Functional abilities and caregiver assistance in Rett syndrome

Sponsors and Collaborators: Faculdades Metropolitanas Unidas University of Sao Paulo Locations: Brazil Faculdades Metropolitanas Unidas São Paulo, Brazil, 04505-001 Information provided by: Faculdades Metropolitanas Unidas ClinicalTrials.gov Identifier: NCT00630422 (completed) Purpose The purpose of this study is to evaluate and determinate the functional abilities in Rett syndrome conforming to the established Pediatric Evaluation of Disability Inventory (PEDI). Rett syndrome (RS) is a progressive neurological disturbance of genetic cause that affects females almost exclusively. It is caused by mutations, usually sporadic, of the MECP2 gene located in the X chromosome. Presented as main characteristics: stagnation in neuromotor development; losses of communication, visual contact, interest for people and objects; and manual stereotypes. In consequence to the serious cognitive and motor compromise, the RS patients have great difficulty in accomplishing day-to-day tasks. The objective of this work was to evaluate the functional abilities and to discover the needs of assistance by the caregiver, conforming to the established Pediatric Evaluation of Disability Inventory (PEDI). That evaluation instrument, which possesses 197 items in the areas of self-care, mobility and social function, was applied to 64 individuals with RS that matched the criteria for the classic form of the disease. Their ages ranged between 2 years and 26 years, with an average of 10 years. Among the 73 PEDI activities in the area of self-care, 52 (71.2%) were not accomplished by any child; in the area of mobility, among the 59 proposed activities, 8 (13.5%) were not done by any RS patient; and finally in the area of social function, none of the 50 (76.9%) activities among 65 were accomplished. The average performance adjusted in a scale from 0 to 100 for the area of self-care was of 8.9/100, varying from 0 to 26; for mobility, it was an average of 30.2/100, varying from 1.7 to 74.5; and of social function was 5.2/100, with variation from 0 to 21.5. The need of attendance was, in a complementary way, greater in the self-care areas and social function than in mobility. We didn't find, in our sample, a relationship between the age and the degree of incapacity, suggesting that RS individual present a compromising level that is from the beginning quite serious. Unfortunately, the smallest compromise of mobility, compared with the areas of self-care and social function, doesn't bring adaptive advantages or greater independence to the RS patients. Source: www.clinicaltrials.gov/ct2/show/NCT00630422

Novel Approach To Treating Rett Syndrome Under Development

A paper published in Nature Neuroscience reveals the presence of methyl CpG binding protein 2 (MeCP2) in glia. MeCP2 is a protein associated with a variety of neurological disorders, including Rett Syndrome, the most physically disabling of the autism spectrum disorders. The researchers show that MeCP2-deficient astrocytes (a subset of glia) stunt the growth of neighboring neurons. Remarkably, these neurons can recover when exposed to normal glia in culture. The discovery was made by Gail Mandel, Ph.D. of the Vollum Institute at Oregon Health and Science University and a Howard Hughes Medical Institute investigator and Nurit Ballas, Ph.D., a research associate, at the time, in the Mandel lab at the State University of New York at Stony Brook. Dr. Mandel is a scientific advisor of the Rett Syndrome Research Trust (RSRT) a recently formed nonprofit organization intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders. 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. Individuals with Rett and their families suffer the emotional and financial cost of the wide range of symptoms and the ongoing struggles to address them. Glial cells, which reside throughout the nervous system, comprise the vast majority (90%) of cells in the brain. Glia support and interact with neurons in innumerable ways, from providing the structural underpinnings and guidance of axons and dendrites (the neuronal processes that carry information), to creating protective insulation for axons. These and other glial functions are essential to the health of neurons. Since MECP2 is located on the X chromosome, girls with Rett Syndrome are mosaic: cells with a healthy copy of the gene lie side by side with cells that have the mutated version. Mandel and colleagues found that MECP2- deficient astrocytes could not sustain normal neuronal growth. In fact, their experiments suggest that MeCP2-deficient astrocytes secrete a toxic factor that impacts the entire neighborhood of neurons, including neurons with wildtype (normal) MECP2. Conversely, they found that wildtype astrocytes could restore the stunted growth of MeCP2-deficient neurons. This finding supports the 2007 Science publication by Professor Adrian Bird showing reversal of Rett symptoms in adult mouse models of the disorder. Results from ongoing in vivo mouse studies deleting MeCP2 in glia are promising in terms of supporting the culture studies. “This new study adds to the growing body of evidence that glial cells are critically important contributors to neurological diseases and therefore attractive targets for drug development,” said Ben Barres, Professor and Chair of the Department of Neurobiology at Stanford University and a glial cell expert. Recent studies from multiple groups, including the lab of Dr. Tom Maniatis, a neurodegenerative disease researcher at Harvard University, have implicated glia in Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis – ALS), a devastating neurodegenerative disorder that leads to the death of motor neurons and total paralysis. “In Rett Syndrome, faulty glia seem to poison neurons, inhibiting growth; in ALS glia appear to release a toxic factor that kills motor neurons.” Maniatis stated that “studies of the role of glia in a broad spectrum of neuronal diseases should lead to exciting advances in understanding disease mechanisms.” “Dr. Mandel’s sharp insights have given the scientific community an entirely new way to think about treating Rett Syndrome. One could envision a scenario where halting the secretion of this potential toxic factor could restore health, in particular to the MECP2 positive neurons, which could bring about amelioration of symptoms. I look forward to her lab’s continued contributions as we explore the therapeutic implications of her research,” comments Monica Coenraads, Executive Director of RSRT and parent of a child with the disorder. Other people who worked on the project include Daniel T. Lioy of the Vollum Institute and Christopher Grunseich, M.D. while at the State University of New York at Stony Brook. Nurit Ballas is now a Research Associate Professor in the Department of Biochemistry and Cell Biology at Stony Brook. This project was funded in part by the NIH, HHMI and IRSF. SOURCE: RETT SYNDROME RESEARCH TRUST The ScienceDaily http://www.sciencedaily.com/releases/2009/02/090223094711.htm

A possible treatment for Rett syndrome: MIT study suggests molecule can reverse some symptoms

A molecule that promotes brain development could serve as a possible treatment for Rett syndrome, the most common form of autism in girls, according to researchers at MIT's Picower Institute for Learning and Memory and the Whitehead Institute for Biomedical Research. The researchers found that injecting the molecule into mice that have an equivalent of Rett syndrome helped the animals' faulty brain cells develop normally and reversed some of the disorder's symptoms. The work, reported in the Feb. 10 online edition of the Proceedings of the National Academy of Sciences (PNAS), is expected to lead to new human clinical trials for a derivative of growth factor-1 (IGF-1), currently used to treat growth disorders and control blood glucose. The MIT study indicates that IGF-1 could potentially lessen the severity of symptoms of Rett syndrome. "We demonstrate that a major underlying mechanism behind Rett syndrome in mice is that synapses in the brain remain immature and show persistent, abnormal plasticity into adulthood," said Daniela Tropea, a postdoctoral fellow at the Picower Institute and lead author of the study. "We also propose that a therapeutic based on this mechanism would be directly applicable to humans." Injecting mice with a peptide fragment of IGF-1, used by the brain for neuronal and synaptic development, reverses a large number of symptoms of mice genetically engineered to display Rett syndrome-like symptoms. "IGF-1 is critical for brain development. It activates molecules within neurons that make synapses mature," said study co-author Mriganka Sur, the Newton Professor of Neuroscience at the Picower Institute and head of the MIT Department of Brain and Cognitive Sciences. "This is a mechanism-based therapeutic for Rett syndrome. It is possible that this or similar therapeutics would apply to other forms of autism, which also have as their basis a persistent immaturity of synapses." HELPING NERVE CELLS MATURE Rett syndrome, an inherited neurological disorder, causes loss of speech, reduced head size, breathing and heart abnormalities and autism-like symptoms in one out of 10,000 girls. In 85 percent of girls with Rett syndrome, the culprit is a faulty gene coding for methyl CpG-binding protein 2, (MeCP2), critical for nerve cell maturation. A deficit in MeCP2 stops neurons from growing spines, the branch-like projections needed for cell-to-cell communication. Recent genetic studies have shown that increasing MeCP2 expression in mice led neurons to grow new spines, indicating that the disease could be reversible. Increased IGF-1 seems to make up for the lack of MeCP2. Daily injections of the insulin-like growth factor IGF-1 extended the life spans of infant Rett syndrome mice, improved their motor function and breathing patterns and reduced irregularities in their heart rates. In addition, their brains had more nerve-cell spines. IGF-1 affects almost every cell in the human body, especially in muscle, cartilage, bone, liver, kidney, nerves, skin and lungs. In addition to its insulin-like effects, IGF-1 also regulates cell growth and development in nerve cells. "This is the first realistic way for a drug-like molecule injected into the bloodstream to relieve Rett syndrome symptoms," said Whitehead member Rudolf Jaenisch, whose lab participated in the research. Source: Massachusetts Institute of Technology

MECP2 mutation screening for Rett syndrome in India

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). The MECP2 gene provides instructions for making a protein (MeCP2) that is essential for normal brain development. This protein is found to be important for the function of nerve cells in the brain and is present in high levels in mature nerve cells. Various studies suggest that the MeCP2 protein plays a role in forming connections between nerve cells, where cell-to-cell communication occurs. This protein turns off other genes, preventing them from making proteins when they are not needed. It remains uncertain which genes are targeted by the MeCP2 protein, but such genes are probably important for normal brain function. Most cases of classic Rett syndrome are caused by mutations in the MECP2 gene. Males with mutations in the MECP2 gene often die before birth or in infancy. A small number of males with a MECP2 mutation, however, have developed signs and symptoms similar to those of classic Rett syndrome. Some of these boys have an extra X chromosome in many or all of the body's cells. The extra X chromosome contains a normal copy of the MECP2 gene, which produces enough of the MeCP2 protein for the boys to survive. Other males with features of Rett syndrome have mutations in the MECP2 gene that occur after conception and are present in only a fraction of the body's cells. In rare cases, researchers have discovered that the MECP2 gene is abnormally duplicated in boys with intellectual disability and some developmental problems characteristic of Rett syndrome. Although mutations in the MECP2 gene disrupt the normal function of nerve cells, it is unclear how these mutations lead to the signs and symptoms of Rett syndrome. We are providing mutation screening for MECP2 gene for Indian patients affected with Rett syndrome in our tertiary care hospital and research institute at following address. Genetics Unit, Department of Pediatrics, Old O.T block, Room no. 110, First floor, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029 India Ph: 011-26594585 +919999343421 Patients are evaluated using the diagnostic criteria of Rett syndrome used worldwide and then enrolled for screening of MECP2 mutations and polymorphisms. Reference: http://ghr.nlm.nih.gov/gene=mecp2 (Genetics home reference)

Classical and Atypical variant diagnostic criteria for Rett syndrome

Revised Diagnostic Criteria

At our present level of knowledge, the diagnosis of Rett Syndrome is more a clinical one and can not be ruled out on the basis of MECP2 mutations presence or absence, that means Rett Syndrome can occurs with or without mutations in MECP2, the mutations in MECP2 have also been found in those who does not have any clinical features of either classic or variant Rett Syndrome. Therefore, diagnostic criteria for classical and variant Rett Syndrome is essential and and these should be noted very carefully while clinical examination of the patient. Moreover a patient can be examined two or more times by different team of clinicians to confirm the diagnostic criteria.

Here is the list of essential and supportive diagnostic criteria for classical and Atypical Rett syndrome.

Essential Diagnostic Criteria for classical Rett syndrome (Patient should fulfill all of these)

• Apparently normal prenatal and perinatal period
• Psychomotor development may appear normal through the first six months or may be delayed from birth
• Normal head circumference at birth
• Postnatal deceleration of head growth in most children
• Decrease of purposeful hand skills between ages 6 and 30 months
• Communication dysfunction and social withdrawal in early childhood
• Severely impaired expressive and receptive language and psychomotor impairment
• Stereotypic hand movements such as hand wringing/ squeezing, clapping/ tapping, mouthing and washing
• Impaired or absent locomotion from late infancy

Supportive Criteria for classical Rett syndrome

• Awake disturbances of breathing

• Hyperventilation

• Breath-holding

• Forced expulsion of air or saliva

• EEG abnormalities

• Slow waking background and intermittent rhythmical slowing (3-5 htz)

• Epileptiform discharges, with or without clinical seizures

• Seizures

• Abnormal muscle tone associated with muscle wasting and dystonia

• Peripheral vasomotor disturbances (cold, blue feet and hands)

• Scoliosis/ kyphosis

• Growth retardation

• Hypotrophic small feet

• Bruxism (teeth-grinding)

• Impaired sleep patterns in early infancy

• Profound daytime sleep/ Abnormal sleep cycle

Criteria for Atypical Cases

Inclusion criteria: Patient must meet at least three of six main criteria and at least five of eleven supportive criteria

Six Main Criteria

• Absence or reduction of finger skills

• Loss of babble speech

• Loss of communication skills

• Deceleration of head growth

• Hand stereotypies

• RS disease profile: a regression stage followed by a recovery of interaction, contrasting with slow neuromotor regression

Eleven Supportive Criteria

• Breathing irregularities

• Teeth grinding

• Scoliosis/ kyphosis

• Lower limb muscle atrophy

• Cold, purplish feet

• Bloating

• Abnormal locomotion

• Sleep disturbances

• RS eye pointing

• Pain indifference

• Laughing/ screaming spells

Exclusion Criteria to rule out the diagnosis of Rett syndrome

• Organomegaly or other signs of storage disease

• Retinopathy or optic atrophy

• Evidence or perinatal or postnatal brain damage

• Existence of identifiable metabolic or other progressive neurological disorder

• Acquired neurological disorders resulting from severe infections or head trauma

About Rett Syndrome

Rett syndrome is a neurodevelopmental disorder and primarily affects females. It comes under pervasive devlopmental disorders. This disorder was named after Austrian neurologist Dr. Andreas Rett, who first described it in 1966. The clinical features include a slow rate of head growth, growth retardation in some cases and small hands and feet. Stereotypic, repetitive hand movements such as mouthing, clapping, washing, tapping or wringing are the typical symptom of this disorder. These Symptoms of the disorder include cognitive impairment, speech problems, gait problems and problems with socialization. These children appear normal till 6-18 months of life and after that they start loosing the activities they have gained during theses months. Girls with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and about 50% of females are not ambulatory. Scoliosis, growth failure, and constipation are very common and can be problematic. The symptoms of this disorder are most confused with those of angelman syndrome, cerebral palsy, autism and mental retardation. Till date, very little is known about this disorder in India as children are still misdiagnosed and labeled with other disorders. So we have to make People in India aware about this typical syndrome so that these children can get correct diagnosis as this will help to make people understand about the needs of these angels.