rates of intellectual disability reported in more recent studies are probably the result of broadening of the ASD diagnostic criteria to include Asperger syndrome and children with milder symptoms [Autism and Developmental Disabilities Monitoring Network 2009].
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Seizures develop in approximately 25% of children with autism. In addition, the rate of electroencephalographic abnormalities is increased in children with autism who do not have a history of seizures [Kim et al 2006, Spence & Schneider 2009]. As in the general population, seizures alone are not a sensitive predictor of outcome. However, the prevalence of seizures is higher among individuals with moderate to severe intellectual disability and those with motor deficits [Tuchman & Rapin 2002]. And individuals with autism plus epilepsy have on the average lower IQs and poorer adaptive, behavioral, and social outcomes than those without epilepsy [Hara 2007].
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Structural brain malformations, typically identified by MRI, usually portend a poorer outcome [Miles & Hillman 2000]. In a recent study of 77 children with autistic disorder of unknown cause and uncomplicated by seizures, severe intellectual disability, major anomalies, or focal neurologic signs, neuroradiologists reported that 40% had some abnormality, of which white-matter signal abnormalities, severely dilated Virchow-Robin spaces, and temporal lobe structural abnormalities were the most common [Boddaert et al 2009]. This level of pathology in children with nonsyndromic autism lends support to the controversial recommendation to obtain brain MRIs as a standard diagnostic test in autism.
*

Significant generalized dysmorphology, found in 15% to 20% of individuals with autism, is a reliable indicator of an insult to early development [Miles & Hillman 2000]. Using a classification system that defines generalized dysmorphology, Miles et al [2005] found that in 81% of individuals dysmorphology was predictive of a poor outcome (defined as nonverbal with IQ <55). The presence of significant dysmorphology was also the top predictor of a poor response to early intensive behavioral therapy [Stoelb et al 2004]. The Autism Dysmorphology Measure (ADM), which guides clinicians through an assessment of 12 body areas, was developed to provide non-geneticists with a standardized method for assessing generalized dysmorphology [Miles et al 2008]. The 12 areas assessed are: height, hair growth pattern, ear structure, size and placement, nose size, face size and structure, philtrum, mouth and lips, teeth, hand size, fingers and thumbs, nails, and feet. * Microcephaly (head circumference <2nd centile) occurs in 5%-15% of children with autism [Fombonne et al 1999, Miles et al 2000, Miles et al 2005] and is highly predictive of poor outcome. * Macrocephaly (head circumference greater than the 97th centile), found in approximately 30% of children with autism, does not strongly correlate with outcome or IQ [Miles et al 2000] though Lainhart noted an association with delay in acquisition of first words [Lainhart et al 2006]. Using dysmorphology and microcephaly, autism can be defined as complex or essential [Miles et al 2005]: * Complex autism is defined by the presence of dysmorphic features and/or microcephaly, features which indicate some alteration of early morphogenesis. Approximately 20%-30% of children ascertained because of a diagnosis of autism have complex autism. Complex autism is associated with a poorer prognosis, a lower male-to-female ratio, and a lower sibling recurrence risk than essential autism. Approximately 30% of children with complex autism can be diagnosed with an autism associated syndrome or chromosome disorder using currently available diagnostic tests (see Causes of Autism) [Miles et al 2008]. * Essential autism is defined by the absence of generalized dysmorphology and microcephaly. Approximately 70%-80% of children with autism have essential autism. Children with essential autism are more likely to be male, to have a higher sibling recurrence risk, and to have a greater family history of autism and autism-related disorders such as alcoholism and depression than children with complex autism. As a group, the outcome is better for essential autism than complex autism, though most children with essential autism still do poorly. Currently available testing is less likely to reveal an exact etiologic diagnosis in essential autism than in complex autism. Establishing the Diagnosis The American Psychiatric Association Manual of Psychiatric Diseases, 4th edition, is the primary diagnostic reference for autism used in the US. The update in 2000 changed some of the accompanying text but did not change the diagnostic criteria. (See American Psychiatric Association [2000].) The DSM-IV in 1994 placed autistic disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified (PDD-NOS) under the umbrella diagnostic term ‘pervasive developmental disorders.’ Subsequently, discovery of MECP2 mutations as the cause of Rett syndrome, uncertainty about nosology of childhood disintegrative disorder, and better understanding of the continuity within the autism diagnoses led to adoption of the term autism spectrum disorders (ASD) as the favored umbrella designation for autistic disorder (AD), Asperger syndrome (AS) and PDD-NOS (National Institute of Mental Health). It is expected that the DSM-V, due out in 2012, will further simplify the nosology. Autistic Disorder— DSM-IV Diagnostic Criteria (diagnostic code 299.00) I. A total of six (or more) items from A, B, and C, with at least two from A, and one each from B and C: A. Qualitative impairment in social interaction, as manifested by at least two of the following: B. Qualitative impairments in communication as manifested by at least one of the following: 1. Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction 2. Failure to develop peer relationships appropriate to developmental level 3. A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest) 4. Lack of social or emotional reciprocity 5. Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime) 6. In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others 7. Stereotyped and repetitive use of language or idiosyncratic language 8. Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level 9. Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus 10. Apparently inflexible adherence to specific, nonfunctional routines or rituals 11. Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting or complex whole-body movements) 12. Persistent preoccupation with parts of objects C. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following: II. Delays or abnormal functioning in at least one of the following areas, with onset prior to age three years: 1) social interaction, 2) language as used in social communication, or 3) symbolic or imaginative play III. The disturbance is not better accounted for by Rett syndrome or childhood disintegrative disorder. Asperger syndrome [Asperger 1944, Frith 1991 (English translation)] is characterized by relatively normal language development (including timing, grammar, and vocabulary) but requires all other DSM-IV diagnostic criteria for autism. Individuals with Asperger syndrome are generally loners, are uncomfortable in groups, are unable to empathize with others, do not chat, follow a literal interpretation of speech with no understanding of idioms or jokes, maintain a sameness in routine, follow strict rules, and have an encompassing preoccupation with one domain, such as the weather or computers. Speech may be pedantic or repetitive with odd intonations. IQ must be within the normal range to qualify for the diagnosis. Clumsiness is common. Whether Asperger syndrome is the expression of the high end of the autism spectrum or a discrete genetic entity is unclear. The diagnosis of Asperger syndrome is problematic, with poor concordance between the various diagnostic instruments [Klin et al 2005b]. The Autism Spectrum Screening Questionnaire (ASSQ) [Ehlers et al 1999], the Asperger Syndrome Diagnostic Interview (ASDI) [Gillberg et al 2001], the Australian Scale for Asperger's Syndrome [Garnett & Atwood 1997], and the Childhood Asperger Syndrome Test (CAST) [Scott et al 2002] are also available. A recent video, Asperger's Diagnostic Assessment [Attwood 2004] provides a hands-on tutorial which should be useful to the clinician. Pervasive developmental disorder - not otherwise specified (PDD-NOS). Children with autistic symptoms who do not meet full criteria in all three diagnostic domains can be diagnosed with PDD-NOS. This includes children with milder symptoms of all three autism diagnostic criteria and those meeting full criteria for autism in two of the three domains. Sometimes PDD-NOS is used as an initial or tentative diagnosis for younger children or before diagnostic evaluations are completed. Broader autism phenotype (BAP) may designate siblings or other family members with some autism symptoms [Piven & Palmer 1999, Pickles et al 2000, Geschwind et al 2001]. This terminology was originally adopted by researchers to classify sibs who were likely to have mutations in putative autism genes and reflects the growing awareness of the broad phenotypic spectrum of autism spectrum disorders. Childhood disintegrative disorder is a rare condition manifesting before age ten years in which children who have developed normally for at least two years deteriorate and lose previously acquired language, social, and play skills. The condition may resemble autism in clinical presentation but differs from autism in the pattern of onset, course, and outcome. It is no longer considered one of the pervasive developmental disorders. Diagnostic and Screening Tools To diagnose autism, one must precisely enumerate the autism symptoms and their age of occurrence, which can be done using the DSM-IV or a number of checklists [Filipek et al 2000, Cavagnaro 2007]: * CARS (Childhood Autism Rating Scale) [Schopler et al 1986] consisting of 15 questions scored by the parent and the tester is the most commonly used diagnostic checklist. It is a reliable, well-verified measure which is relatively fast and easy to administer. A score of 30 to 35 indicates mild autism and 36 or higher moderate-to-severe autism. * ABC (Autism Behavior Checklist) [Aman et al 1985] * GARS (Gilliam Autism Rating Scale) [Gilliam 1995] In North America, research criteria for the diagnosis of autism depend primarily on the ADI-R (Autism Diagnostic Interview-Revised) [Lord et al 1994], which is a detailed parent interview, and the somewhat shorter ADOS (Autism Diagnostic Observation Schedule) [Lord et al 1989]. Both scales follow the DSM-IV criteria and were developed in an attempt to sort autism by its behavioral symptoms to permit identification of homogeneous populations. These scales are not widely used in clinical practice because of the time and expense to administer, although the shorter ADOS is becoming more widely used outside of research settings. To guide allocation of services school systems use educationally based “autism eligibility” criteria which are similar but not identical to the medical diagnostic criteria, sometimes leading to conflicts. This is particularly true for the higher-functioning or Asperger syndrome students whose behavioral manifestations need remediation through the schools, but may not meet the educational egibility criteria. It is recommended that all children be screened for autism by their primary health care provider. A positive score on one of these tools is not diagnostic for an ASD but prompts referral to a diagnostic clinic. * M-CHAT (Checklist for Autism in Toddlers-modified) [Robins et al 2001] is the most commonly used screening tool. This 23 item checklist, designed for primary care providers to identify at-risk toddlers at the 18-month visit, can be filled out by parents in the waiting room and is available in Spanish and English [Cavagnaro 2007]. A recent replication study [Kleinman et al 2008] confirmed the validity in detecting possible ASD in both low- and high-risk groups aged 16 to 30 months. It is recommended by the Neurology Quality Standards Subcommittee [Filipek et al 1999, Filipek et al 2000]. * Infant/Toddler Checklist (pdf) from the Communication and Symbolic Behavior Scales Developmental Profile [Wetherby & Prizant 2002] is recommended by the American Academy of Pediatrics to identify at-risk children younger than age 18 months [Johnson & Myers 2007]. Prevalence An increase in the prevalence of all the autism spectrum disorders is being reported worldwide. * Prior to 1990, most studies estimated a general population prevalence for autism of four to five per 10,000 (1/2000-1/2500) [Fombonne 2001]. * During the 1990s, studies of preschool children in Japan, England, and Sweden reported prevalence rates for autism of 21 to 31 per 10,000 (1/476 -1/323) [Arvidsson et al 1997, Baird et al 2000]. * A CDC case-finding study in Brick Township, New Jersey reported prevalence at 40 per 10,000 (1/250) for autism and 67 per 10,000 (1/149) for all PDDs [Autism and Developmental Disabilities Monitoring Network 2009]. * An epidemiologic study from the United Kingdom utilizing specialized visiting nurses who monitor child health and development at ages seven months, 18 to 24 months, and three years reported a prevalence rate of 16.8 per 10,000 (1/595) for autism and 63 per 10,000 (1/159) for all PDDs in children younger than age five years [Chakrabarti & Fombonne 2001]. Those rates were confirmed, reporting a prevalence rate of 22 per 10,000 (1/455) for autism and 59 per 10,000 (1/169) for all PDDs in children younger than age six years [Chakrabarti & Fombonne 2005]. * Two recent studies in the United States reported the diagnosis of an ASD in 1/91 children age three to seventeen years [Kogan et al 2009] and 1/110 children age eight years [Autism and Developmental Disabilities Monitoring Network 2009]. Recent analyses indicate that the “autism epidemic” does not reflect a true increase in the incidence of ASD, but is attributable to increased awareness by both the public and professionals, leading to more complete case finding together with broadening of the diagnostic criteria [Gernsbacher et al 2005, Fombonne et al 2006, Shattuck 2006, Taylor 2006, Atladottir et al 2007]. Studies finding the greatest increase in ASD also note lower rates of intellectual disability in these children. Only 30% of children with PDDs ascertained by Chakrabarti & Fombonne [2005] were intellectually disabled compared with 70% of children in earlier studies. This suggests that many of the higher-functioning children with milder autistic symptoms, such as less severe language impairment and fewer aggressive behaviors had not been counted in past epidemiologic surveys. A recent update on the ongoing epidemiologic surveillance of autism in California indicated that the rise of autism in California shows no sign of plateauing. The study concluded that earlier age at diagnosis and inclusion of milder cases accounted for more than two-thirds of the increase but stated that the extent to which the continued rise could represent a true increase in the occurrence of autism remains unclear [Hertz-Picciotto & Delwiche 2009]. Causes of Autism

Twin and family studies have established the preponderant genetic basis of autism and indicate that the heritability of autism is over 90% [Monaco & Bailey 2001]. Currently a genetic cause can be identified in 20% to 25% of children with autism. A small number of cases of autism can be traced to specific teratogenic exposures. The cause of autism in the remaining 75% to 80% remains unknown.

The growing number of distinct, individually rare genetic causes of autism suggests that the genetic basis of autism resembles that of intellectual disability and cerebral palsy with many syndromes, each individually rare, implicated in the development of autism. But it also seems likely that complex and as-yet-undetermined interactions between “small-effect” inherited changes will also be found to be causative.
Genetic Causes

Known genetic causes of autism include:

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Cytogenetically visible chromosomal abnormalities (~5%)
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Copy number variants (CNVs) (i.e., submicroscopic deletions and duplications) (10%-20%)
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Single gene disorders in which neurologic findings are associated with ASD (~5%)

Cytogenetically Visible Chromosomal Abnormalities

High-resolution chromosome analysis reveals chromosome aneuploidy in approximately 5% of children with ASD. Another 3%-5% have identifiable chromosomal abnormalities using FISH techniques. As expected, unbalanced chromosome abnormalities are found predominantly in children with autism and accompanying dysmorphology [Miles et al 2005, Jacquemont et al 2006, Takahashi & Miles 2009].

Although cytogenetic abnormalities on almost every chromosome have been found in autism, only a few occur commonly enough to be possible loci for autism genes [Wassink et al 2001, Reddy 2005, Vorstman et al 2006]. A curated database of chromosome abnormalities reported in individuals with autism is available at projects.tcag.ca/autism [Marshall et al 2008].

Maternally derived duplication of the Prader-Willi/Angelman syndrome critical region (15q11-q13) is the most commonly observed chromosome abnormality in autism, detected in 1%-3% of children with autism. Most commonly this duplication is the result of a de novo supernumerary isodicentric 15q chromosome and less commonly the result of segregation of a parental chromosome translocation or a maternally derived interstitial 15q duplication. Routine cytogenetic analysis detects supernumerary isodicentric 15q but the diagnosis of interstitial duplications requires interphase FISH analysis or aCGH. The maternally derived 15q11-q13 interstitial duplication is a highly penetrant cause of autism, whereas the paternally derived duplication has little or no phenotypic effect, indicating the significance of genomic imprinting of this region [Hogart et al 2010].

A maternal duplication of 15q, resulting in trisomy for that region, causes subtle effects on the physical phenotype whereas,children with four copies of 15q including those with a supernumerary isodicentric 15 are typically more impaired and may exhibit hypotonia, seizures, microcephaly, and severe developmental delay [Borgatti et al 2001, Dykens et al 2004, Hogart et al 2010].

Trisomy 21. Children with Down syndrome have autism more commonly than expected. The incidence was at least 7% in one study [Kent et al 1999].

45, X Turner syndrome. Girls and women with Turner syndrome who have a maternal X chromosome (45,Xmat) have poorer social cognition skills than girls who have a paternal X chromosome (45,Xpat) [Skuse 2000].

Other. Chromosome abnormalities reported more than once include deletions of 2q37, 18q, 22q13.3, Xp22.3, and the sex chromosome aneuploidies 47,XYY, 47,XXY, and 45,X [Gillberg 1998, Manning et al 2004, Vorstman et al 2006, Jha et al 2007, Marshall et al 2008, Shinawi et al 2009a]. All reported terminal deletions of 2q37 and 22q13.3 have been associated with dysmorphic phenotypes [Lukusa et al 2004, Manning et al 2004]. Characterization of the minimal critical chromosomal regions for the 22q13.3 and the Xp22.3 deletions in persons with autism of unknown cause has led to the identification of mutations in the SHANK3 [Durand et al 2007] and NLGNX4 [Jamain et al 2003] genes, respectively.
Copy Number Variants (CNVs)

Array comparative genomic hybridization (aCGH) is steadily replacing high-resolution chromosome analysis and FISH in the evaluation of children with autism. Clinically available platforms used in aCGH are designed to test for known deletion/duplication syndromes on the entire genome plus assessment of subtelomeric regions. The platforms used in aCGH vary in the density and type of molecular markers (BAC, SNP, and oligonucleotide clones) and are constantly being upgraded as new CNV hot spots are identified.

Currently, aCGH identifies clinically relevant de novo genomic imbalances in 7%-10% of individuals with autism of unknown cause [Sebat et al 2007, Christian et al 2008, Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]; the yield was higher in those whom the authors identified as having “syndromic” autism.

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Using a 1-Mb genome-wide array, Jacquemont et al [2006] identified clinically relevant CNVs in 27.5% (8/29) of individuals with autism and dysmorphology, who previously had a normal karyotype as determined by routine cytogenetic studies.
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Using an oligonucleotide array, Sebat et al [2007] found de novo copy number changes in 10% of children from simplex families (i.e., autism in a single family member) and 2% from multiplex families (i.e., autism in multiple family members) compared to 1% in controls.
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Using a dense genome-wide SNP array, Marshall et al [2008] found unbalanced CNVs in 44% of 427 unrelated families with autism that were not present in control families. Many of these CNVs were inherited and only 7% were de novo in persons with autism of unknown cause.
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A whole-genome CNV study using 550,000 SNP markers on a cohort of 859 individuals with ASD and 1,409 healthy children of European ancestry revealed several pathogenic genomic changes in genes encoding neuronal cell-adhesion molecules (NRXN1, CNTN4, NLGN1, and ASTN2) and in genes involved in the ubiquitin pathways (UBE3A, PARK2, RFWD2, and FBXO40) [Glessner et al 2009].

These studies highlight the potential of array-based techniques. At this time, however, caution must be exercised in interpreting these results and their relation to autism. The de novo occurrence of a copy number variation is not absolute evidence of its pathogenicity. Distinguishing characteristics of pathogenic CNVs include (1) de novo event not found in either parent or inherited from an affected parent, (2) deletions or duplications which include genes known to be expressed in the brain, (3) large CNVs, and (4) deletions, as opposed to duplications

Some CNVs associated with autism include the following:

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16p11.2 deletion syndrome is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder (ASD). Developmental delays are more related to diminished language and cognitive function than motor disability. Although IQ scores range from mild intellectual disability to normal, those with IQ scores in the average range typically have other developmental issues such as language delay or ASD. Expressive language appears to be more affected than receptive language. Weiss et al [2008] reported 16p11.2 deletions or duplications in approximately 1% of individuals with autism and 1.5% of children with developmental or language delays. Marshall et al [2008] observed a similar 1% frequency.

The 16p11.2 deletion often occurs de novo, but may be transmitted from parent to child in an autosomal dominant manner. Of note, however: the same 16p11.2 CNVs can be observed in a variety of other disorders including schizophrenia, bipolar disorder, seizures, ADHD, and dyslexia, as well as apparently unaffected family members; thus, interpretation of the significance of this CNV can be difficult [McCarthy et al 2009, Rosenfeld et al 2010, Shinawi et al 2010].

This CNV is located at a hot spot of genomic instability caused by duplicated blocks of DNA that lead to unequal crossing over during meiosis and is detectable by clinical oligonucleotide aCGH platforms and some bacterial artificial chromosome (BAC)-based platforms. Other test methods that can detect this deletion include multiplex ligation-dependent probe amplification (MLPA), metaphase fluorescence in situ hybridization (FISH), and quantitative polymerase chain reaction PCR (qPCR).
*

15q13.3 deletion syndrome has been associated with intellectual disability and epilepsy [Sharp et al 2008] and ASD [Ben Shachar et al 2009, Miller et al 2009, Pagnamenta et al 2009] and appears to be clinically variable. More recent data suggest that haploinsufficiency of CHRNA7 is causative for the majority of neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome [Shinawi et al 2009b].

Single Gene Disorders

The following singe gene disorders are commonly observed to cause syndromic autism.

Fragile X syndrome. Whereas 1% to 3% of children ascertained on the basis of an autism diagnosis have fragile X syndrome, at least half the children with fragile X syndrome have some autistic behaviors, including avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities. In one study of 63 males with fragile X syndrome, 30% met criteria for autistic disorder and 30% criteria for PDD-NOS [Harris et al 2008].

Fragile X syndrome is caused by expansion of the CGG trinucleotide repeat in the FMR1 gene to the full mutation size of 200 or more CGG repeats.

A considerable number of children being evaluated for autism are found to have FMR1 premutations (55-200 CGG repeats) [Goodlin-Jones et al 2004, Cornish et al 2005, Reddy 2005, Farzin et al 2006, Loesch et al 2007]. Farzin et al [2006] studied 14 boys with premutations ascertained through an autism clinic and found 71% met ASD diagnostic criteria. In the authors’ experience, ten of 488 (2%) persons ascertained through a dedicated autism clinic had either an FMR1 full mutation or premutation. Of the five children with a full mutation, only one was diagnosed with autistic disorder; four did not meet criteria for an ASD diagnosis. For the five premutation carriers, four were diagnosed with autistic disorder and one with PDD-NOS [Takahashi & Miles 2009]. This underscores the importance of performing FMR1 molecular genetic testing in all children being evaluated for an autism spectrum disorder.

Molecular studies indicate the FMR1 gene may cause the autism phenotype via two mechanisms: RNA toxicity to the neurons and gene silencing that affects neuronal connectivity [Schenck et al 2003, Handa et al 2005, Hagerman et al 2008].

PTEN macrocephaly syndrome. The PTEN (phosphatase and tensin homolog) gene was initially described as a tumor suppressor gene associated with a broad group of disorders referred to as PTEN hamartoma tumor syndrome which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. More recently, PTEN gene mutations have been associated with autism and macrocephaly [Zori et al 1998, Parisi et al 2001, Delatycki et al 2003, Butler et al 2005, Buxbaum et al 2007a]. Correspondingly, PTEN is recognized to play an important role in brain development, including neuronal survival and synaptic plasticity.

The frequency of PTEN mutations as a cause of ASD is unclear; results from studies of children ascertained through autism and macrocephaly range from 1% [Buxbaum et al 2007a] to 8.3% [Varga et al 2009] to 17% [Butler et al 2005]. Both de novo and familial PTEN mutations have been identified in this population. It may be significant that more of the children studied by Buxbaum et al [2007a] were from multiplex families, whereas the children studied by Butler et al [2005] were from simplex families.

Children with ASD found to have a PTEN mutation generally have extreme macrocephaly ranging from +3.7 SD to +9.6 SD (average: +5.4 SD) [Buxbaum et al 2007a]. In addition, mutation of PTEN is not specific for autism: Varga et al [2009] found children with macrocephaly and intellectual disability but not autism had a similar chance of having a PTEN mutation.

Because PTEN germline mutations are associated with the phenotypically broad PTEN hamartoma tumor syndrome, it is recommended that children with PTEN mutations and their families be evaluated by a medical geneticist for clinical signs of any of the related disorders. Moreover, because these disorders carry a risk of cancer, including cancer of the breast, thyroid, endometrium, and kidney, these individuals need to be involved in a tumor surveillance program. See PTEN Hamartoma Tumor Syndrome.

Sotos syndrome. Sotos syndrome is characterized by the cardinal features of typical facial appearance, overgrowth (height and head circumference ≥2 SD above the mean), and learning disability ranging from mild (children attend mainstream schools and are likely to be independent as adults) to severe (lifelong care and support are required). Sotos syndrome is associated with the major features of behavioral problems, congenital cardiac anomalies, neonatal jaundice, renal anomalies, scoliosis, and seizures. Though Sotos syndrome is probably not a significant cause of classic autism [Buxbaum et al 2007b], children with Sotos syndrome and behavioral problems such as difficulty with peer group relationships and lack of awareness of social cues may be referred to autism clinics.

Eighty to 90% of individuals with Sotos have a demonstrable mutation or deletion of NSD1; inheritance is autosomal dominant.

Rett syndrome is one of the original DSM-IV-designated pervasive developmental disorders and the only one for which a specific genetic etiology has been identified [Amir et al 1999]. Ninety-six percent of individuals with classic Rett syndrome have mutations in the X-linked MECP2 gene [Moretti & Zoghbi 2006]. Though the vast majority of individuals with MECP2 mutations are girls, MECP2 mutations are identified in 1%-2% of males with developmental disorders, including infantile encephalopathy, intellectual disability with motor deficits and early-onset bipolar disorder and schizophrenia. Most males are identified in families with an X-linked pattern of intellectual disability.

The phenotype of MECP2-confirmed Rett syndrome overlaps considerably with autism of unknown cause; children with both often have a period of normal development followed by loss of language with stereotypic hand movements. However, Rett syndrome can usually be distinguished clinically based on a decreasing rate of head growth, progressive gait disturbance, and hand-wringing in early childhood. Initially, the distinction may be difficult: a study of two Rett syndrome databases found that 17.6% (55/313) of girls with MECP2-confirmed Rett syndrome had been given an early diagnosis of autism [Young et al 2008]. Those girls had significantly milder Rett syndrome symptoms, were more likely to remain ambulatory, retained some functional hand use, and developed specific Rett syndrome symptoms later. They were also more likely to have the mutation p.Arg306Cys or p.Thr158Met. The recommendation of Young et al [2008] that all girls diagnosed with autism be monitored carefully for evolving signs of Rett syndrome (including a deceleration in head growth) seems justified.

Overall, MECP2 mutations have been reported in approximately 1% of children diagnosed with autism [Moretti & Zoghbi 2006, Lintas & Persico 2009]. It is not clear at this time whether this justifies MECP2 molecular genetic testing in girls diagnosed with apparently classic autism, especially girls who will be followed on a regular basis in a clinic with expertise in both disorders.

Evidence of variable expression of the protein MeCP2 in the brains of individuals with both autism and Rett syndrome and evidence that MeCP2 deficiency can reduce expression of the genes UBE3A and GABRB3 implicated in autism, indicate some causal relationship between the two disorders [Samaco et al 2004, Samaco et al 2005]. Intensive study of the role of MeCP2 in maintaining neuronal function and evidence of symptom reversal of neuronal symptoms in mice following reactivation of the silenced Mecp2 gene is projected to have implications for autism treatment [Bird 2008].

Tuberous sclerosis complex (TSC). Although 25%-50% of intellectually disabled individuals with TSC fulfill autism diagnostic criteria, only 1.1%-1.3% of individuals initially diagnosed with ASD have TSC [Fombonne et al 1997b, Baker et al 1998, Asano et al 2001, de Vries et al 2007]. Early-onset infantile spasms and temporal lobe tubers on MRI examination increase the chance that children with TSC2 mutations will also develop autism [Bolton 2004].

In a prospective study of children with TSC evaluated using the ADOS, 66% of infants met criteria for autism or ASD at age 18 months, 54% at age 24 months, 46% at age 36 months, and 50% at age 60 months.The children with both TSC and autism were more cognitively impaired than those with TSC only [Jeste et al 2008].

An evaluation for signs of TSC including skin lesions (hypopigmented macules, shagreen patches, adenoma sebaceum) and a family history consistent with autosomal dominant inheritance of findings suggestive of TSC (seizures, skin lesions, intellectual disability) are generally sufficient to indicate or rule out the diagnosis of TSC in children with autism. Molecular genetic testing for the two causative genes, TSC1 and TSC2, is clinically available. Recurrence risks for families with a child with autism associated with TSC may be significantly higher than for for families with autism of unknown cause. Mechanisms underlying autism in TSC are unknown.

Neurofibromatosis type 1 (NF1). Although NF1 has been diagnosed in children with autism, it is unclear whether this is a true association or the chance simultaneous occurrence of two relatively common childhood disorders [Fombonne et al 1997b, Battaglia & Carey 2006, Schaefer & Lutz 2006]. No genetic overlap between mutations in the NF1 gene and autism has been demonstrated [Zafeiriou et al 2007].

Timothy syndrome. Timothy syndrome, a disorder of calcium channels caused by a mutation in the CACNA1C gene, is characterized by severe QT prolongation, syndactyly, cardiac defects, dysmorphic faces, developmental delays, and autistic symptoms [Splawski et al 2004]. Inheritance is autosomal dominant.

Joubert syndrome. This autosomal recessive disorder is characterized by partial or complete agenesis of the cerebellar vermis, seen as the “molar tooth sign” on MRI, abnormal breathing, abnormal eye movement, cognitive impairment, and behavioral problems. A subset of Joubert syndrome appears related to the AHI1 gene, encoding the ‘jouberin’ protein [Alvarez Retuerto et al 2008]. In one study, three of 11 children with Joubert syndrome met diagnostic criteria for autism and one of 11 for PDD-NOS [Ozonoff et al 1999]. However, Takahashi et al [2005] delineated behavioral and genetic differences between autism and Joubert syndrome, implying that they are etiologically distinct disorders. In a report by Muhle et al [2004] of monozygotic twins with Joubert syndrome, the twin with the more severe cerebellar abnormality had autism, suggesting that some disorders may have the potential to cause the autism phenotype if as-yet unidentified autism regions or circuits of the brain are affected.

Metabolic conditions

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Mitochondrial disorders. Although mitochondrial respiratory chain disorders have only been reported in individuals with autism on rare occasions, elevated plasma concentrations of lactate have been frequently noted [Coleman 2005, Correia et al 2006]. A population-based study of 69 children with autism reported an elevated plasma lactate concentration in 20% (14/69); five of the eleven children undergoing muscle biopsy had a deficiency of one or more respiratory chain complexes, most frequently complexes I, IV, and V, based on enzymatic complex activity less than 20% of normal [Oliveira et al 2005]. If confirmed, this would be the largest etiologic autism subgroup. Identifying a mitochondrial disorder is more likely in autistic children with atypical features such as hypotonia, failure to thrive, and intermittent episodes of regression than in children without these findings. Weissman et al [2008] analyzed data from 25 persons with a mitochondrial disorder and an initial diagnosis of autism and found they could all be distinguished from autism of unknown cause on the basis of an abnormal neurologic examination and/or an elevated plasma lactate concentration. In addition, mitochondrial dysfunction has also been reported in persons with ASD without additional neurologic features [Pons et al 2004, Smith et al 2009].
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Phenylketonuria (PKU). Co-morbidity of ASD and untreated PKU has been described but the autism diagnosis is usually complicated by the severe intellectual disability found in these children. A systematic study showed that none of 62 persons with PKU who were diagnosed and treated early met diagnostic criteria for autism, whereas two of 35 (5.7%) persons with PKU who were diagnosed late fulfilled the diagnostic criteria for ASD [Baieli et al 2003].
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Adenylosuccinate lyase deficiency. This rare autosomal disorder of de novo purine synthesis results in the accumulation of succinylpurines in body fluids. In about half of affected individuals the variable clinical manifestations include developmental delay, seizures, and autism symptoms including failure to make eye contact, repetitive behavior, agitation, temper tantrums, and aggression [Van den Berghe et al 1997]. In one study, one out of 420 children with PDD was found to have adenylosuccinate lyase deficiency [Stathis et al 2000].
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Creatine deficiency syndromes (CCDSs). The CCDSs, inborn errors of creatine metabolism, include the two creatine biosynthetic disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency (or GATM deficiency), and the creatine transporter defect, SLC6A8 deficiency. Intellectual disability and seizures are common to all three CCDSs. Approximately 80% of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; approximately 45% have pyramidal/ extrapyramidal findings. Onset is between ages three months and three years. Only five individuals with AGAT deficiency have been reported. The phenotype of SLC6A8 deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, and behavioral disorder. Onset is between ages two and 66 years. Approximately 50% of females heterozygous for SLC6A8 deficiency have learning and behavior problems.

The prevalence of creatine deficiency syndromes in those with ASD appears to be low. Sequencing of the SLC6A8 gene in 100 males with ASD did not detect deleterious mutations [Newmeyer et al 2007].
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Smith-Lemli-Opitz syndrome (SLOS). This autosomal recessive multiple congenital anomaly and intellectual disability syndrome is caused by a deficiency of 7-dehydrocholesterol reductase, an essential enzyme in the biosynthesis of cholesterol. SLOS can be associated with autism and other behavioral characteristics such as repeated self-injury, sensory hyper-reactivity, temperature dysregulation, and sleep disturbance [Tierney et al 2001, Tierney et al 2006]. Rates of autistic behavior reported in individuals with SLOS range from 50% to 86% [Manzi et al 2008]. One study found that three-fourths of the children with SLOS had ASD, about 50% diagnosed with autistic disorder and the rest with PDD-NOS [Sikora et al 2006]; no correlation was found between the abnormal metabolites and the presence or severity of autistic symptoms.

Other single gene disorders. Autism or autistic features have been described in children with many other single gene disorders. Most are associated with severe intellectual disability and significant dysmorphology and rarely are referred for medical evaluation with an initial question of autism. The list includes:

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Cohen syndrome [Howlin et al 2005]
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Cole Hughes macrocephaly syndrome [Naqvi et al 2000]
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San Filippo syndrome
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Cornelia de Lange syndrome
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Angelman syndrome [Sahoo et al 2006, Bonati et al 2007]
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Williams syndrome [Klein-Tasman et al 2007] and its reciprocal 7q11.23 microduplication syndrome [Berg et al 2007, Van der Aa et al 2009]
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17p11.2p11.2 duplication syndrome [Potocki et al 2007]
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22q11.1 deletion syndrome [Niklasson et al 2009]
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WAGR (wilms tumor, aniridia, genitourinary anomalies and mental retardation) syndrome [Xu et al 2008]
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Duchenne muscular dystrophy [Wu et al 2005b]

Developmental Syndromes of Undetermined Etiology—Commonly Observed

Moebius syndrome or sequence. Defined by unilateral or bilateral palsy of the sixth and seventh cranial nerves, Moebius syndrome is characterized by facial paralysis with inability to smile and fully abduct the eyes.It is often associated with abnormal tearing, seizures, hearing loss, and limb anomalies. About 30% of children with Moebius syndrome develop ASD [Johansson et al 2001, Stromland et al 2002, Bandim et al 2003]. A recent study confirmed the observations of Johansson et al [2001] that ASD occurs more frequently in individuals with Moebius syndrome with concurrent intellectual disability [Briegel et al 2009]. Presumably caused by an early disruption of embryonic blood supply leading to brain stem disruption, Moebius syndrome has been compared to thalidomide embryopathy which also damages the sixth and seventh cranial nerve and causes autism.

Landau-Kleffner syndrome (LKS). A small subset of children with ASD and late regression have LKS. These children develop sudden or gradual isolated language regression associated with seizures (epileptic aphasia) and/or severe EEG abnormality in deep sleep [Cortesi et al 2007]. In general, both the seizures and language impairment improve with normalization of EEG abnormalities [Spence & Schneider 2009].
Environmental Causes

The search for environmental causes of autism has been driven by the considerable increase in autism prevalence recorded over the last 20 years and the incomplete concordance for autism in monozygotic (MZ) twins.

In utero exposures, including valproic acid, thalidomide, and misoprostol (an abortifactant commonly used in South America) are recognized causes of autism. The Liverpool and Manchester Neurodevelopment Group recently reported a long-term study of 632 children exposed to antiepileptic drugs (AEDs) during gestation and found that children exposed to valproate in utero were seven times more likely to develop autism than those not exposed to AEDs. None of the families had a known family history of autism. They recommend that women taking valproate be informed of the risk for autism in children exposed during gestation [Bromley et al 2008].

Other factors that have been considered as causes of autism include expanded use of assisted reproductive technologies (ART) [Knoester et al 2007] and tocolytic drugs such terbutaline [Connors et al 2005].

Childhood immunizations given around the time that regressive-onset autism is recognized have been a focus of concern. Organic mercury, which constitutes roughly 50% of the preservative thimerosal used in certain injectable vaccines, and the measles-mumps-rubella (MMR) vaccine, which never contained mercury, have been studied. Though parental concern is still significant, multiple studies and lines of scientific evidence have identified no support for a relationship between immunizations and autism [DeStefano & Thompson 2004, Institute of Medicine 2004, Taylor 2006, Schechter & Grether 2008]. The original studies by Wakefield et al [1998] and Wakefield [1999] suggesting an associated between immunizations and autism have been disproved and the work was retracted by the journal The Lancet [Murch et al 2004]. One of the tragedies resulting from fear of an autism epidemic was the decreased use of childhood immunizations leading to out outbreaks of measles and childhood deaths [Jansen et al 2003, Offit 2008].
Multifactorial Inheritance

The heritability estimate of autistic disorder, calculated from recurrence risk data and monozygotic (MZ): dizygotic (DZ) twin concordance data, is more than 90%. Many have considered autism of unknown cause a multifactorial disorder based on the: (1) high heritability, (2) failure to identify major autism genes, (3) 4:1 male-to-female sex ratio, and (4) sibling recurrence risk of approximately 4% [Chakrabarti & Fombonne 2001, Gillberg et al 2001].

The multifactorial threshold model predicts that:

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The more frequently affected sex (male) has a lower recurrence risk than the less frequently affected sex (female).
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The less often affected sex (female) is more severely affected than the more often affected sex (male).

Studies indicate that autism does not follow this model:

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Sibs of male and female probands with autism of unknown cause have the same risk of developing autism [Miles et al 2004].
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The proportion of relatives with a mild subclinical autism phenotype, defined as increased impulsivity, aloofness, shyness, over-sensitivity, irritability, eccentricity and anxiety, is not increased when the proband is female [Pickles et al 2000].
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When analyses are limited to probands with essential autism, females have less severe autistic symptoms than males [Miles et al 2004].

Lack of support for the classic multifactorial threshold model, however, does not eliminate the possibility that many genes are involved in autism. Instead, it suggests that genetic heterogeneity is the main impediment to understanding the inheritance of autism.
Genes that Cause or Increase the Risk of Autism

Determining specific genetic changes that increase the risk of developing autism is an area of intense study. The large-scale genetic studies of the last decade have ruled out the possibility that single gene of large affect causes a high proportion of autism. Rather it appears that a a significant number of highly penetrant autism alleles will be discovered in families. Study of these rare alleles will be essential to elucidating the pathogenetic mechanisms involved in the development of autism.

Array CGH has increased detection of copy number variants (CNVs) in autism and paved the way for identification of a number of new autism genes [Szatmari et al 2007]. Some CNVs may help identify highly penetrant causal mutations, while others may lead to the discovery of multiple common genetic variations which act in concert, possibly with environmental triggers to cause autism. Persuasive evidence for this common disease-common variant hypothesis in autism includes the presence of subtle sub-clinical autism symptoms in relatives of children with autism [Constantino et al 2009]. It is also probable that some CNVs may alter the expression of genes in the immediate vicinity of the CNV.

Table 1 which lists known and putative autism genes is unquestionably incomplete, as new candidate genes are being reported at an unprecedented rate. The genes are organized by pathogenesis to highlight the progress made in the functional assessment of autism candidate genes and pathways. In addition, some genes are included because of their compelling initial descriptionsthat still await confirmation. Selected references address both molecular and pathophysiologic descriptions.

Authoritative reviews of the current status of candidate genes and loci include: Veenstra-VanderWeele & Cook [2004], Wassink et al [2004], Grice & Buxbaum [2006], Gupta & State [2007], Szatmari et al [2007], Morrow et al [2008], O’Roak & State [2008], Sutcliffe [2008], Simons Foundation Autism Research Initeative [2009].

SFARI gene is a new comprehensive, Web-based, searchable list of candidate genes associated with ASD. The candidate genes are richly annotated for their relevance to autism, along with an in-depth, up-to-date view of their molecular function extracted from the current scientific literature.

The Genetic Association Database provides online access to human genetic association studies performed on autism and other complex disorders.

Evaluation Stretegy

In addition to behavioral assessment to establish the diagnosis of autism and cognitive testing, the evaluation strategy for all individuals with autism includes a medical evaluation to identify medical issues that affect the development and behavior of nonverbal children and a clinical genetics evaluation to elucidate diagnostic possibilities. This basic evaluation should be expanded if the medical or family history and/or physical examination raise concerns about metabolic, medical, or neurologic conditions. Recent reports from the American Academy of Pediatrics [Johnson & Myers 2007] and the American College of Medical Genetics [Schaefer & Mendelsohn 2008] provide practical approaches to the evaluation of children with ASD.

Family history. A three-generation pedigree should be obtained with attention to behavioral and neurologic diagnoses. Relatives with behaviors that are possible manifestations of autism may be examined directly or their records reviewed. Language, social, and psychiatric disorders, including alcoholism and possibly other addictive disorders, occur more often in relatives, including sibs, of clearly autistic probands, particularly those with essential autism [Fombonne et al 1997a, Bolton et al 1998, Piven & Palmer 1999, Pickles et al 2000, Miles et al 2003].

Clinical examination. Physical examination should include the following:

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Measurement of height, weight, and occipital-frontal circumference (OFC) to identify (1) microcephaly or growth retardation which suggest various chromosome and monogenic syndromes, and (2) macrocephaly, which is present in approximately 35% of children with autism. In children with macrocephaly the molecularly defined macrocephaly syndromes that also cause autism, especially fragile X syndrome and PTEN hamartoma tumor syndrome, should be considered.
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Dysmorphology examination to look for developmental anomalies which date the onset of the disorder. An in depth dysmorphology examination by a medical geneticist provides the best data on which to base the diagnostic plan. In addition, the brief Autism Dysmorphology Measure has been developed for use by non-dysmorphologists who evaluate children with autism [Miles et al 2008].
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Skin examination (including Woods lamp examination) for evidence of tuberous sclerosis complex or neurofibromatosis type 1.
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Assessment for signs of specific disorders known to be associated with autism:
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PTEN mutation—macrocephaly, hamartomas or lipomas, freckles on the penis
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Moebius syndrome—facial muscle weakness, incomplete abduction of eyes
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Tuberous sclerosis complex—hypopigmented macules, shagreen patches, facial adenoma sebaceum
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Fragile X syndrome—macroorchidism, long face, large ears
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Mitochondrial disorders—failure to thrive, fatigue, hypotonia, recurrent episodes of regression

Laboratory testing. The following testing is recommended at the time of initial evaluation for all children with an ASD:

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Array comparative genomic hybridization (aCGH) has replaced high-resolution chromosome analysis as the test of choice for the evaluation of any child with an autism spectrum disorder. Note: Cytogenetic analysis, in addition to aCGH, is recommended when the family history suggests transmission of a balanced chromosome rearrangement.
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FMR1 molecular genetic testing for full mutations and premutations

The following should be considered based on the physical examination, review of systems, and family history:

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Electroencephalogram if clinical signs of seizures or developmental regression are present. The utility of obtaining EEGs routinely is debated. It is clear that a significant number of children have EEG abnormalities and the likelihood of observing an abnormality increases with the duration of the EEG.
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MRI. The brain MRI is indicated when the history and physical examination or neurologic examination suggests a localized lesion, tuberous sclerosis complex, Joubert syndrome, or an early environmental insult. Its routine use is controversial because of the expense and need for sedation or anesthesia by an anesthesiologist.
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Metabolic testing. Metabolic evaluation, including quantitative plasma amino acids; urine organic acids; purines, creatine and guanidinoacetate in urine; serum concentration of lactate, pyruvate, creatine kinase, and uric acid; and CBC is of limited benefit for the majority of individuals with autism. However, because diagnosing and treating a metabolic disorder can significantly alter prognosis, selective and targeted metabolic work-up is recommended based on history and physical examination. The evaluation should include review of the child’s newborn screening test results. Further studies are needed to determine the prevalence of mitochondrial respiratory chain disorders in autism, especially those with recurrent setbacks, hypotonia, and failure to thrive.
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Molecular genetic testing for a number of genes is clinically available and should be obtained if the phenotype and/or family history suggest the diagnosis

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Mode of Inheritance

Genetic counseling for families of probands with a chromosomal disorder, copy number variant, or a single gene disorder is based on information relevant to the primary diagnosis.

The mode of inheritance for autism of unknown cause is not known.
Risk to Family Members—Autism of Unknown Cause

Parents of a proband. No data on the risk to parents of a proband of having autism of unknown cause are available; however, parents of children with an ASD are more likely to exhibit mild autistic phenotypes, such as social awkwardness and a variety of psychiatric disorders including alcoholism, depression, obsessive-compulsive disorder, and panic and anxiety disorders when compared to parents of children with non-ASD disorders such as Down syndrome [Piven & Palmer 1999, Miles et al 2003, Wilcox et al 2003, Lauritsen et al 2005, Yirmiya & Shaked 2005]. In several studies rates of 10%-45% for social impairment, aloofness, shyness, and pragmatic language impairment were present in at least one parent of children with autism spectrum disorders [Freitag 2007]. Cederlund & Gillberg [2004] reported that 70% of probands with autism of unknown cause studied had a first- or second-degree relative with autistic symptoms, and that 15% had fathers with Asperger syndrome.

Sibs of a proband. The empiric aggregate risk to sibs of individuals with autism of unknown cause varies across studies but is generally considered to range from 5% to 10% for autism and 10% to 15% for milder symptoms, including language, social, and psychiatric disorders [Bolton et al 1994, Lauritsen et al 2005, Miles et al 2005, Landa 2008, Selkirk et al 2009]. For families with two or more affected children, the recurrence risk approaches 35% [Ritvo et al 1989]. No recurrence risk data are available for families who have one autistic child plus another child or relative with mild autistic symptoms. Therefore, the amount of weight to put on mild autistic symptoms in siblings, parents, and other relatives when estimating recurrence risk for families is unknown.

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Essential autism
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Male sibs (brothers) of a proband with essential autism have a 7% risk for autism and an additional 7% risk for milder autism spectrum symptoms [Miles et al 2005].
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Female sibs (sisters) of a proband with essential autism have a 1% risk for autism. The risk for milder autism spectrum disorder is unknown [Miles et al 2005].
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Complex autism. The recurrence risk to sibs of a proband with complex autism is 1% for autism and an additional 2% for milder autism spectrum symptoms [Miles et al 2005].

Offspring of a proband. No data are available.
Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing for families at risk of having a child with a chromosomal disorder, copy number variant, or a single gene disorder known to be associated with autism may be available for the specific etiology; search the GeneTests Laboratory Directory for information on the specific syndrome to asses the availability of prenatal testing.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with autism, the following evaluations are recommended:

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Medical evaluation. A complete medical evaluation and review of systems to assess growth and identify health problems that may interfere with optimum development and progress. In particular, note:
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Sleep. Problems falling asleep, early or mid-night wakening and parasomnias are common. Routine sleep hygiene recommendations, search for underlying physical causes, and referral to sleep specialists are warranted. Medications should be delayed until underlying causes are ruled out.
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Gastrointestinal symptoms including both constipation and diarrhea are common in autism and respond to medical management. Referral to a gastroenterologist is recommended if symptoms are chronic
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Obesity. Children with autism are often treated with medications, such as atypical antipsychotics which can increase hunger and lead to weight gain. In addition, many children and teenagers are physically inactive, preferring the computer and video games.
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Hearing evaluation
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Neurologic dysfunction. Signs of seizures, focal neurologic deficits
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Cognitive testing. A cognitive assessment by a psychologist experienced in autism evaluations; however, since IQ scores may change especially in young children it is recommended that children be retested every three years. This is usually done through the school system and those records should be obtained.
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Language/communication assessment. Assess whether the child is functionally verbal or only has occasional words or echolalia. Language assessment by a trained speech/language pathologist with access to training modalities and communication modalities such as Picture Exchange Communication System (PECS). Even children who appear functionally verbal generally need ongoing speech and language therapy to gain skills in pragmatics and social and receptive communication.
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Behavioral evaluation. Assess for repetitive behaviors, aggression, self-injurious behavior, mood, and anxiety.
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Educational programs and interventions. Assess adequacy and progress.
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Family functioning, including financial resources including qualifications for Medicaid, Social Security Supplemental Income, and other state specific programs

Treatment of Manifestations

Optimally, an autism intervention program uses an experienced team of medical, behavioral, and educational specialists. Working with an established team is easiest for families; however, many physicians and families have successfully assembled programs that work well.

Early diagnosis and early intensive behavioral therapy are essential to an optimal outcome. Two comprehensive treatment reviews are Educating Children with Autism [Lord et al 2001] and Management of Children with Autism Spectrum Disorders from the American Academy of Pediatrics [Myers & Johnson 2007] are both available online. Also recommended is an evaluation of single-subject studies to determine which educational practices meet the criteria of "evidence-based practice" [Odom et al 2003].
Behavioral and Educational Therapy

Many interventions have been developed for children and youth with autism in the past 20 years. The effects of some of these interventions have been documented in peer-reviewed published research. Other interventions, although marketed to parents, have not been rigorously tested. The goal for practitioners is to prescribe and (as applicable) use scientifically based practices (SBP) when developing and implementing intervention plans. SBPs are those practices that have a substantial research base and are shown to be effective with children and youth with autism. Simpson [2005] provided a synthesis of autism intervention research and assigned classifications based on the level of empirical support. The classification categories are: scientifically based practice, promising practice, limited supporting information for practice, and not recommended. The interventions discussed below are considered either scientifically based or promising practices. The majority of interventions with empirical evidence of efficacy use structured behavioral and educational approaches to teach children to comprehend and use language, attend to their environment, imitate others, interact socially, and play appropriately with toys. Features include a functional approach to behavior problems and predictable and routine classroom and home arrangements with planned transitions between activities and environments.
Universal Support and Skill-Based Strategies

Environmental supports are changes to the environment that help the individual with ASD be more successful without requiring acquisition of new skills. Often these supports serve as a foundation for other targeted practices. These supports typically provide physical organization of the work space, task organization, clarity of transitions, and visual schedules/strategies.

The Treatment and Education of Autistic and related Communication-handicapped Children (TEACCH) program is a scientific-based example of a practice designed to increase students’ independence through physical and task organization [Mesibov et al 2004]. The intervention is designed to create environments (most typically classrooms and related learning settings) that provide clear expectations, structure, and predictability and reduce tendencies by children with ASD to over or under attend to stimuli through the use of physical structures. Work stations are created with clear task areas, break areas, task cues to provide support for sequencing of steps, materials and behavior expectations. Many materials and areas are color coded and supplemented with visuals, either written or pictorial. Although TEACCH procedures are more frequently used in school settings, many practitioners incorporate many of these structures into community and home environments (e.g., a bin of preferred items with visual play cues for children to use while mom is cooking). Another frequently used strategy is Visual Schedules which are designed to increase predictability and reduce anxiety. Visual representations of tasks or events, including their sequence, duration, temporal distance, cause and effect without an overall reliance on auditory processing is beneficial to learners with ASD [Mesibov & Howley 2003]. Visual strategies alone do not teach communication and should not be confused with promising formalized scientific practice strategies that use visual representations. See Communication in this section.

Applied Behavior Analysis (ABA) is an intervention based on the use of behavioral principles to change, reduce, or increase behaviors. It incorporates high levels of environmental support and uses them to target skill acquisition across multiple developmental domains. ABA has no age boundaries and teaches target behaviors coupled with specific processes for responses to increase (reinforce) or decrease behaviors. ABA programs are based on repeated analyses of an individual’s strengths related to environmental functioning [Alberto & Troutman 2008]. This approach is referred to as “functional analysis” and is an integral component of the federal laws that regulate the delivery of special education services [ILIAD 2004 (Individuals with Disabilities Education Act)]. Functional analysis seeks to identify the purpose for which an individual exhibits a maladaptive or prosocial behavior. This allows development of individualized and effective environmental supports and skill-based techniques to teach new behaviors. ABA, including functional analysis, is the intervention technique with the strongest research base supporting its effectiveness in both ASD and non-ASD populations.

A number of evidence-based or emerging practices, including Discrete Trial Teaching and Pivotal Response Training, are based on ABA principles. One such technique that is expected to emerge shortly as scientific is Incidental Teaching, which uses basic concepts of ABA in the child’s natural environment [McGee et al 1999, Peterson et al 2005].

Incidental Teaching is implemented around the child’s interests and typical activities, using natural supports such as favorite toys, people or foods as the basis for teaching new skills. To date, research has demonstrated success across all levels of cognitive and ASD symptomology, and most age ranges, especially in early childhood [McGee et al 1999]. Skills acquired through Incidental Teaching are considered more generalizable to day-to-day functioning when compared to methods like discrete trial training, which breaks down single tasks and teaches them separately [Lord et al 2001, Simpson et al 2005].

Individuals with average intelligence or mild cognitive disability often benefit from a more cognitive processing strategy called Cognitive Behavior Intervention or cognitive learning strategies [Bauminger 2002, Solomon et al 2004, Webb et al 2004, Tse et al 2007].

Cognitive Behavior Intervention, categorized as a promising practice for ASD, teaches problem solving schemas using systematic application of environmental supports, rules, and principles which lead to self-management and behavior regulation. It is anticipated as more research is being published that this strategy will soon be moved to scientific-based status for ASD. This practice is particularly helpful for teaching self-management skills and regulating one’s own behavior.

Sensory Integration (SI) is the organization and processing of sensory information for specific functional use. Proponents of sensory integration therapy view the aberrant behavior of children with autism as an attempt to establish an internal state of equilibrium. Scientific theory exists for this view, but little empiric data support its use. It is currently rated a promising practice by Simpson and colleagues based on a growing body of literature [Simpson et al 2005]. Despite a lack of specific data to support its use for ASD, caregivers at home and in the classroom report decreased hyperactivity, inattention, and self-stimulation following SI therapy. Although the program should be designed by an occupational therapist with training in sensory integration, many of the techniques, including brushing, use of weighted vests, swinging, and jumping are easily adapted to home and school use.

Communication. Communication impairment is one of the defining features of autism. Effective interventions to teach language and communication are also based on the principals of applied behavior analysis (ABA) and vary by the extent to which teaching is integrated into the child’s normal activities. At one end of the spectrum is discrete trial training that consists of intensive, rigidly structured, adult-directed, one-on-one interventions [Prizant et al 2000]. Debate exists about the appropriateness and ultimate success of teaching language skills outside of the contexts in which language is used. However, programs that use a discrete-trial training format are supported by published data and are rated as evidence-based practice [Heflin & Alaimo 2007]. Principles of ABA are also used in interventions in which instruction is embedded in home and classroom routines and the interaction is either shared or child directed. For example, Pivotal Response Training, Incidental Teaching, and the Picture Exchange Communication System are three naturalistic interventions considered to be scientifically based or a promising practice [Simpson 2005]. These naturalistic interventions can be used at school or home, and although the primary focus is language, they also target cognitive, play, and social communication skills.

Pivotal Response Training (PRT) [Koegel & Kern Koegel 2006], a scientifically based practice [Simpson et al 2005], was developed to teach skills and behaviors that enhance the child’s ability to learn and maintain new behaviors by natural consequences in typical environments. The main components of PRT are child choice, interspersing new tasks with those already mastered, reinforcing child attempts, gaining the child’s attention before giving directions, and teaching with multiple cues. PRT uses the child’s preferred activities and interests to provide motivation for learning new skills. Incidental teaching [Kaiser 2000], a promising practice [Simpson et al 2005] uses naturally occurring routines and activities, including play activities to encourage child initiations, particularly child requests. Adults reinforce the child’s language by providing access to requested activities or objects, modeling appropriate language and building turn-taking routines. Because language is taught in context, incidental teaching can be used to teach a variety of skills.

Picture Exchange Communication System (PECS) [Bondy et al 2004], a promising practice [Simpson et al 2005], was developed as a functional communication system for nonverbal children. With PECS, children use visual representations to request a desired object or activity. Children can also be taught to use the visual representations to comment on objects or activities of interest. Children progress through six phases of training that include exchanging a picture for an object or activity, making choices among pictures, and answering questions. Although not the original intent, many young children who use PECS do learn to talk.

Social. Individuals with autism experience social deficits that inhibit their ability to make and sustain friendships and navigate complex social environments. In social situations, these individuals generally lack the skills to initiate social interactions and fail to respond appropriately, leading to common descriptors such as socially awkward, self-centered, or inflexible. They also do not pick up nonverbal social cues and social prompts, and tend to display socially unacceptable behavior [Myles & Simpson 2002]. Without effective and targeted intervention, these deficits significantly affect long-term prognosis [Howlin & Karpf 2004].

Young children and those more affected by autism symptoms may benefit from play-oriented strategies, which are particularly effective for developing skills in turn-taking, sharing functional communication, and waiting, all of which are essential for effective social interactions. Play-based interventions such as Integrated Play Group and Milieu Teaching target individualized goals for the child and are distinct from ‘play therapy,’ which is often not effective for children with ASD, due in part to the emphasis of symbolic representation [Wolfberg 1999]. Learning Experiences: An Alternative Program for Preschoolers and Parents (LEAP) is a scientifically based intervention specifically focusing on social skills that generally takes place in a preschool setting but can also be implemented at home [Strain & Hoyson 2000].

Similar to the cognitive behavior interventions is a group of promising practices categorized as Social Decision Making Strategies [Simpson et al 2005]. These practices provide steps for making decisions, generating alternatives and understanding appropriate solutions in social situations. Examples include: social autopsies (deconstructing social situations that went wrong), stop-plot-go-so (determining the ‘who,’ ‘what,’ ‘when,’ ‘where,’ and ‘then what’ of social situations) and ‘stop,’ ‘observe,’ ‘deliberate,’ and ‘act’ (SODA) [Myles & Simpson 2003].

Another promising practice is Social Stories™, which is used to increase appropriate behavior and decrease problem behavior by explaining social situations in ways that are understandable to the student [Gray 2000]. The assumption is that problem behavior is caused by lack of understanding of what is expected or what is going to happen next; social stories build understanding, allowing the student to behave appropriately. Social stories are inexpensive to create and take much less time and expertise to implement than other interventions. Social Stories have been used successfully with children with ASD across a continuum of ages and abilities. Some variations are called Power Cards and Comic Scripts [Gagnon 2001].

Medical management. Although most children with autism are healthy, evidence is mounting that medical disorders have a significant effect on behaviors, level of functioning, and response to educational therapies. Sensory issues including a blunted pain response, inability to tell others when they are uncomfortable, and poor tolerance of medical evaluations can lead to suboptimal medical care. Emerging areas of research include gastrointestinal, feeding, sleep, metabolic, and pain disorders [Linday et al 2001, Bradley et al 2004, Polimeni et al 2005]. Evidence of gastroesophogeal reflux causing insomnia and self-injurious behaviors are compelling and indicate that physicians need to have a high index of suspicion, especially with unexplained behavioral exacerbations, and to provide the same level of medical intervention as in typically developing children. The Autism Treatment Network (ATN) is a consortium of 15 autism treatment center which was formed with support of Autism Speaks and the National Institutes of Health to develop a medically based approach to the diagnosis and treatment of individuals with autism. Algorithms for the initial assessment of children with autism as well as guidelines for continued medical care and surveillance are being developed and can be accessed through the Web site as well as through planned publications.

The use of medications has increased as newer medications, especially the atypical antipsychotics, which affect both the serotonin and dopamine systems, and serotonin reuptake inhibitors (SRIs), which modulate the serotonin system, have been studied in children. In 1997, the National Institute of Mental Health formed the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network to investigate the safety and efficacy of drugs for treating the behaviors associated with autism. Reports from that consortium have provided authoritative reviews of the pharmacotherapy of autism [McDougle et al 2005, Posey et al 2008]. The conclusions:

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No medications are autism specific. Medications should be selected to ameliorate a specific symptom such as aggressive or self-injurious behavior, agitation, anxiety, poor sleep and repetitive or stereotypic behaviors that interfere with learning and social interactions [Bodfish 2004, McDougle et al 2005].
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A medication that alleviates one maladaptive behavior, such as aggression or hyperactivity, may have no effect on core autistic symptoms.
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Marked differences exist in the efficacy and side effects of drugs in adults vs children.
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Individual antipsychotic medications within the same class may differ with respect to their potency and side effect profile.
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Affected individuals may respond differently to the same medication. The response to a medication may reflect genetic differences between individuals, the waxing and waning of the behaviors over time, the progression of the disorder, and/or placebo effect.
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Medication management should be integrated into a family centered, multi-modal behavioral and educational program.

In the treatment of the catatonia syndrome, antipsychotic medications are contraindicated and treatment with benzodiazepines and electroconvulsive therapy has been helpful [Wing & Shah 2000, Billstedt et al 2005, Kakooza-Mwesige et al 2008].

Alternative therapies. Complementary and alternative medical (CAM) treatments are commonly used for children with autism [Hanson et al 2007]. Levy & Hyman [2008] reviewed the evidence supporting the most frequently used treatments, including categories of mind-body medicine, energy medicine, and biologically based, manipulative, and body-based practices. Clinical providers need to understand the evidence for efficacy (or lack thereof) and potential side effects.

Though parents generally consider CAM practices a safe alternative to prescribed medications, most treatments have not been adequately studied and do not have evidence to support their use. Some CAM practices, such as administration of secretin, facilitated communication, auditory training, have evidence to reject their use. A few CAM practices such as administration of melatonin have emerging evidence to support their use.
Surveillance

Children with autism should be followed at least annually to monitor health, educational, language, and behavioral progress. An update of the areas covered in the initial evaluation is recommended. Identification of specific complications is a targeted goal of the Autism Treatment Network, which will be following a large cohort of individuals into adulthood. Since diagnostic and treatment recommendations will continue to be revised, periodic diagnostic reappraisals by a medical geneticist or an autism center are recommended. As more individuals receive etiologic diagnoses, diagnosis-specific surveillance profiles will be developed.

Complications for which evidence supports routine monitoring include:

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Seizures
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Sleep disturbances
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Feeding problems
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Gastrointestinal symptoms
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Medication-specific side effects
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Mood and psychiatric dysfunction
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Medication-induced complications. All children on medications should be closely monitored for medication side effects.

Agents/Circumstances to Avoid

A hands-off or wait-and-see approach should be avoided because children with autism are unlikely to be able to navigate the social world and develop reciprocal communication skills without intensive therapeutic intervention.

Families need to be cautioned about unproven and potentially dangerous “alternative therapies” that may be promoted either by well-meaning but naïve people or by unscrupulous groups, individuals, or clinics.
Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Resources

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page link.
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285. Vincent JB, Kolozsvari D, Roberts WS, Bolton PF, Gurling HM, Scherer SW. Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet. 2004;129B:82–4. [PubMed: 15274046]
286. Volkmar F, Chawarska K, Klin A. Autism in infancy and early childhood. Annu Rev Psychol. 2005;56:315–36. [PubMed: 15709938]
287. Vorstman JA, Staal WG, van Daalen E, van Engeland H, Hochstenbach PF, Franke L. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry. 2006;11(1):18–28.
288. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P, Valentine A, Davies SE, Walker-Smith JA. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351:637–41. [PubMed: 9500320]
289. Wakefield AJ. MMR vaccination and autism. Lancet. 1999;354:949–50. [PubMed: 10489978]
290. Wassink TH, Piven J, Patil SR. Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatric Genetics. 2001;11:57–63. [PubMed: 11525418]
291. Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC. Evaluation of FOXP2 as an autism susceptibility gene. Am J Med Genet. 2002;114:566–9. [PubMed: 12116195]
292. Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE, Sheffield VC. Examination of AVPR1a as an autism susceptibility gene. Mol Psychiatry. 2004;9:968–72. [PubMed: 15098001]
293. Webb BJ, Miller SP, Pierce TB, Strawser S, Jones WP. Effects of social skill instruction for high-functioning adolescents with autism spectrum disorders. In: Focus on Autism and Other Developmental Disabilities. Available at foa.sagepub.com. 2004. Accessed 4-10-10.
294. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358:667–75. [PubMed: 18184952]
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300. Wolfberg PJ. Play and imagination in children with autism. New York: Teachers College Press, 1999.
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Suggested Reading

1. Attwood T. The Complete Guide to Asperger's Syndrome. London: Jessica Kingsley Publishers, Ltd; 2007.
2. Chawarska K, Klin A, Volkmar FR,eds. Autism Spectrum Disorders in Infants and Toddlers, Diagnosis, Assessment, and Treatment. New York: The Guilford Press; 2008.
3. Goldstein S, Naglieri JA, Ozonoff S, eds. Assessment of Autism Spectrum Disorders. New York: The Guilford Press; 2009.
4. Immunization Safety Review Committee, Stratton K, Gable A, Shetty P, McCormick M, eds. Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism. Washington, DC: The National Academies Press. Available at books.nap.edu. 2010. Accessed 4-10-10.
5. McAfee J. Navigating the Social World: A Curriculum for Individuals with Asperger's Syndrome, High Functioning Autism and Related Disorders. Arlington, TX: Future Horizons; 2002.
6. National Institute of Mental Health. Autism Spectrum Disorders: Pervasive Developmental Disorders. Available in pdf. 2004. Accessed 4-10-10.

Source:NCBI Bookshelf and GeneReviews

Note: Click on the title of the post to read the original post

Autism Awareness Efforts Boost Early Diagnoses

2011-05-22T20:31:00.002+05:30

May 13, 2011 —

Efforts to increase awareness about the early signs of autism appear to be working, a new study shows.

Researchers with the CDC, Harvard Medical School, and United Health Group found that the number of children younger than age 3 who were enrolled in early intervention programs for autism spectrum disorders (ASD) in Massachusetts rose 66% in children born between 2001 and 2005.

Mounting evidence suggests that the impairments of autism -- including deficits in speech, IQ, and social skills -- can be tempered or even reversed if therapy is started early.

So the government has funded public health campaigns to increase awareness of the first signs of autism and the importance of early diagnosis among parents and health care providers.

Some states, including Massachusetts, have passed laws mandating insurance coverage for early interventions.

Advocacy and professional groups have also ramped up their efforts to encourage early diagnosis, and there's been more media coverage of the disorder, says study researcher Susan E. Manning, MD, MPH, an epidemiologist with the CDC and the Massachusetts Department of Public Health.

Taken together, she says, those efforts are probably responsible for much of the increase observed in the study.

Experts who were not involved in the study say that to the extent the increase in early diagnosis is a reflection of successful public awareness efforts, it is positive news.

"This is exactly what researchers who are working so hard to identify the early markers of autism and to develop these efficacious early interventions want to see happen," says Rebecca Landa, PhD, director of the Center for Autism and Related Disorders at Kennedy Krieger Institute, Baltimore.

But researchers could not rule out the possibility that some of the new diagnoses represented an actual uptick in affected children.

"Some of this could be due to an actual true increase in autism," Manning says, "But how much of that, of the overall increase, is accounted for by a true increase in autism is hard to tease out because all the other factors come into play."

Expansion of Autism Symptom List

Other experts say the increase noted in the study probably also reflects the expansion of symptoms that are used to define autism spectrum disorders. They worry some young children may be getting a diagnosis based on symptoms they'll eventually outgrow.

"Because ASD now includes only a few symptoms of classic autism, children who previously were not diagnosed with ASD are now being identified," says Stephen Camarata, PhD, an autism specialist and professor of hearing and speech sciences at Vanderbilt University in Nashville, Tenn.

Camarata says "late talking," or talking after the age of 2, which affects about 10% of all toddlers, is an example.

"If late talking is now viewed as diagnostic for putting a child on 'the autism spectrum,' then all late talkers will be identified as autistic," Camarata says.

"This is important because, if there is nothing else wrong -- no other symptoms of autism or other disability such as cognitive impairment -- approximately 60%-70% of the late talkers catch up by the time they reach 3 years old," he tells WebMD.

Tracking Early Autism Diagnoses

For the study, researchers cross-referenced data on births in Massachusetts between 2001 and 2005 with records on children enrolled in the state's early-intervention programs for autism spectrum disorders before their third birthday.

The study included 385,631 children without documented autism spectrum disorders and 3,013 enrolled in early-intervention programs.

To be referred to an early-intervention program, children had to have failed a screening test of 23 questions called the modified checklist of autism in toddlers. The test asked questions about a child's ability to interact with others, pretend during play, walk, speak, and hear.

Information on parental characteristics like age, education level, and race, were derived from birth certificates.

Researchers also included information about whether the children were born prematurely or at low birth weights or whether they were single births or multiples.

Autism Incidence: Boys vs. Girls

The incidence of autism spectrum disorders in children less than 3 years of age increased from 56 per 10,000 in children born in 2001 to 93 per 10,000 in children born in 2005.

There was a greater increase in boys than in girls.

Among boys, the early autism diagnoses increased 70% between children born in 2001 and those born in 2005. They went up 39% in girls.

That means boys were about 4.5 times more likely than girls to be given an early diagnosis of autism spectrum disorder.

That's not a huge surprise, researchers say, given that autism is known to be about three to four times more prevalent in boys than in girls.

Low birth weights, premature births, and multiple births were all at increased risk of an early diagnosis of autism spectrum disorder, the study found.

Autism diagnoses were more likely in children born to older mothers, especially those over 45. A father's age or education appeared to have no impact on the likelihood of an autism diagnosis, however.

The study also found something intriguing with regards to race and ethnicity. At the beginning of the study, white children had a higher likelihood of early diagnosis. White children were nearly 30% more likely than African-American children and 90% more likely than Hispanic children to be referred to an early-intervention program. By the end of the study, those differences had disappeared.

"For a long time, it's been felt that minority children were out there at equal rates but we just weren't doing a good job of finding those children," Landa says.

The fact that rate of early diagnoses equalized by the end of the study, she says, suggests that outreach programs to minority communities are working.

Indeed, researchers say, all groups appear to be benefiting from greater public health efforts.

"The fact that we're getting them in early is great, because the earlier we can identify children and get them enrolled in appropriate services, the better the chances are to optimize their developmental and educational outcomes," Manning says.

SOURCES:

Manning, S. Pediatrics, online, May 16, 2011.

Robins, D. Journal of Autism and Development Disorders, 2001.

Rebecca Landa, PhD, director, Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore.

Susan E. Manning, MD, MPH, epidemiologist, CDC; Massachusetts Department of Public Health.

Rett Syndrome

2011-05-21T14:28:00.000+05:30

Rett syndrome

Rett syndrome is a disorder of the nervous system that leads to developmental reversals, especially in the areas of expressive language and hand use.
Causes, incidence, and risk factors

Rett syndrome occurs almost exclusively in girls and may be misdiagnosed as autism or cerebral palsy.

Studies have linked many Rett syndrome cases to a defect in the methl-CpG-binding protein 2 (MeCP2) gene. This gene is on the X chromosome. Females have two X chromosomes, so even when one has this significant defect, the other X chromosome is normal enough for the child to survive.

Males born with this defective gene do not have a second X chromosome to make up for the problem. Therefore, the defect usually results in miscarriage, stillbirth, or very early death.

The condition affects about 1 out of 10,000 children. Groups of the disease have appeared within families and certain geographic regions, including Norway, Sweden, and northern Italy.
Symptoms

An infant with Rett syndrome usually has normal development for the first 6 - 18 months. Symptoms range from mild to severe.

Symptoms may include:

*

Apraxia
*

Breathing problems -- problems tend to get worse with stress; breathing is usually normal during sleep and abnormal while awake
*

Change in development
*

Excessive saliva and drooling
*

Floppy arms and legs -- frequently the first sign
*

Intellectual disabilities and learning difficulties (assessing cognitive skills in those with Rett syndrome, however, is difficult because of the speech and hand motion abnormalities)
*

Scoliosis
*

Shaky, unsteady, or stiff gait; or toe walking
*

Seizures
*

Slowing head growth beginning at approximately 5 - 6 months of age
*

Loss of normal sleep patterns
*

Loss of purposeful hand movements; for example, the grasp used to pick up small objects is replaced by repetitive hand motions like hand wringing or constant placement of hands in mouth
*

Loss of social engagement
*

Ongoing, severe constipation and gastroesophageal reflux (GERD)
*

Poor circulation that can lead to cold and bluish arms and legs
*

Severe language development problems

NOTE:

Problems in breathing pattern may be the most upsetting and difficult symptom for parents to watch. Why they happen and what to do about them is not well understood. Most experts in Rett syndrome recommend that parents remain calm through an episode of irregular breathing like breath holding. It may help to remind yourself that normal breathing always returns and that your child will become used to the abnormal breathing pattern.
Signs and tests

Genetic testing may be done to look for the gene defect associated with the syndrome. However, since the defect is not identified in everyone with the disease, the diagnosis of Rett syndrome is based on symptoms.

There are several different types of Rett syndrome:

*

Atypical
*

Classical (meets the diagnostic criteria)
*

Provisional (some symptoms appear between ages 1 and 3)

Rett syndrome is classified as atypical if:

*

It begins early (soon after birth) or late (beyond 18 months of age, sometimes as late as 3 or 4 years old)
*

Speech and hand skill problems are mild
*

It is appears in a boy (very rare)

Treatment

Treatment may include:

*

Assistance with feeding and diapering
*

Methods to treat constipation and GERD
*

Physical therapy to help prevent the hands from contracting
*

Weight bearing exercises for those with scoliosis

Supplemental feedings can help those with slowed growth. A feeding tube may be needed if the patient breathes in (aspirates) food. Diets high in calories and fat, as well as nasogastric tube feeds, can help increase weight and height. Weight gain may improve alertness and social interactions.

Medications such as carbamazepine may be used to treat seizures. Other medications or supplements that have been used or studied include:

*

Bromocriptine
*

Dextromethorphan
*

Folate and betaine
*

L-carnitine, which may help improve language skills, muscle mass, alertness, energy and quality of life while decreasing constipation and daytime sleepiness
*

L-dopa for motor rigidity in later stages of the disease

Stem cell therapy, alone or in combination with gene therapy, is another hopeful treatment.

Support Groups

International Rett Syndrome Association - www.rettsyndrome.org

Expectations (prognosis)

The disease slowly progresses until the patient is a teenager. Then, symptoms may improve. For example, seizures or breathing problems tend to lessen in late adolescence.

Developmental regression or delays vary. Usually, a child with Rett syndrome sits up properly but may not crawl. For those who do crawl, many do so by scooting on their tummy without using their hands.

Similarly, some children walk independently within the normal age range, while others are delayed, don't learn to walk independently at all, or don't learn to walk until late childhood or early adolescence. For those children who do learn to walk at the normal time, some keep that ability for their lifetime, while other children lose the skill.

Life expectancies are not well studied, although survival at least until the mid-20s is likely. The average life expectancy of a girl with Rett syndrome may be mid-40s. Death is often related to seizure, aspiration pneumonia, malnutrition, and accidents.
Calling your health care provider

Call your health care provider if you have any concerns about your child's development, if you notice a lack of normal development with motor or language skills in a child, or if there are associated disorders that need treatment.
Prevention

The likelihood of having another child with Rett syndrome is less than 1%.

References

1. Shah PE, Dalton R, Boris NW. Pervasive developmental disorders and childhood psychosis. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 29.

Review Date: 11/12/2010.

Reviewed by: Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

Source: Pubmed Health

The Difference Between Autism

2011-04-22T15:02:00.000+05:30

By Lisa Jo Rudy, About.com Guide April 12, 2011

Yes, the grammatical error was intentional!

Autism Awareness Month is a great time to get out the word about issues in autism. One of the toughest for everyone, including people on the spectrum, parents, teachers, therapists and doctors, is the incredible disparity among people with autism. How do you make the world aware of a single disorder that can present itself so very differently in different individuals? How do you create policies, undertake research or provide services for a group of people who have radically different needs? How do you plan a school program, provide therapies, or even access support when your situation is practically unique?

Of course the answer is - there is no one "autism," and that issue lies at the heart of many of the problems experienced by members of the disparate group that is sometimes called the "autism community."

Some of the biggest differences we face include -

* Differences in physical symptoms. Some people with autism also have serious physical problems including (but not limited to) sensory dysfunctions, seizures, gastrointestinal problems, sleep issues and food allergies.
* Differences in functional level. One person with autism is brilliant, intense, extremely anxious and often depressed. Another is non-verbal and physically aggressive. A third is low-key, affectionate, verbal, but lacking in social and communication skills. Which of these people is most functional? The answer isn't always obvious. What is obvious is that these people can't do the same things, don't need the same supports, and have very little in common as individuals.
* Differences in onset of the disorder. Particularly for parents of children with autism, differences in personal experience can create huge rifts. While one parent saw her child "descend" into autism almost overnight, another sees that her son, who has always been different, is also an awful lot like Uncle Bill - the brilliant but quirky engineer. Differences like these are causing huge battles over questions like "what causes autism?," "can autism be prevented?" and "is autism a difference or a disability?"

So what are the different types of autism? How different are they from one another? Unfortunately, even the official categories of autism (there are five) don't make clear distinctions. And those categories will likely be reduced to just three when new guidelines for diagnosis are put in place in 2013. Here are some definitions, though, that may help families better understand "the difference between autism."

Types of Autism

What Are Pervasive Developmental Disorders?

"Pervasive Developmental Disorder" is a formal term that means exactly the same thing as the less formal "autism spectrum disorder." As with the autism spectrum, the group of disorders described as pervasive developmental disorders includes autistic disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), Asperger syndrome, Childhood Disintegrative Disorder and Rett Syndrome.

What Is Asperger Syndrome?

Often called "the little professor" or "geek" syndrome, Asperger syndrome describes individuals at the highest-functioning end of the autism spectrum. Unlike other autism spectrum disorders, Asperger syndrome is often diagnosed in teens and adults. People with Asperger syndrome generally develop spoken language in the same way as typically developing children, but have issues with social communication that become more pronounced as they get older. Because people with Asperger syndrome are often very intelligent - but "quirky" - the disorder is sometimes nicknamed "geek syndrome" or "little professor syndrome."

What Is Mild Autism?

The term "mild autism" is not an official diagnosis. It's simply a more descriptive term than "Asperger syndrome" or "autism." Generally speaking, when people use the term mild autism they are referring to individuals whose symptoms fit an autism spectrum diagnosis, but who has strong verbal skills and few behavioral issues. Those individuals may, however, have significant problems with social communication. They may also have problems coping with too much sensory input (loud noise, bright lights, etc.).

What Is High Functioning Autism?

Like "mild" autism, high functioning autism (sometimes shortened to HFA) is a made-up term that's become more and more commonly used. HFA is a tricky term, because it can be hard to distinguish a person with HFA from a person with Asperger syndrome. The official distinction is that people with HFA had or have speech delays, while people with Asperger Syndrome have normal speech development. But there may also be very real differences in terms of social awareness, personality characteristics, and other traits. The jury is still debating the fine distinctions.

What Is PDD-NOS?

"Pervasive Developmental Disorder Not Otherwise Specified" is a mouthful of words that are often applied to people on the autism spectrum. It describes individuals who don't fully fit the criteria for other specific diagnoses, but are nevertheless autistic. Unfortunately, there is no easy way to define the symptoms of PDD-NOS, which may range from very mild to very severe. As a result, the term is rarely used outside of practioners' offices. Most parents, therapists and teachers prefer to use more descriptive (though less official) terms to describe their children, students and patients with PDD-NOS.

What Is Severe Autism (Autistic Disorder)?

Severe autism is officially termed autistic disorder. It goes by many other names, though, including profound autism, low functioning autism, or classic autism. People with autistic disorder are often non-verbal and intellectually disabled, and may have very challenging behaviors.

What Is Rett Syndrome?

Rett syndrome is a genetic disorder that affects only girls. It is the only one of the autism spectrum disorders that can be diagnosed medically (so far). Girls with Rett syndrome develop severe symptoms including the hallmark social communication challenges of autism. In addition, Rett syndrome can profoundly impair girls' ability to use their hands usefully.

Source: About.com

Rett syndrome Clinical trials

2011-04-04T23:03:00.000+05:30

Source: International Rett Syndrome Foundation

FAQ about the IGF-1 Rett Syndrome Trial

2011-04-04T23:01:00.000+05:30

"Treatment of Rett Syndrome with IGF-1"

PI: Omar Khwaja MD, PhD

Frequently Asked Questions (FAQ)
Download a PDF version of these FAQ
Q: Who is eligible for this clinical trial?
A: Eligible participants will be girls between the ages of 2 and 12 years, have a positive MECP2 genetic test and reside in the United States for the duration of the study.

Q: My child has a mutation in CDKL5, can we still participate?
A: No; all the work that has contributed to the development of this study has been conducted in mice with mutations in MECP2. Therefore, we do not know what the effects will be on children with CDKL5 mutations and at this time we are not enrolling children with this condition.

Q: What is the difference between Phase 1 and Phase 2?
A: Phase 1: A total of 10 girls will be enrolled in Phase 1. The objective of Phase 1 is to determine the tolerability of IGF-1 in the Rett Syndrome population. The visit schedule for Phase 1 includes three 24-hour inpatient stays and three outpatient visits (lasting approximately 3 hours each). At the end of the fourth week, participants will come to the hospital for a day-long visit lasting approximately 8 hours. Subjects that choose to participate in Phase 1 will automatically be enrolled in Phase 2, where they will receive an additional 20 weeks of treatment with IGF-1.

Phase 2: Phase 2 is a placebo controlled study lasting a total of 50 weeks. 30 girls will be enrolled in this phase. Participants will receive treatment (either IGF-1 or placebo) for 20-weeks, followed by 20 weeks of the alternate treatment (for example, if a subject received placebo for the first 20 weeks, she will be treated with IGF-1 for the following 20 weeks). There is a 6-week break between the two 20-week increments, during which participants will receive no treatment. In Phase 2, parents are required to bring their child to Children's Hospital, Boston every 4 weeks throughout the duration of the study.

Q: How will children be selected for participation?
A: The complete "inclusion criteria" is listed in the consent forms which have been sent to families interested in enrolling their children in this study (Note: if you have not received these documents, please e-mail rettresearch@childrens.harvard.edu and we will forward these to you). If the number of children that meet criteria exceeds 40; the potential participants will be randomized and chosen by a lottery. We will notify parents if their child has been selected to confirm that they still wish to enroll.

Q: When will the children be selected?
A: Children will be enrolled steadily over the first year of the study.

Phase 1: Enrollment for this phase is currently closed. For those who have sent in applications for Phase 1, we will schedule screening visits in March 2011 and begin treating participants in April.

Phase 2: Enrollment for this phase is currently open. We anticipate starting screening for this phase in August 2011.

Q: How do I apply for participation in this study?
A: Please send an email to rettresearch@childrens.harvard.edu and we will send you the necessary information and forms for enrollment.

Q: Once selections are made, will a more defined schedule of visits be provided?
A: Yes; at enrollment you will select a schedule schema. Once the first visit has occurred, this schedule is "set in stone" and cannot be altered under any circumstances.

Q: How soon after the initial screening/visits will the trial begin?
A: This will depend on you and your family's schedule. You may select when you would like the visits to begin.

Q: Can people outside of the Northeast enroll in Phase 1?
A: While Phase 1 is open to anyone, those who choose to enroll will most likely reside in the New England area as participants are required to visit the hospital twice a week for safety monitoring.

Q: If we choose not to participate in Phase 1, will this reduce our daughter's chance of being chosen for Phase 2?
A: No; participation in Phase 1 will in no way affect her eligibility for Phase 2.

Q: If I do not get selected for Phase 1, do I have to apply again for Phase 2?
A: No, the girls that are not selected for Phase 1 will automatically roll-over for enrollment in Phase 2.

Q: Can I go to my local Rett syndrome clinic for the evaluations?
A: No; the only site approved for clinical evaluations is Children's Hospital Boston.

Q: I tried to sign the consent forms, but they say "Not Valid"; now what?
A: These consent forms are intended for your review only. The official consent form will be signed in-person after your daughter has been selected and you have met with the research team to confirm her eligibility.

Q: Is there a hotel close to the hospital?
A: Yes, the closest hotel, the Inn at Longwood Medical, is next door to the hospital.

Q: Are there any discounted rates on airfare or hotel stay if you are traveling with a special needs child that is receiving treatment in a hospital setting such as this trial?
A: For airfare, check out Miracle Flights for Kids or Angel Flight. For families that cannot afford a hotel, there are a handful of rooms resourced within the hospital. However, these rooms are only available on a first-come, first-served basis and cannot be reserved well in advance. Unfortunately, we are not able to compensate families for lodging or travel.
For further information about this study, please contact:
Phone: 617-355-5230
Fax: 617-730-4669
Email: rettresearch@childrens.harvard.edu

Source: Children's Hospital Boston

Research funding a distant dream for less 'popular' diseases: Less 'popular' diseases not seeing proper contributions

2011-03-30T12:54:00.000+05:30

By AMY NEFF ROTH
Observer-Dispatch
Posted Mar 28, 2011 @ 05:00 AM

Three-year-old Raymond Gallo might not be able to walk or hear without a weekly dose of intravenous medicine that attacks the effects of Hunter syndrome, a rare genetic disease. But thanks to that medicine, Raymond can watch and hear his favorite TV shows – “Dora,” “Diego” and “iCarly” – walk up to a baby to say hi or walk over to his mom for a hug. Just don’t ask him to walk outside in the winter; Raymond, who lives in Boonville, hates the snow.

Before Raymond’s medicine was approved by the federal Food and Drug Administration in 2006, most early-onset Hunter syndrome patients like him died between the ages of 10 and 20. As things stand, Raymond’s prognosis is uncertain.

Every year, thousands of area residents turn out to raise money for medical research at events such as America’s Greatest Heart Run & Walk or the American Cancer Society’s Relay for Life. These events give private citizens the ability to vote, with their feet, on where the billions of dollars the United States invests in medical research each year should go.

Many choose causes based on their history with a disease – as survivors, caregivers, loved ones or friends.
Some have been touched by stories in the media, some by the involvement of a celebrity such as Christopher Reeve or Michael J. Fox.

But it’s much harder to find advocates for kids such as Raymond; Hunter syndrome and 6,000 other so-called orphan diseases affect fewer than 200,000 Americans each.

So while Americans invested $139 billion into medical research in 2009, as estimated by the nonprofit Research!America, treatments and cures remain a distant dream for patients with less “popular” diseases.

There simply isn’t enough money to go around.

Money for research comes from many sources: private industry, the largest contributor; the federal government, especially the National Institutes of Health; local and state governments; private foundations; and the health care nonprofits for which residents walk, run and jump rope to raise money.

Each group has its own decision-making process, but it always involves scientists judging the merits of research proposals. No one wants to invest in unsuccessful or insignificant research.

“My perspective is that our current way of funding medical research in the U.S. resembles Winston Churchill’s quote about democracy, (that) it’s the worst form of government in the world, except for all the others,” said Dr. Patrick McNulty, chief of cardiology at Bassett Medical Center in Cooperstown, and a former researcher who reviews research grants for the American Heart Association and the National Institutes of Health.

The system would be hard to improve, agreed Jonathan Moreno, professor of medical ethics and of the history and sociology of science at the University of Pennsylvania in Philadelphia. “The fact is that there is no completely objective metric,” he said.

Buying hope

Research money doesn’t just buy better treatments: It buys hope for patients with incurable diseases and their families.

Raymond’s parents, Jennifer and Richard, are praying that his “miracle” medicine – administered over the course of five hours every Monday – will save him until researchers can find a cure.

The Gallos’ concern isn’t just for Raymond; their daughter Kaitlin, 7, could be a carrier of the Hunter gene.
Patients with Hunter syndrome, most often boys, lack an enzyme that helps them break down certain kinds of sugar which then build up in the body. There is a milder late-onset form, but for early onset patients such as Raymond, symptoms can include aggressive behavior, hyperactivity, mental retardation, spasticity, coarse facial features, progressive deafness, carpal tunnel syndrome, joint stiffness and a large head.

As an infant, Raymond was happy, but just wasn’t hitting developmental milestones, Jennifer said. But his pediatrician kept insisting everything was OK. A new doctor diagnosed him when he was just over a year old.

The couple, both teachers, hasn’t put in long hours researching their son’s condition, as some families do.
“If you look online, it’s very scary,” Jennifer said.

“I know enough that it would make me crazy,” Richard added.

Instead, the couple stays in touch with experts they trust for information, they said.

Developments in the human genome, nanotechnology and stem cell research have given scientists wonderful opportunities to make new discoveries, said Steven Goodman, vice president for research and dean of the College of Graduate Studies at Upstate Medical University in Syracuse.

“I personally think we’re at a place where progress could be made at an unprecedented rate,” he said.

That can’t happen, though, without more investment in research, Goodman said.

Meanwhile, the House of Representatives has passed a bill that would cut the NIH’s budget this year by $1.6 billion, or 5.2 percent.

Cause celebre

Science is not the only factor affecting research funding. Other factors creep in, too: politics, campaigns by health-related advocacy groups, celebrity spokespeople, lobbying, public opinion and profits. Just think of those ubiquitous pink ribbons and Jerry Lewis’ telethon.

Dr. Charles Antzelevitch, executive director and director of research for Masonic Medical Research Laboratory in Utica, said he’s been working with pharmaceutical companies for 15 years to develop drugs for the rare, but potentially fatal genetic cardiac arrhythmias he researches. But Antzelevitch said he’s been disappointed by the lack of industry focus.

“The profit margin is not there,” he said.

Raymond’s disease might once have been overlooked by drug companies. But the Orphan Drug Act of 1983 gave special encouragements to drug makers to develop treatments for orphan diseases such as Hunter syndrome, which affect fewer than 200,000 Americans. In the decade before the program began, fewer than 10 “orphan drugs” were approved, according to the FDA. Since 1983, 366 have been approved.

But profits aren’t Antzelevitch’s only concern with the funding system.

“We get very concerned when we see the National Institutes of Health, for example, having dictates from Congress based on these lobbying efforts by celebrities, and so forth, and individual lobbying groups,” he said. “It’s important to be responsive to the populace, but you really need to put the money where it can advance science in a meaningful way, and it’s the scientific community, I think, that can best judge where the money can do the most good.”

But for Goodman, celebrity involvement, advocacy campaigns and anything else that brings attention to medical research is good. The field can use all the attention – and funding – it can get, he said.

And more celebrities are taking the time to sit down with scientists to learn how they can help, forging an alliance that can create positive awareness, Moreno said. But not always; Patrick Swayze’s death from pancreatic cancer in 2009 did not seem to bring the disease to the fore.

It’s hard, Moreno said, to figure out why some diseases get more attention and funding than others.
Mary Shulsky, of Deerfield, thinks so, too. Her husband, John, 66, and his “big brother,” identical twin Jim, who was born three minutes earlier, were diagnosed with pancreatic cancer during the same week in early September.

The NIH keeps track of its annual funding in 229 research categories in which Congress has shown an interest historically. Seven organ cancers are on the list. Pancreatic is not.

John was diagnosed as stage four, and given six months to a year to live; his cancer counts were way down mid-month, which is keeping him optimistic, he said.

Jim, of Whitesboro, is stage two. An avid outdoorsman, Jim said the diagnosis came out of the blue “because you don’t hear about it. All you do is hear is about the other types.”

Pancreatic cancer has the lowest survival rate of any cancer – less than 6 percent at the five-year mark – because it is most often diagnosed in the late stages. There is no screening test and there are few early-stage symptoms. Jim lucked out in a sense because a tumor blocking his bile duct gave him early symptoms.

John wasn’t so lucky. He and Mary had planned on traveling after retirement, but John kept putting off retirement because he loved his job at Indium Corp.’s plant in Utica, Mary said. In fact he’s still officially an employee out on disability, she said.

Mary remembers the moment John’s doctor broke the news.

“I knew when we sat down. I could tell by the look on his face. He said, ‘I’m very sorry. It’s cancer,’” she recalled.

“All of our plans and hopes and dreams …,” she began, before choking up, unable to go on.
“It was devastating. I just can’t describe it.”

And now Mary also is concerned for her two children and two nephews because of the family’s evident genetic link to the cancer.

“We just keep hoping for a miracle,” Mary said. “There are only 37,000 people that die of this every year, and it’s not enough for them to get the funding that they need to do the research, like breast cancer. They get all kinds of funding.”
Copyright 2011 The Observer-Dispatch, Utica, New York. Some rights reserved

Breakthrough in delivering drugs to the brain

2011-03-21T23:38:00.000+05:30

By James Gallagher Health reporter, BBC News

A new way of delivering drugs to the brain has been developed by scientists at the University of Oxford.

They used the body's own transporters - exosomes - to deliver drugs in an experiment on mice.

The authors say the study, in Nature Biotechnology, could be vital for treating diseases such as Alzheimer's, Parkinson's and Muscular Dystrophy.

The Alzheimer's Society said the study was "exciting" and could lead to more effective treatments.
Research barrier

One of the medical challenges with diseases of the brain is getting any treatment to cross the blood-brain barrier.

The barrier exists to protect the brain, preventing bacteria from crossing over from the blood, while letting oxygen through.

However, this has also produced problems for medicine, as drugs can also be blocked.

In this study the researchers used exosomes to cross that barrier.

Exosomes are like the body's own fleet of incredibly small vans, transporting materials between cells.

The team at Oxford harvested exosomes from mouse dentritic cells, part of the immune system, which naturally produce large numbers of exosomes.

They then fused the exosomes with targeting proteins from the rabies virus, which binds to acetylcholine receptors in brain cells, so the exosome would target the brain.

They filled the exosomes with a piece of genetic code, siRNA, and injected them back into the mice.

The siRNA was delivered to the brain cells and turned off a gene, BACE1, which is involved in Alzheimer's disease.

The authors reported a 60% reduction in the gene's activity.

"These are dramatic and exciting results" said the lead researcher Dr Matthew Wood.

"This is the first time this natural system has been exploited for drug delivery."
Customised

The research group believes that the method could modified to treat other conditions and other parts of the body.

Dr Wood said: "We are working on sending exosomes to muscle, but you can envisage targeting any tissue.

"It can also be made specific by changing the drug used."

The researchers are now going to test the treatment on mice with Alzheimer's disease to see if their condition changes.

The team expect to begin trials in human patients within five years.

Dr Susanne Sorensen, head of research at the Alzheimer's Society, said: "In this exciting study, researchers may have overcome a major barrier to the delivery of potential new drugs for many neurological diseases including Alzheimer's.

She said the blood-brain barrier had been an "enormous issue as many potential drugs have not been properly tested because you couldn't get enough of them into the brain."

She added: "If this delivery method proves safe in humans, then we may see more effective drugs being made available for people with Alzheimer's in the future."

Dr Simon Ridley, head of research at Alzheimer's Research UK, said: "This is innovative research, but at such an early stage it's still a long way from becoming a treatment for patients.

"Designing drugs that cross the blood brain barrier is a key goal of research that holds the promise of improving the effectiveness of Alzheimer's treatments in the future."

Source: BBC News

April is World's Autism Awareness Month

2011-03-16T00:21:00.000+05:30

April is Autism Awareness Month, and April 2nd is International Autism Awareness Day. Please wear blue clour to raise awareness about autism and spread the word by educating others.

For more information on Autism Awareness, please click on the title

Repairing faulty genes

2011-02-24T23:37:00.000+05:30

22 February 2011

Israeli scientists have developed compounds that could be better treatments for genetic diseases than current drugs.

Timor Baasov and his colleagues at the Israel Institute of Technology have improved compounds used to suppress faults in genes called nonsense mutations.

Nonsense mutations, which cause more than 1800 human diseases, are alterations in the genetic code that stop protein production prematurely, leading to truncated or nonfunctional proteins. Gene therapy is one treatment, but it's had limited success. With suppression therapy, small molecules allow cells' protein producing equipment to skip over nonsense mutations to restore the proteins. Aminoglycosides - antibiotic amine-modified sugars - are the only clinically available drug family known to be effective in suppression therapy, but at effective doses, the compounds have high human toxicity.

To reduce the toxicity, the team introduced a methyl group onto two aminoglycosides. They tested the new derivatives in an in vitro suppression test on six different nonsense mutations for different diseases and carried out toxicity tests on human cells. They found that the compounds exhibited significantly improved activity and reduced toxicity compared to gentamicin, an aminoglycoside antibiotic used to treat bacterial infections.

'Treating genetic disorders is one of the biggest challenges of modern medicine. The likelihood that suppression therapy could be used clinically is very feasible,' says Baasov.

'The data emphasise the enormous potential of modified aminoglycosides for [nonsense suppression] therapy to combat nonsense mutation-based disorders with limited or no current therapeutic options,' says Uwe Wolfrum, a cell biologist at the Johannes Gutenberg University of Mainz, Germany. 'This raises hope for future clinical trials.'

'Our lead compounds are under intensive examination on numerous genetic disease models including cystic fibrosis, Hurler syndrome, Rett syndrome and Usher syndrome,' concludes Baasov.

Amaya Camara-Campos

Source: RSC

Note: To read original post click on the title of the post.

Licence rules hinder work on rare disease

2011-02-18T22:40:00.000+05:30

Animal model off-limits to Rett-syndrome researchers.

Stashed away somewhere in a freezer in Cambridge, Massachusetts, is a mouse embryo that Etienne Joly would dearly like to get his hands on.

Joly is an immunologist based in Toulouse, France, with a keen interest in Rett syndrome, an incurable and debilitating disease that almost exclusively affects young girls. The mouse, developed by a team at the Novartis Institutes for Biomedical Research in Cambridge, carries a fluorescently tagged version of the gene that is mutated in the disease. It is the perfect tool, Joly says, for testing an idea he has about Rett syndrome. But a thicket of legal restrictions puts the mouse off-limits to anyone outside Novartis, even though scientists at the company are no longer using the model in their work on Rett syndrome.

"All scientists and families are asking for is the right to look into this disease and to try to understand it better," says Joly, who has embarked on a letter-writing campaign against the restrictions. "And when you know that there is a tool, but you can't use it because some lawyer says that you can't have the materials, then you get angry." Scientists and experts in intellectual-property issues say that the case shows how science can be impeded when onerous licensing rules govern the sharing of research materials.

Girls with Rett syndrome are healthy as babies, then progressively lose the ability to speak, move, eat and breathe normally. Because the disease is rare, affecting just one in 10,000 to 20,000 girls, it is an unattractive target for drug companies. Academic researchers have picked up the slack, and the field has moved at breakneck speed in recent years, from the 1999 discovery that defects in the gene MECP2 cause the disease, to clinical trials of possible treatments today.

Yet no one knows how the mutation causes the disease. A few years ago, Joly, who works at the Institute of Pharmacology and Structural Biology, came up with what he calls a "slightly unconventional" idea that the Rett-syndrome gene might have a role in regulating immune responses in the central nervous system. To explore his hypothesis, Joly needed an animal model that would allow him to trace where the gene is expressed.

In 2008, Joly learned about the engineered mouse. Led by molecular biologist Cecile Blaustein, the Novartis team had joined a copy of the mouse Mecp2 gene to a copy of the gene that makes enhanced green fluorescent protein (EGFP) to produce an animal in which the gene's activity can be traced throughout the brain and body (R. S. Schmid et al. Neuroreport 19, 393–398; 2008).

But after three years of trying, neither Joly nor any other Rett-syndrome researcher has been able to gain access to the mouse. When researchers asked to share it, Blaustein and her colleagues said that they would have liked to but couldn't because of the terms of Novartis's licence on EGFP, which it obtained from GE Healthcare.

Novartis and GE have been unable to negotiate a way to share the mice, says Jeff Lockwood, spokesman for the Novartis Institutes for Biomedical Research — even though Novartis has ended its research project on the mice.

When Monica Coenraads, executive director of the Rett Syndrome Research Trust in Trumbull, Connecticut, tried to broker an agreement to share the mice, GE and Novartis asked the US National Institutes of Health (NIH) in Bethesda, Maryland, to distribute the mice through its Mutant Mouse Regional Resource Centers. But Lili Portilla, senior adviser for technology transfer at the NIH National Center for Research Resources, which funds the resource centre, says that GE placed such burdensome terms on the sharing that the NIH eventually gave up. For instance, researchers would not have been allowed to share the results of their research with the NIH, says Portilla.

GE spokesman Conor McKechnie blames the "third parties" from which GE gained the rights to the EGFP protein for the onerous licensing requirements. But David Einhorn, house counsel at the Jackson Laboratory in Bar Harbor, Maine, which distributes mice to researchers around the world, questions GE's contention. He points out that many other mouse models that incorporate the gene for EGFP have been made and shared without objection from GE or from the institutions that originally discovered and licensed the EGFP patents.
Researchers have had trouble sharing resources for decades, but the situation seems to be getting worse. A 2007 study, for instance, found that 18% of academics' requests for research materials from other academic labs were not fulfilled (see 'Limited access') — almost twice as many as found in a survey taken during the 1990s. For materials requested from industry, the 2007 study found, one-third of academics' requests were declined (J. P. Walsh, W. M. Cohen and C. Cho Res. Pol. 36, 1184–1203; 2007).

Companies that don't want to share their resources don't usually publish papers describing them, says lawyer Tania Bubela of the University of Alberta School of Public Health in Edmonton, Canada. A publication changes the picture, she says. "The obligation of publication is to make your data and reagents available, so that people can replicate the results."
With no sign of a resolution, other labs have resorted to remaking the mouse model. Adrian Bird, director of the University of Edinburgh's Wellcome Trust Centre for Cell Biology, UK, says that his lab has re-engineered the mice and will distribute them through a repository, such as the Jackson Laboratory, as soon as his colony is large enough.

Bird and others say that it is unfortunate that scientists have had to delay research on the syndrome and spend money to regenerate a model that could already be in use.

"If you were to ask the families of people affected by this disease, they would say that every minute counts," says Bird.

Source: Nature News

Note: To see the original page click on the title of the post

Study shows promise for new drug to treat Fragile X

2011-01-08T20:54:00.000+05:30

Rush University Medical Center participating in follow-up study

The first drug to treat the underlying disorder instead of the symptoms of Fragile X, the most common cause of inherited intellectual disability, shows some promise according to a new study published in the January 5 issue of Science Translational Medicine. Researchers from Rush University Medical Center helped design the study and are now participating in the larger follow-up clinical trial.

The data from the early trial of 30 Fragile X patients, found the drug, called AFQ056, made by Novartis Pharmaceuticals, helped improve symptoms in some patients. Patients who had the best response have a kind of "fingerprint" in their DNA that could act as a marker to determine who should get treatment.

"This is an exciting development. It is the first time we have a treatment targeted to the underlying disorder, as opposed to supportive treatment of the behavioral symptoms, in a developmental brain disorder causing intellectual disability. This drug could be a model for treatment of other disorders such as autism," said pediatric neurologist Dr. Elizabeth Berry-Kravis, a study author and director of the Fragile X Clinic and Research Program and the Fragile X-Associated Disorders Program at Rush.

The drug is designed to block the activity of mGluR5, a receptor protein on brain cells that is involved in most aspects of normal brain function, including regulation of the strength of brain connections, a key process required for learning and memory. Fragile X patients have a mutation in a single gene, known as Fragile X Mental Retardation-1 or FMR1. The mutation prevents FMR1 from making its protein, called FMRP, such that FMRP is missing in the brain. FMRP normally acts as a blocker or "brake" for brain cell pathways activated by mGluR5. When FMRP is missing, mGluR5 pathways are overactive resulting in abnormal connections in the brain and the behavioral and cognitive impairments associated with Fragile X.

The research team, led by Sebastien Jacquemont of Vaudois University in Switzerland in collaboration with Baltazar Gomez-Mancilla of Novartis, found no significant effects of treatment when the entire group of 30 patients was analyzed. However, in a subsequent analysis, seven patients who had a fully methylated gene, a gene that was fully shut down, presumably resulting in no FMR protein in the blood or brain, showed significant improvement in behavior, hyperactivity and inappropriate speech with the treatment compared to placebo.

"The treatment period in this pilot study was very short and longer treatment might have been needed to see improvement in the whole group of patients. Importantly, the drug was well-tolerated and there were no safety problems," said Berry-Kravis.

A larger study of the drug is now underway that will recruit 160 patients worldwide and test the effects of a longer period of treatment. Rush University Medical Center is one of the participating sites.

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups. It is the most common known single gene cause of autism or "autistic-like" behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development. The impairment can range from learning disabilities to more severe cognitive and intellectual disabilities.

###

The Fragile X Clinic at Rush was started in 1992 to serve the unique needs of the Fragile X population. The clinic and research center is dedicated to helping people with Fragile X syndrome and their families, as well as furthering understanding of the syndrome, and developing new treatments targeted to the neural basis of the disorder. Dr. Elizabeth Berry-Kravis has been involved in research and clinical work with individuals with Fragile X syndrome for 14 years, and has been honored with the National Fragile X Foundation Jarrett Cole Clinical Award.

Rush is a not-for-profit health care, education and research enterprise comprising Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health. Rush University is home to one of the first medical colleges in the Midwest and one of the nation's top-ranked nursing colleges, as well as graduate programs in allied health, health systems management and biomedical research.

Contact: Kim Waterman
Kimberly_Waterman@rush.edu
312-942-7820
Rush University Medical Center

Public release date: 7-Jan-2011

Source: EurekaAlert

New Clinical Trial: Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)

2010-12-06T01:40:00.001+05:30

Purpose

The investigators are recruiting children for a research study using a medication known as IGF-1 (mecasermin or INCRELEX) to see if it improves the health of children with Rett syndrome (RTT). To participate in the study your child must be female, between the ages of 2 to 12 and have a genetic diagnosis (MECP2 deletion or mutation) of Rett Syndrome. As you may know, there is no treatment for this illness. Currently, the standard management of Rett syndrome is supportive, which means attempting to prevent complications and treatment of symptoms.

This study involves testing an investigational drug, which means that even though IGF-1 is approved by the Food and Drug Administration (FDA) for use in children, it has not been used before to treat Rett syndrome specifically. Information from this research will help determine whether the drug should be approved by the FDA in the future for the treatment of Rett Syndrome.

There are three goals to this study:

1. As one of the features of Rett Syndrome is unstable vital signs, the investigators are trying to determine if IGF-1 has any effect on normalizing your child's pulse, blood pressure and breathing pattern. During PHASE 2, a device called BioRadio® will be used to monitor vital signs in a non-invasive way. This information will be recorded and stored on the accompanying laptop. Before starting PHASE 2, the investigators would like to "beta-test" the BioRadio® in PHASE 1. As such, the investigators may ask you to try using the BioRadio® with your child to test the fit and the performance of the equipment. Should you choose to enroll your child in PHASE 2, the investigators will then ask that your child wear the BioRadio® for two hours, on two consecutive days every four weeks.
2. The safety of IGF-1 in children with Rett syndrome. The study personnel will ask you to complete a medication diary and side effect reporting form on a regular basis. They will assist you in completing this by telephone interviews. Your child will undergo 2 lumbar punctures performed at the bedside in the clinical research facility. In addition, laboratory tests will be performed throughout the study to evaluate the safety of IGF-1. These will be blood tests similar to those provided in routine clinical care. Your child will undergo regular non-invasive comprehensive physical examinations including neurological and eye examination, tonsil evaluation, electrocardiograms (ECG), measurement of height, weight and head circumference.
3. IGF-1 may improve your child's behavior, communication and speech. In order to measure this, the investigators will evaluate your child once during each month of treatment with neurodevelopmental assessments and a neurological exam. All of the tests used during these evaluations are non-invasive. the investigators will also ask you what your impressions are about her behavior and day-to-day activities through a structured parental interview and various questionnaires.

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To read more about this, please click on the title

Source: Clinicaltrials.gov

Rett Syndrome Documentary on CNN-IBN

2010-12-04T16:35:00.000+05:30

Rett syndrome story (Indian Rett syndrome foundation)

Please watch CNN-IBN Channel today (4th December) at 9.30 PM and tomorrow (5th December) at 5.30PM and 10.30PM

Share this information with other too.

Support Rett Syndrome Research Trust at NO cost to you

2010-11-30T14:37:00.000+05:30

Support Rett Syndrome Research Trust at NO cost to you

New Data Uncover Common Molecular Pathways Between Rett Syndrome, Autism and Schizophrenia

2010-11-16T00:20:00.000+05:30

The laboratory of Huda Zoghbi, where the discovery that mutations in the gene MECP2 cause the severe childhood neurological disorder Rett Syndrome was made, has taken yet another step toward unraveling the complex epigenetic functions of this gene, implicated also in cases of autism, bipolar disease and childhood onset schizophrenia. The November 11 issue of Nature reports that removing MECP2 from a small group of neurons that typically make the inhibitory neurotransmitter, GABA, recapitulates many symptoms of Rett as well as numerous neuropsychiatric disorders.

The identification of the genetic basis of Rett allowed the development of a number of mouse models of the disorder, accurately reproducing the range of symptoms seen in humans. These are considered to be among the best existing models of neurological disease.

While removing MECP2 from every cell results in full-blown Rett symptoms, the Zoghbi lab during the past few years has been using genetic tools to knock out the gene from distinct subsets of specialized brain cells called neurons, in an attempt to correlate certain neuronal populations with specific symptoms.

GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the brain. Neurons releasing GABA regulate the nervous system by acting like traffic lights on the brain’s information highway. Zoghbi and Hsiao-Tuan Chao, a postdoctoral fellow in the lab and lead author of the study, use this analogy to describe the action of GABA in allowing for a balanced level of neuronal activity by controlling the strength and timing of information transfer. Surprisingly, Zoghbi, Chao and colleagues found that removing MeCP2 from the small number of GABA-producing neurons reduced production of the neurotransmitter by about 30%. This reduction reproduced many symptoms of Rett including the paw-clasping that mimics the classical hand-wringing stereotypies. After a brief period of apparently normal development, the mice display brain hyperexcitability, impaired respiration, and loss of muscle control and strength and premature lethality. Learning, memory and sensory responses are also altered. Interestingly, the mice engaged in repetitive movements reminiscent of compulsive behavior seen in a number of neuropsychiatric disorders.

The study raises a number of important points. It implicates GABA as a key player in Rett and suggests that boosting the activity of GABA -producing neurons may help to alleviate the severity of some symptoms. It also begs the question: If a 30% reduction in GABA causes Rett symptoms, could a more subtle perturbation of 10% or 20% lead to certain neuropsychiatric disorders? This study suggests a possible pathway which can now be explored to answer the question fully.

“This study revealed to us the critical role of MECP2 in modulating the levels of GABA in inhibitory neurons and pinpointed all the neuropsychiatric symptoms that develop when the function of inhibitory neurons is compromised. Identifying the cellular and chemical basis of such symptoms is a first step in efforts aimed at understanding and, one day, treating such disorders,” said Zoghbi.

Dr. Zoghbi, who was first drawn into Rett research through her clinical experience at Baylor College of Medicine, is a Howard Hughes investigator and a Rett Syndrome Research Trust Scientific Advisor.

Monica Coenraads, Executive Director at the Rett Syndrome Research Trust which helped to fund this work, says “The field of Rett research has benefited incalculably from Huda Zoghbi’s dedication and perseverance. Her latest results suggest that GABAergic pathways are ripe for exploration not only as therapeutic intervention for Rett Syndrome but also for a much wider class of neurological disease.”

About Rett Syndrome
Rett Syndrome strikes little girls almost exclusively, with first symptoms usually appearing before the age of 18 months. These children lose speech, motor control and functional hand use, and many suffer from seizures, orthopedic and severe digestive problems, breathing and other autonomic impairments. Although some victims of Rett Syndrome do not survive childhood, most live to become adults who require total, round-the-clock care.

About Rett Syndrome Research Trust
The Rett Syndrome Research Trust is the premier organization devoted exclusively to promoting international research on Rett Syndrome and related MECP2 disorders. The goal is clear: to heal children and adults who will otherwise suffer from this disorder for the rest of their lives. With experience and tight focus, RSRT has an unparalleled knowledge base and extensive networking abilities in the world of high level research. RSRT is in a unique position to stimulate, evaluate, support and monitor ambitious and novel scientific projects. www.reverserett.org

About Baylor College of Medicine
Baylor College of Medicine in Houston is recognized as a premier academic health science center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked as one of the top 25 medical schools for research in U.S. News & World Report. BCM is listed 13th among all U.S. medical schools for National Institutes of Health funding, and No. 2 in the nation in federal funding for research and development in the biological sciences at universities and colleges by the National Science Foundation. Located in the Texas Medical Center, BCM has affiliations with eight teaching hospitals, each known for medical excellence. Currently, BCM trains more than 3,000 medical, graduate, nurse anesthesia, and physician assistant students, as well as residents and post-doctoral fellows. BCM is also home to the Baylor Clinic, an adult clinical practice that includes advanced technologies for faster, more accurate diagnosis and treatment, access to the latest clinical trials and discoveries, and groundbreaking healthcare based on proven research.

Source: Rett Syndrome Research Trust

Contact Person:
Monica Coenraads
Executive Director, RSRT
monica@rsrt.org
203.445.0041

PTC Therapeutics: Development of treatment for Genetic Disorder

2010-11-16T00:13:00.000+05:30

PTC applies its expertise in RNA biology and drug development to pioneer novel oral treatments for patients living with serious and life-threatening conditions.

Ataluren for Genetic Disorders

Ataluren (PTC124®) is an investigational drug designed to enable the formation of a functioning protein in patients with genetic disorders due to a nonsense mutation.

A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Ataluren is currently being investigated for use in patients with nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA) .

Click here to read Frequently Asked Questions about ataluren.

Translation of an mRNA into protein

Mechanism of Action
In healthy individuals, ribosomes translate the informational code in the mRNA into protein until arriving at a normal stop signal in the mRNA, at which point the ribosome appropriately stops translation and a functioning protein results.

Nonsense mutations, however, create a premature stop signal in the mRNA. This premature stop signal causes the ribosome to halt translation before a functioning protein is generated, creating a shortened, nonfunctioning protein. The resulting disease is determined by which protein cannot be expressed in its entirety and is no longer functional (eg, the CFTR protein in nmCF. the Factor VIII/Factor IX protein in nmHA/B or the dystrophin protein in nmDBMD ).

Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal.

Ataluren, taken orally, has the potential to address the underlying cause of the disease by overriding the premature stop signal, enabling the synthesis of a functioning protein. Ataluren does not alter the patient’s genetic code or introduce genetic materials into the body.

Nonsense Mutation Genetic Disorders
The National Institutes of Health (NIH) Office of Rare Diseases estimated that rare diseases affect 25 million people in the US and that the majority of these people have genetic disorders. In more than 2,400 genetic disorders, a nonsense mutation causes the disease in an average of 5 to 15% of the patients. Besides nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD), nonsense mutation cystic fibrosis (nmCF), nonsense mutation hemophilia A & B (nmHA/B) and nonsense mutation methylmalonic acidemia (nmMMA), these genetic disorders include a range of serious diseases across multiple therapeutic areas including, spinal muscular atrophy, lysosomal storage disorders, and some forms of cancer.

PTC124 Targets Genetic Disorders Caused by Nonsense Mutations

(Click the link above to read the article)

Genetic Testing
Ataluren has the potential to treat any genetic disorder caused by a nonsense mutation. Although current clinical trials involve only nonsense mutation CF and nonsense mutation HA/B, future trials are anticipated in other genetic disorders caused by a nonsense mutation. To determine whether a genetic disorder is caused by a nonsense mutation, patients require genetic testing. Genetic testing is done by a simple blood test that is ordered by a physician working in concert with a genetic lab.

Laboratories performing genetic testing vary by disorder and location. The NIH-funded website, www.genetest.org provides a listing of laboratories and contact information.

Ongoing Clinical Trials

* nmCF: PTC has initiated a longer-term, Phase 3 clinical study of ataluren in patients with nonsense mutation CF. The main goals of this study are to understand whether ataluren can improve how nmCF patients feel and function and whether the drug can safely be given over a long period. The trial is a multi-center, randomized, double-blind, placebo-controlled study.
* nmHA/B: PTC has initiated a Phase 2a clinical trial of ataluren in patients with nonsense mutation hemophilia type A and B (nmHA and nmHB). The trial is a multi-center, open label, dose escalation study. The main goals of the trial are to determine whether treatment with ataluren can result in an increase in Factor VIII or IX levels and whether the drug can safely be given to people with severe hemophilia due to a nonsense mutation.
* nmMMA: PTC has initiated a Phase 2 clinical trial of ataluren in patients with nonsense mutation methylmalonic acidemia (nmMMA). The trial is a non-randomized, open-label trial. Its main goals are to understand whether ataluren can be tolerated and can decrease MMacid levels.

Completed Clinical Trials

*

Phase 2b Data nonsense mutation DBMD (nmDBMD): Final analyses of Phase 2b efficacy data suggest the investigational new drug ataluren slowed the loss of walking ability in patients. The primary endpoint of the Phase 2b trial was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter (approximately 97 feet) difference in the average change in 6MWD when comparing the ataluren (10-, 10-, 20-mg/kg) and placebo arms. This result is consistent with the study hypothesis of a 30-meter difference and the average change in 6MWD observed in registration-directed trials of approved drugs for other diseases.

* Phase 2a Data nonsense mutation DBMD (nmDBMD): Data from Phase 2a clinical trials of ataluren in pediatric patients with nmDBMD show that administration of ataluren is associated with production of functional dystrophin. Ataluren treatment has also been associated with statistically significant reductions in the leakage of muscle-derived creatine kinase into the blood.
* Phase 2a Data nonsense mutation CF (nmCF): Data from Phase 2a clinical trials of ataluren in pediatric and adult patients with nmCF show that administration of ataluren results in production of functional CFTR and statistically significant improvements in CFTR chloride channel function in the airways. Ataluren treatment was associated with reductions in cough frequency and improvements in pulmonary function tests.
* Adverse Events and Safety Profile: Across all clinical studies to date, including Phase 1 healthy-volunteer studies, ataluren has been generally well tolerated. Mean compliance has been >90% in all studies.

Grants
The development of ataluren has also been supported by grants from:

* Cystic Fibrosis Foundation
* Parent Project Muscular Dystrophy
* Muscular Dystrophy Association
* FDA’s Office of Orphan Products Development
*
National Center for Research Resources
* National Heart, Lung, and Blood Institute

The FDA has granted PTC124® (ataluren) Subpart E designation for expedited development, evaluation, and marketing and has granted Orphan Drug designations for the treatment of CF and DBMD due to nonsense mutations. PTC124® (ataluren) has also been granted orphan drug status for the treatment of CF and DBMD by the European Commission.

Partnership with Genzyme
PTC Therapeutics, Inc. and Genzyme Corporation have an exclusive collaboration to develop and commercialize ataluren. PTC will commercialize ataluren in the United States and Canada and Genzyme will commercialize ataluren in all other countries.

To receive status updates on ataluren, please visit the Contact Us page of the website and join our mailing list.

Patients, families and advocacy groups may also contact Ms. Diane Goetz, Director, Patient and Professional Relations, 866-282-5873 or 908-912-9256 or patientinfo@ptcbio.com.

Source: PTC Therapeutics

Note: Click the title to read more about PTC therapeutics and its developments.

RETT SYNDROME IN A PETRI DISH: Rett Syndrome Research trust Interview series

2010-11-16T00:00:00.001+05:30

On November 11th the high-profile journal Cell published a paper by Alysson Muotri, Ph.D. entitled A Model for Neural Development and Treatment of Rett Syndrome Using Human Induced Pluripotent Stem Cells. The stem cell field has seen amazing progress in the last few years. Induced Pluripotent Stem Cells (iPS cells) is an especially hot area because of the clinical implications. Simply put, iPS cells allow you to study diseased cells up close and personal through their entire lifecycle. Importantly, any deficits that are identified in the cells can be used as read-outs in drug screening endeavors.

Interviewed by Monica Coenraads
(Co-Founder, Trustee, Executive Director of RSRT)

I’ve had the pleasure of knowing Dr. Muotri for a number of years, in fact since his introduction to Rett about six years ago. He became interested in the disorder while doing his post-doc in the lab of Fred (Rusty) Gage at the Salk Institute in La Jolla, CA. Thankfully his interest has continued now that he is an independent investigator at UCSD.

Below is an excerpt from a conversation Dr. Muotri and Monica Coenraads had regarding his paper.

MC Dr. Muotri, congratulations on your Cell paper which has strong implications for drug development and therefore is of interest to anyone who loves a child with Rett Syndrome. I know this is a very hectic time so thank you for taking time out to speak with me.

I’m curious, what drew you to a science career?

AM I’ve always been interested in understanding how things work. I reasoned that science was the most obvious way to achieve that. You know that I’m from Brazil. I received my PhD in genetics from the University of São Paulo. I started off in the cancer biology field but quickly switched to neuroscience in 2002 when I moved to the Salk Institute. I was there for 6 years until I got my current position here at UCSD two years ago.

MC I’m assuming it was a significant switch moving into neuroscience from cancer biology.

AM Yes, it was a bit intimidating in the beginning because there was so much to learn. But I welcomed the challenge. And as it turned out my experiences from cancer were beneficial for my transition into neuroscience. For example, when I moved to Rusty’s lab one of the first observations we made was related to a phenomenon called transposons. I knew from my previous work that retrotransposons are very active in cancer cells and I remember discussing this with my neuroscience colleagues. Most of them were not very familiar with this phenomenon and assumed it was insignificant. My feeling was that if these transpositions were really happening in the brain it would be better to look at it closely because it could be involved in a new mechanism related to brain development.

MC Since retrotransposons are actually the topic of your next Rett paper coming out in Nature soon let me take a moment to give our readers a little background information.

Retrotransposons are sequences of DNA that move around and insert themselves into new positions within the genome. Barbara McClintock received the Nobel Prize in 1983 for her discovery of this phenomenon. Historically retrotransposons have been considered “junk DNA” because they occupy around 50% of the mammalian genome and do not have a clear function in the cell. It’s probably more likely that transposons have a biological function which remains, for the moment, unknown to us. Retrotransposons have been linked to disease.

Dr. Muotri, would you like to give us a glimpse into your upcoming paper that deals with retrotransposons in Rett Syndrome?

AM So the idea is that retrotransposons , which jump around inserting themselves into the genome, result in neurons, in the same individual, which are genetically different from each other. We observed that MECP2, the gene involved in Rett Syndrome, is a major repressor of this activity. Also, we determined that these jumping events are pretty much exclusive to the brain and MECP2 seems to be one of the gate keepers controlling the amount of the activity.

MC So in a brain that is deficient in the MeCP2 protein there would be increased jumping events?

AM That is right. It remains to be seen whether these extra events contribute to the symptoms of Rett or whether the brain simply compensates and manages to work around them. We are working on this question now.

MC Fascinating. I look forward to continuing our dialogue on this subject as your research progresses. Two high profile papers in one month – very impressive.

Now, getting back to iPS. This is a field that has seen amazing advances in a short period of time. Can you highlight for our readers the excitement surrounding these cells?

AM The dream of neuroscientists is to understand the early stages of a neurological disorder. Until recently we had two options to achieve this. One is to develop a mouse model that will hopefully recapitulate the symptoms seen in humans. Of course a limitation of a mouse model is that it’s a mouse and not a human – the brain of a human is so much more complex. The other option is post-mortem brain tissue. The problem is that at that stage the damage is already done and what you see is the end stage of a disease. To really study a disease it’s beneficial to have the most primitive cell line possible and then to coax these cells into a variety of different cell populations and to study what happens at various time points.

An important breakthrough happened a few years ago that has made this type of work very feasible. The Japanese group headed by Shinya Yamanaka surprised the world when they showed that you can reprogram cells that have already differentiated back to a more naïve state resembling a human embryonic stem cell. This allows us to capture the genome of a person, including any genetic mutations, and allows us to study the neurons and other cells of interest and see how a disease progresses and what changes happen at the molecular level.

MC In general the Rett field has relied on the mouse models as their standard assay. In terms of drug screening that’s a very expensive assay. Having iPS lines with MECP2 mutations gives scientists the ability to have a cellular assay to screen for therapeutics. Thousands, and in fact, hundreds of thousands of compounds can be efficiently and quickly screened in cell lines using either low or high throughput technologies.

Can you tell us about the phenotypes that you have identified in the cells. (a phenotype is an observable characteristic or trait)

AM One of the phenotypes was related to cell soma size (cell body) of a neuron. Just looking at neurons under the microscope we saw that Rett neurons are reduced in size by 10%. That might not seem like a big deal but when you consider the 3 dimensional structure of the neuron; a 10% reduction is very significant. So size was the simplest read-out that we found.

Another phenotype is related to the morphology of neurons. (Morphology is the study of the structure and form of an organism.) The idea to look at morphology was inspired by the reports over the last decade from post-mortem brain tissue in both people and animal models. We focused on the number of spine densities in neurons and we also saw a reduction. (A dendritic spine, or simply spine, is a small membranous protrusion from a neuron’s dendrite that typically receives input from a synapse.) We looked at neuronal networks and found deficiencies in their ability to communicate.

MC You made iPS cells with different MECP2 mutations. You found that the phenotypes were consistent among mutations. Can you elaborate?

AM Yes, the four different mutations we studied led to similar phenotypes. At least the phenotypes we looked at. We were convinced that this was a strong suggestion pointing to a loss of MeCP2 function. Thus, we knocked down MeCP2 expression from control neurons and obtained the same result. We then, restored the normal MeCP2 gene in Rett neurons, suppressing the phenotypes. In combination, these experiments suggest that MeCP2 is responsible for the alterations in Rett neurons. The fact that several MeCP2 mutants revealed a similar phenotype has clinical relevancy because it may indicate that a single drug may correct them all.

MC So the goal is to use these cells as a platform for drug screening.

AM Absolutely. As a proof of principle we added a growth factor, IGF1, to the cells. As you know a paper was published in PNAS in early 2009 showing that a compound similar to IGF1 improved some of the symptoms in mice so we decided to try it in our system. We found that IGF1 corrected the phenotype, in fact it over-corrected. The over-correction is something that needs to be considered in terms of the clinical trial, a proper dose tuning in each patient is desirable. Also, something to keep in mind is that while I put IGF1 directly into the cells in the clinical trial the IGF1 has to get into the brain and we know that that doesn’t happen as much as we would like.

The other drug we tried is gentamicin , an antibiotic that has the ability to “read through” premature stop codons (nonsense mutations that end in X, such as 255X, 168X) . We found that gentamicin restored levels of the MeCP2 and phenotypically rescued the cells.

MC That is pretty interesting especially in light of the fact that read through drugs act by substituting the stop codon with a random amino acid. So in effect they swap out one mutation for another.

AM We checked that and found that the protein level was normal but there was no way for us to see what mutation was inserted. Part of the new protein that is synthesized in the presence of gentamicin, is probably correct and we believe that is exactly what is reverting the phenotypes.

MC It’s important to note that gentamicin is highly toxic and doesn’t cross the blood brain barrier very well either so this is not a drug that can be used now for the treatment of Rett Syndrome. There are however other drugs with similar modes of action that being tested in animal models.

But the take home message from your data is that iPS cell lines are an in vitro model system for Rett Syndrome and can be utilized in a drug screening platform. What are next steps to utilize the iPS lines as a platform for drug screening?

AM The next step is to scale this up and that is not easy to do. Because the experiments are very sensitive to variables and there are many steps during the conversion of the iPS cells to neurons. Thus, we need to systematically validate all the variables and make the system as robust as possible. Finally, we need to choose the appropriate read-outs (the cellular phenotypes) we would like to use. It is important to design these experiments carefully so one doesn’t lose time with false positives. My lab was recently awarded a CIRM grant (California Institute for Regenerative Medicine) exactly to optimize these steps, so I would like to start this as soon as possible. Finally, I would like to test libraries of drugs that previously failed clinical trials for other diseases. Drug repositioning, as this concept is called, is attractive because repurposed drugs can bypass much of the early cost and time needed to bring a drug to market.

MC I found your paper very encouraging for a number of reasons. Firstly, your data continues to confirm and validate the concept that Rett is reversible. Secondly, you showed that the iPS platform can be used for drug screening. Thirdly, your data suggests that while there may be many mutations in MECP2, they may share common phenotypes. That may be an important issue in terms of treatment strategies.

Dr. Muotri, I’m sure I speak for every Rett family who reads this interview … we wish you great luck and god speed in your work.

Source: Rett Syndrome Research Trust (RSRT)

Note: Click on the title the full interview and video

Women of the year 2010: Julia Roberts

2010-11-15T23:48:00.000+05:30

Julia Roberts: The Class Act

She is a Woman of the Year because: “There are not a lot of people who can do everything she does, and be brilliant, and be gorgeous, and raise all those children. Formidable, my dear. Bravo.”
—Joanne Woodward, actress

November 1, 2010
by Susan Dominus

You have to admire that Julia Roberts arrives at an interview in the kind of standard-issue black pants that mothers rely on when they want to look presentable. Wearing the barest hint of makeup, she’s soon chatting about the challenge of running a house with three kids—six-year-old twins Hazel and Phinnaeus, and three-year-old Henry. “Trust me,” she confides, “some weeks are cleaner than other weeks.”

Not that she’s had much time lately to worry about the housecleaning. Her 2010 has been huge. She’s graced countless magazine covers and TV shows on behalf of her blockbuster Eat, Pray, Love; she produced a documentary on the power of motherhood that will air on Oprah’s OWN network in January; and she filmed her next sure-to-be hit, Larry Crowne, with pal Tom Hanks.

Despite her successes, though, Roberts says, “It’s all about the home.” Turns out one of the world’s biggest female movie stars (collective box office: more than $2 billion) is an eco-sensitive earth mother who composts and drives a tractor at her New Mexico ranch. At 43, the Oscar winner chooses roles that allow her to spend quality time with her family—proof, as she’s said, that “becoming famous doesn’t make you crazy.” Once called the Hillary of Hollywood for her trailblazing—she was the first actress to get more than $20 million for a film—Roberts has used that money and clout for good. Since 1997 she’s supported Paul Newman’s Hole in the Wall Gang camp for children with grave illnesses. She also campaigns to fund research for Rett Syndrome (a neurodevelopmental disorder that can destroy kids’ ability to walk and speak) and serves on the board of Earth Biofuels, which promotes renewable energy.

But it’s Roberts’ unique, lit-from-within quality that’s made her everyone’s favorite screen icon. In the words of Eat, Pray, Love author Elizabeth Gilbert, “The only other job she could have would be professional fairy.” Well, she did once play Tinkerbell.

Source: Glamour

Inhibitory neurons key to understanding neuropsychiatric disorders

2010-11-15T23:42:00.000+05:30

HOUSTON -- (Nov. 11, 2010) – The brain works because 100 billion of its special nerve cells called neurons regulate trillions of connections that carry and process information. The behavior of each neuron is precisely determined by the proper function of many genes.

In 1999, Baylor College of Medicine (www.bcm.edu) researcher Dr. Huda Zoghbi (http://www.bcm.edu/genetics/index.cfm?pmid=11053), and her colleagues identified mutations in one of these genes called MECP2 as the culprit in a devastating neurological disorder called Rett syndrome (http://www.nichd.nih.gov/health/topics/rett_syndrome.cfm). In new research in mice published in the current issue of the journal Nature (www.nature.com), Zoghbi and her colleagues demonstrate that the loss of the protein MeCP2 in a special group of inhibitory nerve cells in the brain reproduces nearly all Rett syndrome features.

Children, mostly girls, born with Rett syndrome, appear normal at first, but stop or slow intellectual and motor development between three months and three years of age, losing speech, developing learning and gait problems. Some of their symptoms resemble those of autism.

These inhibitory (gamma-amino-butyric-acid [GABA]-ergic) neurons make up only 15 to 20 percent of the total number of neurons in the brain. Loss of MeCP2 causes a 30 to 40 percent reduction in the amount of GABA, the specific signaling chemical made by these neurons. This loss impairs how these neurons communicate with other neurons in the brain. These inhibitory neurons keep the brakes on the communication system, enabling proper transfer of information.

"In effect, the lack of MeCP2 impairs the GABAergic neurons that are key regulators governing the transfer of information in the brain", said Dr. Hsiao-Tuan Chao (http://www.bcm.edu/labs/zoghbi/Lab_members_info/chao.html), an M.D./Ph.D student in Zoghbi's laboratory and first author of the report.

Chao made the discovery by developing a powerful new tool or mouse model that allowed researchers to remove MeCP2 from only the GABAergic neurons.

"We did this study thinking that perhaps all we would see was a few symptoms of Rett syndrome," said Chao. "Strikingly, we saw that removing MeCP2 solely from GABAergic neurons reproduced almost all the features of Rett syndrome, including cognitive deficits, breathing difficulties, compulsive behavior, and repetitive stereotyped movements. The study tells us that MeCP2 is a key protein for the function of these neurons."

Once the authors determined that the key problem rested with the GABAergic neurons, they sought to find out how the lack of MeCP2 disturbed the function of these neurons. Chao discovered that losing MeCP2 caused the GABAergic neurons to release less of the neurotransmitter, GABA. This occurs because losing MeCP2 reduces the amount of the enzymes required for the production of GABA.

Intriguingly, prior studies showed that expression of these enzymes is also reduced in some patients with autism, schizophrenia and bipolar disorder, said Chao.

"This tells us a lot about what is going on in the brains of people with Rett syndrome, autism or even schizophrenia," said Chao. "A child is born healthy. She starts to grow and then begins to lose developmental milestones. Communication between neurons is impaired, in part due to reduced signals from GABAergic neurons."

"This study taught us that an alteration in the signal from GABAergic neurons is sufficient to produce features of autism and other neuropsychiatric disorders," said Zoghbi, a Howard Hughes Medical Institute investigator and director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

###

Others who took part in this work include Hongmei Chen, Rodney C. Samaco, Mingshan Xue, Maria Chahrour, Jong Yoo, Jeffrey L. Neul, Hui-Chen Lu, Jeffrey L. Noebels and Christian Rosenmund, all of BCM, John L.R. Rubenstein of University of Calfornia in San Francisco, Marc Ekker of University of Ottawa in Ontario, and Shiaoching Gong and Nathaniel Heintz of The Rockefeller University in New York.

Funding for this work came from the Howard Hughes Medical Institute, the National Institute of Neurological Disorders and Stroke, the Simons Foundation, the Rett Syndrome Research Trust, the Intellectual and Developmental Disability Research Centers, the International Rett Syndrome Foundation, Autism Speaks, the National Institute of Mental Health, Baylor Research Advocates for Student Scientists and McNair Fellowships.

When the embargo lifts, this report will be available at www.nature.com.

For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/news.

Source: EurekaAlert

Website of Indian Rett Syndrome Foundation

2010-11-11T15:42:00.004+05:30

The Website of Indian Rett syndrome Foundation was launched by Major General Ian Cardozo, Chairman of Rehabilitation Council of India and Mrs. Poonam Natrajan, Chairperson, National Trust of India in the 3rd Annual Rett Syndrome Awareness meeting, which was organized by Indian Rett Syndrome foundation and was hosted by Department of Pediatrics, AIIMS, New Delhi on 31st October, 2010.

Please click on the link or copy and paste the following link to visit the website of "Indian Rett Syndrome Foundation". You can also click on the title above to visit the site.

http://www.rettsyndrome.in/

Indian Rett Syndrome Foundation

Life threatening breathing disorder of Rett syndrome prevented

2010-10-06T00:59:00.001+05:30

October 2010

A group of researchers at the University of Bristol have sequestered the potentially fatal breath holding episodes associated with the autistic-spectrum disorder Rett syndrome.
Rett syndrome is a developmental disorder of the brain that affects around 1 in10,000 young girls. One of the worse clinical disorders is the intermittent episodes of breath holding, putting the patient at risk of asphyxiation and further brain damage. Other disorders include repetitive hand movements, digestive and bowel problems, seizures, learning disability with lack of verbal skills and social withdrawal, making it a thoroughly debilitating disease.

However, an international team of researchers based at Bristol’s School of Physiology & Pharmacology have discovered a way to prevent these episodes of breath holding in a mouse model of Rett syndrome. Using a unique combination of drugs, they have discovered that the area of the brain that allows breathing to persist throughout life without interruption has reduced levels of a transmitter substance called aminobutyric acid.

Professor Julian Paton, who co-led the research, said: “These findings make a significant step in our understanding of the reasons why breathing is intermittent in Rett syndrome and give exciting hope for the future for alleviating young girls from these awful life threatening episodes of breath holding, which they experience regularly throughout the day.”

This autistic condition is caused by a spontaneous mutation in the gene that encodes for methyl-CpG-binding protein 2 or MeCP2. MeCP2 is very abundant in the brain and is a transcription factor that decodes DNA essential for making proteins in brain cells.

The researchers found that by increasing both the amount of aminobutyric acid (a vital brain signalling substance) and stimulating a specific type of serotonin receptor within the brain to suppress the activity of brain cells that normally depress inhalation, this abolished the life threatening episodes of breathing arrests.

“These exciting findings are particularly relevant since the drugs we used already have approval for use in humans to treat other illnesses, so the hope is that our findings can soon be translated across to sufferers of Rett Syndrome, and possibly other breathing disorders” said Professor John Bissonnette from the Oregon Health and Science University in Portland who co-led the study.

The findings of the study, which was funded by the International Rett Syndrome Foundation and the National Institutes of Health, are revealed in a paper published by the journal – Proceedings in the National Academy of Science (PNAS).

Note: Click on the title to read the original News

Source: Bristol University News

Third Annual Rett syndrome Awareness Meeting

2010-10-03T01:47:00.000+05:30

The month of October is celebrated as "Rett syndrome Awareness Month" all around the world. We are going to organize our third Annual Rett Awareness Meet.

Date and Time
Sunday, October 31 · 10:00am - 5:00pm

Location
Teaching Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, INDIA

Come and Join us to Raise More Awareness about Rett syndrome, a neurodevelopmental disorder. which primarily affects girls.

If you have any queries, please contact us at

E-mail: info.rett@yahoo.com

Regards,

Indian Rett Syndrome Foundation & Genetics Unit, Dept. of Pediatrics, AIIMS

New Delhi, INDIA

Weblink: www.rettsyndromeindia.blogspot.com

In their Nurture: Interesting article on role of epigenetics and mother's love

2010-09-15T14:05:00.000+05:30

Click on the title to read the full article

Source: Nature news

From eugenic euthanasia to habilitation of "disabled'' children- Andreas Rett's contribution

2010-09-13T18:52:00.001+05:30

By Ronen GM and colleagues

Note: Click on the title to read and download the full article

Source: Google Docs

Genome-wide, yet narrow

2010-09-13T18:49:00.000+05:30

By Petrus J de Vries

Note: Click on the title to read and download the full article

Source: Google Docs

Endocrinological study on growth retardation in Rett syndrome

2010-09-13T18:46:00.000+05:30

Interesting Article by

Dr. Huppke and Colleagues

Source: Google Docs

Can Children with Autism Recover? If So, How?

2010-09-13T18:44:00.000+05:30

Interesting article by

Molly Helt and colleagues

Source: Google Docs

Sudden Death and Cardiac Arrhythmias in Rett Syndrome

2010-09-13T18:42:00.000+05:30

Source: Google Docs

X Chromosome Inactivation and Autoimmunity

2010-09-13T18:41:00.000+05:30

Interesting article by Dr. Brooks

Source: Google docs

Diagnostic Criteria for Zappella variant of Rett syndrome (the preserved speech variant)

2010-09-13T18:38:00.000+05:30

Interesting Article by

Dr. Renieri and colleagues

Souce: Google Docs

Insulin-Like Growth Factor-I Stimulates Histone H3 and H4 Acetylation in the Brain in Vivo

2010-09-13T18:36:00.000+05:30

Source: Google docs

Genetics and neuropsychiatric disorders: Treatment during adulthood

2010-09-13T18:29:00.000+05:30

A very Interesting article by

Dan Ehninger & Alcino J Silva

Source: Google Docs

BDNF Gene Val66met Polymorphism Associated Grey Matter Changes in Human Brain

2010-09-13T18:27:00.000+05:30

Very Interesting Article by

Eker et al

Source: Google Docs

Rett Syndrome Documentry Promo Video

2010-09-07T01:06:00.000+05:30

The story behind Rett Syndrome is complicated. It involves a devastating genetic affliction that starts with young girls and includes incredible family dynamics, groundbreaking treatment, care and science. The film will focus on Rett families and the optimism surrounding treatments and forward thinking scientific breakthroughs.

Source: REM Entertainment Channel

Please Vote to Turn Research into Reality for Girls with Rett Syndrome: Last week of Voting

2010-08-23T22:25:00.000+05:30

MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212

2010-08-16T13:42:00.000+05:30

Very recent and interesting article by team of "The Scripps Research Institute–Scripps Florida"

Authors:
Heh-In Im, Jonathan A Hollander, Purva Bali & Paul J Kenny

Source: Nature Neuroscience

Note: Click on the title to read full article

MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants

2010-08-16T13:39:00.000+05:30

Very interesting study by Deng et al., 2010

Source: Nature neuroscience

Note: click on the title to read full article

MECP2 Duplication syndrome

2010-08-13T03:10:00.000+05:30

Source: www.mecp2duplication.com

Cocaine Addiction Linked to Protein That Causes Rett Syndrome

2010-08-13T02:57:00.000+05:30

Drug Discovery & Development - August 11, 2010

Scientists from the Florida campus of The Scripps Research Institute have identified a protein that may act as the trigger controlling the addictive impact of cocaine in the brain. The findings may one day lead to new therapies to treat addiction.

The study was published on August 15, 2010, in the journal Nature Neuroscience.

The results from the new study strongly suggest that a protein known as methyl CpG binding protein 2 (MeCP2) interacts with a type of genetic material known as microRNA to control an individual’s motivation to consume cocaine.

“The study shows that MeCP2 blunts the amount by which microRNA-212 is increased in response to cocaine,” said Paul Kenny, an associate professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. “We have previously shown that miR-212 is very protective against cocaine addiction. Therefore, the conclusion is that MeCP2 may regulate vulnerability to addiction in some people through its inhibitory influence on miR-212. Without this influence, the expression of miiR-212 would be far greater in response to cocaine use, and the risk of addiction would likely be far lower.”

This is the first time that MeCP2 has been shown to play a role in regulating cocaine addiction. Previously, the protein was most linked to Rett syndrome, a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females.

Interactions Shape Vulnerability
These new findings come on the heels of another cocaine addiction study by Kenny and his Scripps Florida colleagues published in the journal Nature in early July. That study showed for the first time that miR-212 — a type of small non-protein coding RNA that can regulate the expression levels of hundreds or even thousands of genes —influenced response to the drug in rats. Animals with increased miR-212 expression were less motivated to consume cocaine, pointing to the protective effects of miR-212 against cocaine addiction.

“The new findings are a significant advance from this previous study,” Kenny said, “because they clearly demonstrate why microRNA-212 is not always fully protective – because MeCP2 regulates by how much miR-212 levels will increase in response to cocaine. This suggests that our initial findings may be central to explaining the complex process of addiction, and understanding how miR-212 signaling is regulated will be important. This study adds another level of detail to the blueprint.”

A major goal of drug abuse research is to understand why certain individuals make the switch from casual to compulsive drug use and develop into addicts. Periods of easy access to the drug, along with repeated overconsumption, can quickly trigger the emergence of addiction-like abnormalities in animal models.

In the new study, the scientists first looked at the expression of MeCP2 in the brain after exposure to cocaine. They found that expression was increased in those animals given extended access to the drug.

“At that point,” Kenny said, “we wanted to know if this increase was behaviorally significant – did it influence the motivation to take the drug?"

Using a virus to disrupt expression of MeCP2, the scientists found that rats consumed less and less cocaine. Intriguingly, levels of miR-212 were also far higher in those animals. Because increases in miR-212 suppress attraction to cocaine, the disruption of MeCP2, in essence, put miR-212 in charge and reduced vulnerability to the drug.

“We concluded that MeCP2 may play an important role in addiction by regulating the magnitude by which miR-212 expression is increased in response to cocaine," said Kenny. "In other words, MeCP2 seems to control just how much you can protect yourself against the addictive properties of cocaine."

Intriguingly, that was not the end of the story. In addition to MeCP2 blunting miR-212 expression, the scientists also found that the opposite was also true – that miR-212 could in turn decrease levels of MeCP2. This suggests that both are locked together in a regulatory loop. Importantly, the two had opposite effects on the expression of a particular growth factor in the brain – called BDNF – that regulates just how rewarding cocaine is.

While the new study fills in an important piece of the puzzle, the Kenny lab is hard at work to further increase our understanding of addiction.

“We still don’t know what exactly influences the activity levels of MeCP2 on miR-212 expression,” Kenny said. “Now we plan to explore what drives it – whether it’s environmentally driven, and if genetic and epigenetic influences are important.”

Source: The Scripps Research Institute

Yet Another Door Opens: Neuroimmunology: Rett Syndrome Research Trust Interview Series

2010-08-11T23:13:00.000+05:30

Considering Microglia, T Cells and Bone Marrow Transplants in Rett Syndrome

Today we interview Jonathan Kipnis, PhD, a neuroimmunologist who is looking at how the immune system interacts with the nervous system in Rett Syndrome, and is experimenting with ways to engage that interaction to impact Rett symptoms. The immune system is complex and multifaceted, with inflammatory and anti-inflammatory actions and modulatory influences on various other substances, including neurotrophic factors such as BDNF, familiar to parents who follow Rett research. RSRT is supporting his innovative exploration of bone marrow transplants in Rett models.
..........

To read full Interview, please click on the title

Source: Rett Syndrome Research Trust

Wimbledon finalist Vera Zvonareva has embraced fight vs. Rett Syndrome

2010-08-11T23:07:00.000+05:30

Father’s mission to find a cure for his girl

2010-08-03T23:09:00.000+05:30

A DAD has helped set up a charity for his disabled daughter, who suffers from a rare genetic condition.

Andy Stevenson, aged 41, of Pinewood Road, Burtonwood, registered the Rett Syndrome Research Trust (RSRT) UK for 10-year-old Beth, who suffers from the neurological disease, which causes severe physical and learning difficulties.

‘A cure for Rett syndrome is possible in the near future. I am keen to do all I can to help that happen ...'
Andy Stevenson

Rett syndrome, which has no cure, is an autism spectrum disorder that can develop in otherwise healthy young girls, just as they are beginning to speak and walk, robbing them of these emerging skills.

Beth needs 24-hour care, spends most of her time in a wheelchair, is unable to speak and suffers from epilepsy.

Andy, a golf pro at Mersey Valley Golf and Country Club who is married to Lisa, aged 42, said: “All the trustees are very excited that we are up and running. A cure for Rett syndrome is possible in the near future.

“I am keen to do all I can to help that happen for Beth and future generations.”

Andy founded the charity with five other families affected by Rett syndrome and he hopes their efforts will lead to improved treatments to ensure it becomes the first ever reversible brain disorder.

To help achieve this RSRT UK will work closely with a US partner of the same name.

The organisation’s first event, a gala reception, is planned for November 18, and will be held in London with guest of honour Professor Adrian Bird of the University of Edinburgh, who is a scientific advisor to the trust.

Rachael Bloom, chairman of the board of trustees who has a 14-year-old daughter who suffers with the disorder, said: “RSRT UK formed when a group of families came together with the belief that parents must take an active role in the fight against Rett syndrome.

“We want to see this research driven to its conclusion, replicating the results of the reversal experiments not in mice, but in girls and women living with Rett syndrome today.”

When Beth was diagnosed in 2002, Andy’s fundraising challange saw him take part in the Leeds and Loch Ness marathons. He also completed a gruelling assault course called Tough Guy, which took place in Wolverhampton in January and involved running through fire and crawling under barbed wire.

For more information visit reverserett.org.uk

Source:# This Is Cheshire » News

New Epigenetic Player Implicated in Mental Retardation and Facial Birth Defects

2010-07-29T02:05:00.000+05:30

The study, published online July 11 in the journal Nature, reveals that this enzyme is a histone demethylase and works with a key genetic partner to help keep neuronal cells alive during development of the embryonic brain. Patients with this form of mental retardation are known to have mutations in the gene that encodes the active part of this enzyme. The findings may help scientists further understand the underlying biological reasons why X-linked disorders cause cognitive impairment and develop new therapies to treat or prevent them.

"Human genetics has made great strides in identifying genes as potential causes of diseases and disorders, but we don't know much about how they work," says senior author Yang Shi, PhD, the Merton Bernfield Professor of Neonatology in the Newborn Medicine division at Children's. "We knew this was a biologically relevant gene. We wanted to understand the etiology, so we asked why the gene causes problems when it is mutated. Here, we have identified a direct target in neuronal and craniofacial development."

The fast-moving young field known as epigenetics is revealing the dynamic structures and processes that organize, index and control access to the information stored in the DNA code. The epigenetic program orchestrates different combinations of gene activity -- allowing cells with identical genomes to be transformed into more than 200 different specialized tissues and organs in our bodies.

When most people think of DNA, they picture the iconic spiraling ladder of naked DNA. But in nature, the twisting double-helix strands actually spool around clusters of proteins called histones with protruding "tails" that act like specialized antennas, transmitting directions for DNA. This dynamic structure, called chromatin, extends the genetic code by offering, measuring or limiting access to different genes.

Several years ago, Shi and his colleagues identified the first enzyme that can detach a molecule known as a methyl group, previously thought to be a permanent fixture, from the histones tails. Then his team and a number of other research groups independently discovered members of a second known family of these enzymes, known collectively as histone demethylases.

The latest study began with a gene mutated in several male patients with X-linked mental retardation and craniofacial abnormalities. The gene codes for an enzyme that looked a lot like a member of the second family of histone demethylases. The mutations in these patients abolished the working part of the enzyme that plucks the methyl group from the histone tail.

Led by Hank Qi, PhD, co-first author and postdoctoral fellow, the researchers demonstrated in human cells that the enzyme, PHF8, indeed works as a histone demethylase. (And it is the first known demethylase discovered for a strategic methylation point on the tail of histone 4 known as H4K20, which other evidence suggests plays a critical role in gene expression and regulation and in the DNA damage response.) In this case, by removing the methyl group, the enzyme appears to maintain active gene transcription.

"The histone methylation and demethylation doesn't turn the gene on or off," Qi says. "When this histone mark changes, it generates an equilibrium important for fine-tuning gene expression."

Despite its widespread presence, the enzyme seems to have a narrowly targeted biological effect on a master genetic regulator of craniofacial development, the transcription factor MSX1. Taking a cue from the scientific literature, Qi and his collaborators, Madathia Sarkissian and Thomas Roberts at Dana-Farber Cancer Institute, tested the normal enzyme function in zebrafish, a popular model for genetic function.

It is hard to judge cognitive impairment in a small fish, but the dramatic impact on craniofacial development was obvious. Fish without the enzyme developed virtually no jawbone, a condition that could be prevented by providing the functioning enzyme, showing its importance in development. As importantly, providing more of the fish version of the MSX1 gene (whose activity the demethylase enzyme encourages) also partially prevented the biological defects caused by the missing enzyme.

Hope for the reversibility of some aspects of mental retardation arose three years ago in a Scottish mouse study of Rett syndrome, a disorder on the autism spectrum that is also a cause of severe mental retardation in girls. The disease is caused by a molecule, MeCP2, that binds to methylated DNA and may be involved in another form of epigenetic regulation.

"In practical terms, we use gene expression as a read out," says Shi, also a professor of pathology at Harvard Medical School. "Epigenetic states affect the expression of critical genes. These studies suggest that the imbalance of histone methylation dynamics plays a critical role in mental retardation. You can imagine a therapeutic approach to enhance the compromised enzymatic activity or to restore the downstream function."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Children's Hospital Boston.

Journal Reference:

1. Hank H. Qi, Madathia Sarkissian, Gang-Qing Hu, Zhibin Wang, Arindam Bhattacharjee, D. Benjamin Gordon, Michelle Gonzales, Fei Lan, Pat P. Ongusaha, Maite Huarte, Nasser K. Yaghi, Huijun Lim, Benjamin A. Garcia, Leonardo Brizuela, Keji Zhao, Thomas M. Roberts & Yang Shi. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature, 2010; DOI: 10.1038/nature09261

source: ScienceDaily

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

2010-07-27T20:45:00.000+05:30

A very recent and interesting article by Dr. Bredford Kerr and his Team.

Source: Pubmed Central

Clinical Trials on Rett Syndrome

2010-07-27T18:51:00.000+05:30

Note: Click on the title to see the page

Source: Clinicaltrials.gov

Vote to 'refresh' research on Rett Syndrome

2010-07-23T01:00:00.000+05:30

Although Rett Syndrome is one of thousands of genetic disorders, it is one of four that was able to be reversed in a lab. In 2007, researchers found a way to reverse it in lab mice, giving hope to many, such as the Nues family of Danville, whose daughter Katie was diagnosed in 2003. Yet, without funding, research to safely replicate it in humans needs more research. This is why Paige Nues is hoping to win a $250,000 grant through the Pepsi Refresh Everything project.

Rett Syndrome is a developmental disorder that affects mostly girls and is realized in infancy. While born normal, symptoms begin to appear anywhere from six months to two years after birth. Eventually, the girls lose the ability to walk, speak and use their hands. Other symptoms include seizures; digestive, heart, breathing and circulation problems; and sometimes scoliosis.

According to Paige Nues, Katie is one of three girls in Danville with the disorder, as well as one of dozens in the Bay Area and one of 400 in California.

A diagnosis will likely mean a lifetime of therapies and while these girls usually live into late adulthood, they aren't capable of independent living.

"It is the most severe form of an Autism Spectrum Disorder, but what is different for our girls, is that for the most part, despite their handicaps, they are incredibly happy and social people," Paige Nues said.

The same is true for Katie Nues, who was diagnosed at 12 months and turns 8 on Sunday, July 25.

"On a day when she's feels well, and is not having seizures or stomach problems, she's bright and extroverted," Paige Nues said. "She loves being around typical kids and being in the community."

Katie is the first of three girls for Paige and her husband Jesse. The impact of the disease on the family has been huge. In order to keep up with therapy appointments and care for Katie, Paige made the difficult decision to stop working.

"It was emotionally devastating," she said. "We had what we thought was the perfect child. We thought we had done all the right things. We met, fell in love and prepared emotionally and financially to start a family. You never think it will go wrong."

Yet, even with the diagnosis, Katie is fairly strong and healthy and has a good relationship with sisters, Melissa, 4, and Abby, 2.

"They don't know her any other way, she's just their big sister," Paige Nues said. "But they definitely know she needs extra help."

One day, Paige recalls, they were headed out for a walk in the neighborhood and Melissa was starting to ride a bike with training wheels. Someone said that Katie couldn't ride a bike, but Melissa said, "Yes she can, she just needs our help." And she can, since Katie has a specialty bike just for her.

While Paige said they try not to put extra responsibilities on the other girls, she said Melissa and Abby "have amazing wisdom and sensitivity about (Katie) already."

The Nues family has been working hard to raise awareness and funds for Rett Syndrome research, so it's only fitting that they are doing all they can to get the word out about the Pepsi Refresh Everything grant. Everywhere they go, whether it they go to the grocery store or the dentist, they bring fliers and ask people to vote for the project.

Currently, "Rett Research to Reality" is in sixth place, and only first and second place receive grant money. Voting can be done daily online through July 31.

"What's intense about this campaign is that it's a cumulative daily vote," Paige Nues said. "People have to be pretty committed. You don't just need a wide network, but one of people committed to put it on their Outlook to do everyday."

With help from a private foundation in Colorado called the Pioneer Fund, they are willing to match up to $1 million to help the International Rett Syndrome Foundation. If they win, the IRSF can put $500,000 towards research.

"What (the lab test) demonstration showed is that the damage done to Katie is reversible," Paige Nues said. "It's not just a cure for newly-diagnosed patients. A cure can be found; it is possible. It's not only possible for the next generation, but it's possible to help Katie today."

Source: Danville Express

Note: Click on the title to read the full original post.

First Announcement: Annual Rett syndrome Awareness Meeting/Symposium

2010-07-09T23:48:00.000+05:30

Dear All,

As October is "Rett syndrome Awareness Month", so we are going to organize our third "Annual Rett syndrome Awareness Meet/Symposium", which is open to everybody.

Come and Join us to Raise More Global Awareness About Rett Syndrome.

Venue and Date:
Date: Sunday, October 31, 2010
Time: 10:00am - 5:00pm
Location:
Lecture Theater-II,
Second Floor, Teaching Block,
All India Institute of Medical Sciences,
Ansari Nagar, New Delhi-110029, INDIA

Please save the date in your schedules and share this with others too and make this event a success for the cause of all Rett Angels and their families. We hope to that you will give us some of your precious time for this cause by joining us and sharing it with others.

If you have any queries, feel free to contact.

Regards,

Indian Rett Syndrome Foundation
www.rettsyndromeindia.blogspot.com
E-mail: info.rett@yahoo.com

Facebook Page: http://www.facebook.com/profile.php?id=779594849#!/event.php?eid=133406410027633&index=1

Vote Pepsi Rett Research to Reality in July!

2010-07-08T20:50:00.000+05:30

Pepsi Refresh Project

Help International Rett Syndrome Foundation Win $250K for Crucial Rett Syndrome Research Funding!
Have you voted today? IRSF is still competing to win $250K from the Pepsi Refresh Project in support of the Research to Reality Campaign for Rett syndrome research.
Today: 4th Place
Think globally, act locally & vote daily

* VOTE once a day, every day in July
o Remember: You have to sign in each time you vote (lower left hand corner)
* Sign up for Daily Email Reminders
* Visit the Research to Reality webpage under www.rettsyndrome.org->Get Involved for more information
* Add the following statement to your email signature, blog, website and/or Facebook status page
o Please Help IRSF Win $250K for Rett Syndrome Research! think globally, act locally & vote daily
Vote for Rett syndrome once per day, every day in July
- Pepsi Refresh Project!
http://www.refresheverything.com/rettresearchtoreality
*Note: Get your friends involved cut & paste this message and add to your email signature

Please note that anyone 13 years of age and over can vote! Get your teenagers and their friends voting today!

Thanks, Regards, Prayers,

Indian Rett syndrome Foundation
www.rettsyndromeindia.blogspot.com

Prolonged QT interval in Rett syndrome

2010-07-02T02:18:00.000+05:30

By
C J Ellaway, G Sholler, H Leonard and J Christodoulou
Arch Dis Child 1999;80:470–472

Source: Pubmed

Rett syndrome, classical and atypical: genealogilcal support for common origin

2010-07-02T02:17:00.000+05:30

By
Hans Olof Akesson, Bengt Hagberg and Jan Wahlstr6m
J Med Genet 1996;33:764-766

Source: Pubmed

Recent insights into hyperventilation from the study of Rett syndrome

2010-07-02T02:15:00.002+05:30

By
Alison M Kerr and Peter O O Julu
Arch Dis Child 1999;80:384–387

Source: Pubmed

Rett Syndrome: Article by Dr. Angus Clarke

2010-07-02T02:13:00.000+05:30

Very Interesting Review Article
Click on title to read it.

Source: Pubmed

Effect of Hand Splints on Stereotypic Hand Behavior of Girls with Rett Syndrome: A Replication Study

2010-07-02T02:07:00.000+05:30

By
Helen Tuten and James Miedaner

Source: Pubmed

Hyperventilation in the awake state: potentially treatable component of Rett syndrome

2010-07-02T02:05:00.000+05:30

D P SOUTHALL,A M KERR,E TIROSH,P AMOS,M H LANG AND J B P STEPHENSON
Archives of Disease in Childhood, 1988, 63, 1039-1048

Source: Pubmed

Selective Cerebral Volume Reduction in Rett Syndrome: A Multiple-Approach MR Imaging Study

2010-07-02T02:01:00.000+05:30

Interesting article by

J.C. Carter, D.C. Lanham, D. Pham, G. Bibat, S. Naidu,W.E. Kaufmann

Am J Neuroradiol 29:436–41 (Mar 2008)

Source: Pubmed

Rett Syndrome The First Forty Years: 1966–2006

2010-07-02T01:53:00.000+05:30

Interesting article by Esteller M, 2007

Click on the title to read the article.

Source: Pubmed

Oral findings in Rett syndrome: A systematic review of the dental literature

2010-07-02T01:40:00.000+05:30

A very interesting article by

Fuertes-González MC, Silvestre FJ, Almerich-Silla JM

Please click on the title to read the same.

Source: Pubmed

Turn Research into Reality for 1000's of girls with Rett Syndrome: Vote everyday till June 30th

2010-06-24T00:51:00.002+05:30

Turn Research into Reality for 1000's of girls with Rett Syndrome

2010-06-13T20:20:00.001+05:30

Turn Research into Reality for 1000's of girls with Rett Syndrome

Pepsi Refresh Everything.

www.refresheverything.com

copy and paste this link in new vindow and sign up and vote or click on the title to directly go to the site. Share it with others too.

Thanks, Regards, Prayers,

Rajni Khajuria

Slightly Early Births Linked to Autism, Dyslexia

2010-06-11T23:21:00.000+05:30

By Kate Kelland

LONDON (Reuters) Jun 09 - Babies born just 1 or 2 weeks before their 40-week gestation due date are more likely to develop learning difficulties such as autism or dyslexia, according to a British study published on Tuesday.

The findings show that even babies born at 39 weeks have an increased risk of a developing a learning disability compared with babies born a week later.

Scientists in Scotland, analyzing the birth history of more than 400,000 schoolchildren, found that while babies born at 40 weeks have a 4% risk of learning difficulties, those born at 37 to 39 weeks of gestation have a 5.1% risk.

"There was an increasing risk of special educational needs as the gestation date fell, so as deliveries got earlier, the risk went up," said Jill Pell, an expert in public health and health policy Glasgow University, who led the study.

"Even being just a week early put the risk up."

It is already known that a baby born prematurely is more likely to have learning difficulties. But the risks for babies born in the 24 to 40 week range had not previously been studied.

Pell found that although the risk of educational difficulties was much higher in preterm than in early term babies, the absolute numbers of children with difficulties in the 37 to 39 week group were higher, because many more babies are born at this time than before 37 weeks.

In her study, early term births accounted for 5.5% percent of cases of learning disabilities, while preterm deliveries accounted for only 3.6% of cases.

According to the World Health Organization, more and more women worldwide are delivering by cesarean section and a "significant proportion" of these surgical procedures are performed without any clear medical need.

Rates of autism have also been rising, but Pell said it would be "a leap too far" to link her findings directly to rates of autism, since autism was only one of a range of learning difficulties considered.

Pell, whose study was published online June 8th in Public Library of Science (PLoS) Medicine, acknowledged that cesarean sections were not the only factor behind early-term births. But she said doctors and women should include the risks of learning difficulties when considering a cesarean.

"It is now normal policy (in cesarean section) to deliver women a week early," she said in a telephone interview. "But if you make a decision...for an elective pre-term delivery, then it has to be a balance, weighing up the risks and potential benefits.

"What this study shows is that special education needs are another factor that need to be considered."

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000289

PLoS Medicine 2010.

Source: Medscape

Utah scientist makes breakthrough in mental illness research

2010-06-02T17:44:00.000+05:30

By Jennifer Stagg

SALT LAKE CITY -- It is heartbreaking to see someone you love suffer from mental illness. Now a famous Utah scientist says he's made a big breakthrough in the research to find a cure.
Doctors have traditionally treated mental illness with drugs to alter the brain's chemistry, but the University of Utah's Nobel Prize-winning geneticist Dr. Mario Capecchi tried a new approach on a lab mouse. He treated the animal for the illness the same way you would many other illnesses -- by treating its immune system.

Capecchi says compulsive behavior doesn't just affect people. In fact, he had a lab mouse who was suffering from the condition trichotillomania, where one pulls their own hair out. Scientists say it was the mouse that led to the ground-breaking discovery as they found a way to cure him.
"There's a direct correlation, in essence, between the immune system and behavior," Capecchi says.
He says scientists have known for years that there is a connection between behavior and the immune system, but they didn't quite understand it. Now he and his team have discovered it all has to do with a tiny cell called microglia.
Microglia were believed to be "scavenger cells" that would clean up damage in the brain, but Capecchi says the cells are much more powerful than they were letting on.
"What we're saying is microglia are much more sophisticated and are actually controlling behavior, and they have to do it by interacting the nerve cells in your brain," Capecchi says.

They found people and animals afflicted with behavior disorders have deformed microglia cells. So, instead of treating mental illness the way doctors traditionally have -- with medication to alter brain chemistry -- they tried a new approach by treating the immune system.
The researchers used a procedure on the mouse that's commonly practiced on cancer patients -- a bone marrow transplant.
"That cured the disease permanently, " Capecchi says. "All the hair grew back, all the lesions were healed, and the mouse no longer removes the body hair."
Capecchi says this new discovery could lead to cures for mental disorders from autism to schizophrenia.
"The book is just opened, and so there are many, many possibilities; and hopefully not only will we pursue it, but also hopefully it will interest other researchers, other investigators, to pursue similar experiments, " Capecchi says.

What are... microglia?
Microglia are immune system cells that originate in bone marrow and migrate from blood to the brain acting as the first and main form of active immune defense in the central nervous system (CNS) defending the brain and spinal cord, constantly excavating the CNS and attacking and engulfing infectious agents.

E-mail: jstagg@ksl.com

FDA and NIH Launch Safety Reporting Web Site

2010-05-29T00:23:00.001+05:30

Kate Johnson

May 25, 2010 — A new Web site aimed at streamlining reporting and surveillance of safety and adverse events has been launched by the US Food and Drug Administration (FDA) and the National Institutes of Health (NIH), the agencies announced yesterday.

"The portal will be a key detection tool in improving the country's nationwide surveillance system and will strengthen our ability to protect the nation's health," FDA Commissioner Margaret A. Hamburg said in a news release.

The Safety Reporting Portal is part of the FDA's MedWatch Plus initiative. Its initial focus is primarily FDA-regulated foods (except dietary supplements and infant formula), as well as animal drugs and food and human gene transfer clinical trials. The FDA's preexisting MedWatch program will continue to focus on drug and medical device safety and adverse event reporting.

"The two systems are very similar and, over time, will merge into 1 system," Patricia El-Hinnawy, a press officer with the FDA, told Medscape Medical News. The Safety Reporting Portal will eventually expand to allow for mandatory reporting of serious events related to dietary supplements, as well as other clinical trials and products. In the meantime, it redirects traffic relating to these issues to the appropriate reporting sites.

When fully developed, the Web site will provide a mechanism for industry, healthcare professionals, and consumers to report a broad range of both pre- and postmarketing information to the federal government.

"This is the first step toward a common electronic reporting system that will offer one-stop shopping, allowing an individual to file a single report to multiple agencies that may have an interest in the event," the FDA notes in a news release.

In addition, the portal is intended to enhance the government's surveillance capabilities. "We will now be able to analyze human and animal safety-related events more quickly and identify those measures needed to protect the public," Dr. Hamburg said.

For More information, click on the title of this news or cut/copy and paste the below link in new window
https://www.safetyreporting.hhs.gov/fpsr/WorkflowLoginIO.aspx?metinstance=02039412009E655E84A96E3B7082E4C0A352E60B

Source: Medscape

Diet Free of Gluten and Casein Has No Effect on Autism Symptoms

2010-05-29T00:19:00.000+05:30

By Daniel M. Keller, PhD

May 24, 2010 (Philadelphia, Pennsylvania) — A gluten-free, casein-free (GFCF) diet or challenges with these food substances did not alter sleep or activity patterns in preschool children with autism spectrum disorder (ASD) who were also receiving intense behavioral therapy, suggests the first study to control for nutritional sufficiency and other interventions.

Slight differences in social language, approach, and play that were seen at 2 hours after gluten or casein exposure were not apparent at 24 hours, lead author Susan Hyman, MD, chief of the Division of Neurodevelopmental and Behavioral Pediatrics and associate professor of pediatrics at the University of Rochester in New York, reported here at the 9th Annual International Meeting for Autism Research.

Although dietary interventions are often used with children with ASD, have a popular image among the public, and result in anecdotal reports of improvement, prior trials have not borne out such positive outcomes. Dr. Hyman explained that she and her colleagues therefore designed a study to test whether a commonly used dietary intervention was safe and effective.

Study Population Stable at Baseline

Researchers recruited 22 children (age, 30 - 54 months) who were very consistent in their clinical presentations (positive on the Autism Diagnostic Interview and the Autism Diagnostic Observation Schedule), their medical conditions, and the therapies they were receiving, which was an early intensive behavioral intervention program. "This is important because if you're changing other parameters, you want to have other effective treatments stable," Dr. Hyman said. Children were excluded from the study if they had celiac disease, food allergies, or deficient iron stores.

The investigators formulated and monitored a nutritionally sound, strict GFCF diet, which they maintained children on for a minimum of 4 weeks. A staff of dieticians worked with the families to identify a food that their child would eat and that could be formulated to be indistinguishable with or without the test ingredients.

Fourteen of the children were able to maintain the diet and allow data collection. They remained on the diet and were observed and then challenged with the food substances (20 g wheat flour, 20 g evaporated milk, both, or placebo) only if they were at their behavioral baselines. Challenges were administered in a randomized, double-blind fashion. Each child received a food challenge on 3 separate occasions over 12 weeks.

To ensure nutritional adequacy, laboratory monitoring, body mass index, weight, and growth recording occurred at baseline, 6, 8, and 30 weeks. The researchers also collected behavioral data at these times, as well as the day before and 2 and 24 hours after each food challenge.

No Difference in Activity Levels After Dietary Challenge

Dr. Hyman reported that there was no difference in the length of sleep recorded by parents over the course of the study before and after challenges and compared with baseline. There were also no changes in the number of night wakings or in the number or consistency of stools.

Compared with placebo challenges, no significant differences occurred in length of sleep or waking with gluten (P = .21 and P = .10, respectively), casein (P = .48 and P = .15, respectively), or both (P = .99 and P = .18, respectively). Similarly, there were no differences in stool consistency compared with placebo.

Children's activity levels recorded by parents, researchers, or applied behavior analysis program teachers did not differ after placebo, gluten, casein, or gluten/casein challenges. These observations were consistent with recordings from actigraphs — watch-like devices that measure activity.

Dr. Hyman noted that these measures are not specific to autism. Thus, the play-based Ritvo-Freeman Real Life Rating Scale for autism was used to gauge sensory motor behaviors, social approach, and language. "With correction for multiple comparisons, there was no difference with the challenges compared to placebo, and there was no difference with introduction of the diet," she said.

To see whether any individual responses were obscured by group statistics, the researchers examined the single subject data but did not identify any child with significant effects after dietary challenges or who had improvements in core features of autism during the trial.

In summary, Dr. Hyman said, "The data that we have do not demonstrate effect of the GFCF diet on the behaviors we measured." However, she said that study limitations include the study's small size and that all the included children were in an effective early intervention program (≥10 hours/week), were of similar age, and were all stabilized on a monitored diet. Furthermore, none of the children was iron- or vitamin D-deficient.

Dr. Hyman said a question remains whether any autistic children could respond to the diet used in the study. For example, children with celiac disease or bad gastrointestinal symptoms were not included. "So could it be that children who have more significant [gastrointestinal] symptoms are the ones that drive the anecdotal reports?" she asked. Another possibility is that foods designed to exclude gluten could also then lack food preservatives or dyes, which is another open question.

Dr. Hyman concluded, "The data that we have do not offer support for the [GFCF] diet in young children who carry a diagnosis of autism and who are receiving other effective behavioral and educational interventions." She cautioned that these data should not be extrapolated to any child with food allergies or intolerances or other gastrointestinal problems, and that "any child who is on the diet needs to be monitored from a nutritional standpoint to make certain that all of the things that we know about typical child development are monitored for."

Jonathan Green, MD, professor of child and adolescent psychiatry at the University of Manchester, United Kingdom, commented that "studies of dietary interventions like this are extremely difficult to do." He calls himself "an interventionist" and leads the Medical Research Council preschool autism communication trial, currently the largest intervention trial internationally in this subject area.

"The [University of Rochester] study is of significance even though sample size is really small, but they really took a lot of trouble to blind the dietary intervention, and that's the really difficult thing to do," he said. He also commended Dr. Hyman's rigor in recording even what she called "oops events," where the child got a bit of food that was not planned, such as a cookie from grandma.

Dr. Green said that although there are hundreds of foods and ingredients that could be tested, he thought that Dr. Hyman addressed well 2 of parents' concerns by testing gluten and casein. "She's done the right test. She's used the right kind of methodology, which is really difficult on a small group of kids, and her results are pretty clear," he said.

Addressing the possibility that an autistic child with a preexisting gut problem would feel better on a gluten-free diet, he warned, "That, however, does not mean it's having an effect on the autism itself, and that's the point of what Dr. Hyman did.... What she's suggesting is that the diet in itself doesn't have a specific effect on autism as such." He said this kind of information should reach parents, who should see that autism researchers take their concerns seriously, and who thus need to believe the science.

In Dr. Hyman's opinion, "The real future of autism treatment is going to be informed by science. It's going to be informed by what we really do know about the brain and the designer interventions," she said. "What we have now in terms of intervention is empiric observation."

Source: Medscape

New Finding Adds Weight to Ketogenic Diet for Childhood Seizures

2010-05-29T00:17:00.000+05:30

May 27, 2010 — The ketogenic diet is an effective alternative for pediatric patients with persistent seizures who have not responded to other therapies, say investigators. Reporting results from the largest analysis to date, researchers from Johns Hopkins Children's Center, Baltimore, Maryland, show that about two-thirds of refractory patients respond to the high-fat, low-carbohydrate diet.

"Stopping or reducing the number of seizures can go a long way toward preserving neurological function, and the ketogenic diet should be our immediate next line of defense in children with persistent infantile spasms who don’t improve with medication," senior investigator Eric Kossoff, MD, a pediatric neurologist and director of the ketogenic diet program at Hopkins, said in a news release.

The new study is a follow-up of a 2002 report that showed the diet worked well in a small number of children with infantile spasms. The current report, published online in Epilepsia, includes 104 pediatric patients.

The ketogenic diet provides just enough protein for body growth and repair and sufficient calories to maintain a healthy weight. The classic ketogenic diet contains a 4:1 ratio of fat to combined protein and carbohydrate.

"We have seen a significant increase in referrals for the ketogenic diet for intractable infantile spasms," note the study authors. They have also started using the diet in new-onset cases. "The purpose of this study was to use the increased patient cohort to evaluate for predictive factors for success, compare results over time, and evaluate long-term seizure, electroencephalogram, and developmental outcomes."

The researchers show that nearly 40% of children became seizure free for at least 6 months. Most of these have remained seizure free for at least 2 years.

Table. Spasm Reduction at Each Follow-up

Reduction,% 3 Months,% 6 Months,% 9 Months,% 1 Year,% 2 Years,%
Seizure free 18 28 32 30 33
>90 13 11 14 13 11
50–90 32 25 27 34 33
<50 37 36 27 23 23

The investigators also report significant improvements in development and electroencephalograms, as well as a reduction in the number of concurrent anticonvulsants.

The mean age of patients was 1.2 years. Previous therapy included on average 3.6 anticonvulsants. Most patients had tried corticosteroids or vigabatrin.

The researchers used the diet first line in 18 patients with newly diagnosed seizures never treated with drugs. Ten of these patients became seizure free within 2 weeks of starting the diet.

The finding suggests that in some children the diet may work well as first-line therapy. Debating at the American Epilepsy Society 63rd Annual Scientific Conference in December, experts weighed the pros and cons of this approach.

Speaker Elizabeth Donner, MD, from the Hospital for Sick Children in Toronto, Ontario, Canada, argued at the meeting that the ketogenic diet is effective and should be considered first line in infantile spasms and especially in GLUT1 and pyruvate dehydrogenase deficiency.

First Line In GLUT1 and Pyruvate Dehydrogenase Deficiency

"Antiepileptic drugs do bad things to children," Dr. Donner said, naming a long list of adverse effects — many serious and some involving cognitive impairment. "In some cases, antiepileptic drugs can even make seizures worse," she said.

Dr. Donner suggested that since the ketogenic diet works quickly, it makes sense to try it first line.

Speaker Douglas Nordli, MD, from the Children's Memorial Hospital in Chicago, Illinois, agreed the ketogenic diet can be used first line in patients with GLUT1 or pyruvate dehydrogenase deficiency. However, he argued there is otherwise limited evidence confirming the benefits of the diet.

Dr. Nordli says it is not easy for dieticians and families to start a ketogenic diet emergently, so he will continue to try 1 or 2 medications first.

"The diet is not completely innocuous," he added, noting that it can be especially dangerous for patients with underlying metabolic defects.

Common adverse effects include constipation, heartburn, diarrhea, behavior problems, kidney stones, and temporary spikes in cholesterol levels. In this study, adverse effects were observed in a third of children. Some also experienced diminished growth (6%).

"We would do a disservice to the ketogenic diet to propose it first line without sufficient prospective comparative data," Dr. Nordli said. "Articles showing a probable beneficial effect are not the same as comparative superiority to existing agents."

Speaking to Medscape Neurology, lead study author Amanda Hong, a medical student at Hopkins, said her team agrees. "Additional prospective, multicenter studies are needed."

This study was funded by Johns Hopkins University and the National Institutes of Health. Dr. Kossoff has received financial support from Nutricia Inc for unrelated research pertaining to their products.

Epilepsia. Published online April 30, 2010.

Source: Medscape