World Autism Awareness Day (April 2)

On December 18, 2007, the United Nations General Assembly adopted resolution 62/139, tabled by the State of Qatar, which declares April 2 as World Autism Awareness Day (WAAD) in perpetuity. Her Highness Sheikha Mozah Bint Nasser Al-Missned, Consort of His Highness Sheikh Hamad Bin Khalifa Al-Thani, the Emir of the State of Qatar, supported the campaign for a World Autism Awareness Day through the current 62nd UN General Assembly Session, garnering consensus support from all United Nations Member States.


This UN resolution is one of only three official disease-specific United Nations Days and will bring the world's attention to autism, a pervasive disorder that affects tens of millions. The World Autism Awareness Day resolution encourages all Member States to take measures to raise awareness about autism throughout society and to encourage early diagnosis and early intervention. It further expresses deep concern at the prevalence and high rate of autism in children in all regions of the world and the consequent developmental challenges.

World Autism Awareness Day shines a bright light on autism as a growing global health crisis. WAAD activities help to increase and develop world knowledge of the autism epidemic and impart information regarding the importance of early diagnosis and early intervention. Additionally, WAAD celebrates the unique talents and skills of persons with autism and is a day when individuals with autism are warmly welcomed and embraced in community events around the globe.

By bringing together autism organizations all around the world, we will give a voice to the millions of individuals worldwide who are undiagnosed, misunderstood and looking for help. Please join us in our effort to inspire compassion, inclusion and hope.

U.N. notes that World Autism Awareness Day is meant "to highlight the need to help improve the lives of children and adults who suffer from the disorder so they can lead full and meaningful lives."


A lifelong disability, autism includes a group of brain development disorders that typically develop during an individual's first three years of life. It is well-documented to occur worldwide, according to Autism Speaks.

A number of events are being held internationally to commemorate World Autism Awareness Day 2010. Many events are being held today, and others are being held throughout April (and a few have already passed). A list of Autism Awareness Day events can be found here.

U.N. Secretary-General Ban Ki-moon released the following statement for World Autism Awareness Day 2010:
"Let us join persons with autism, their families and their advocates in a community of voices for greater awareness and understanding. Let us also look within, and re-evaluate our attitudes and those of our societies so we can remove the prejudices that discriminate against persons with disabilities. Let us dedicate ourselves to creating a fair and caring society that affords true dignity and rights for all."


Important Link to read more:
http://www.worldautismawarenessday.org/site/c.egLMI2ODKpF/b.3917077/k.186A/About_World_Autism_Awareness_Day.htm
http://www.youtube.com/watch?v=wpsI20cC4q0&feature=player_embedded#
http://www.autismspeaks.org/

Melior enters drug discovery collaboration with Rett Syndrome Research Trust

March 30, 2010, Exton, PA - Melior Discovery, Inc. announced today that it has entered into collaboration with the Rett Syndrome Research Trust to screen drug-candidates in an in vivo model of Rett Syndrome.

Melior Discovery has developed world-class expertise in screening compounds for potential therapeutic activity in animal models. Melior will apply this expertise to the evaluation of large numbers of drug-candidates in a specialized model of Rett Syndrome. "This partnership is further illustration of Melior's truly unique capabilities and competence in high throughput in vivo pharmacology," said Andrew Reaume PhD, CEO, Melior Discovery.

Rett Syndrome, the most physically disabling of the autism spectrum disorders, strikes young 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, around-the-clock care.

The disorder is caused by alterations of an X-linked gene, MECP2. The animal models that have been developed mimic the disorder well and provide an excellent system to test potential drug candidates.

"We are pleased to be working with Melior and have been impressed with their ability to rapidly and effectively evaluate compounds in animal models. We look forward to our collaboration as we strive to identify compounds to ameliorate the devastating symptoms of Rett," added Monica Coenraads, Executive Director of the Rett Syndrome Research Trust.

About Melior Discovery, Inc.

Melior Discovery is leading the transformation of pharmaceutical drug repositioning with its unique theraTRACE® platform of multiplexed in vivo models. Melior is using this capability to build an internal pipeline of development candidates. Melior Discovery also partners with pharmaceutical and biopharmaceutical companies to expand their drug development pipelines by using the theraTRACE® platform, and individual animal models, in conjunction with the Company's in-depth in vivo pharmacology expertise.

Melior Discovery is located in Exton, PA. The Company is privately held with investors that include Cammeby's Capital Group, VenturEast, Osage Ventures, Mid-Atlantic Angel Group, and BioAdvance.

About the Rett Syndrome Research Trust

The Rett Syndrome Research Trust is a nonprofit research organization formed in the wake of the dramatic pre-clinical reversal of Rett Syndrome symptoms. The Trust is intensively focused on the development of treatments and cures for Rett Syndrome and related MECP2 disorders. To learn more about the Trust please visit http://www.reverserett.org/.

New theory of Down syndrome cause may lead to new therapies

COLUMBUS, Ohio – Conventional wisdom among scientists for years has suggested that because individuals with Down syndrome have an extra chromosome, the disorder most likely results from the presence of too many genes or proteins contained in that additional structure.


But a recent study reveals that just the opposite could be true – that a deficiency of a protein in the brain of Down syndrome patients could contribute to the cognitive impairment and congenital heart defects that characterize the syndrome.

Scientists have shown in a series of experiments that there are lower levels of this protein in the brains of humans and mice with Down syndrome than are present in humans and mice without the disorder.

The researchers also showed that manually manipulating pieces of RNA that regulate the protein could increase protein levels in both human cell lines and mouse brains. In fact, an experimental drug that acts on those RNA segments returned this protein to normal levels in mice that model the syndrome.

When this RNA segment is overexpressed – meaning that more of it is present than needed in a cell – the protein level goes down, or is underexpressed. A total of at least five of these RNA segments are naturally overexpressed in persons with Down syndrome because the segments are housed on chromosome 21 – the chromosome that causes the disorder.

"We're talking about a paradigm-shifting idea that maybe we should look for underexpressed proteins and not overexpressed proteins in Down syndrome," said Terry Elton, senior author of the study and a professor of pharmacology at Ohio State University.

"What this offers to the Down syndrome community is the potential for at least five new therapeutic targets to pursue."

The Centers for Disease Control and Prevention estimates that about 13 of every 10,000 babies born in the United States each year have Down syndrome, characterized primarily by a mild-to-moderate range of intellectual disabilities, possible delayed language development and difficulties with physical coordination.

The study is published in a recent issue of the Journal of Biological Chemistry.

Elton, also interim director of Ohio State's Davis Heart and Lung Research Institute, stumbled upon this theory about Down syndrome while working on a different protein associated with cardiovascular disease. It turns out the protein he has studied for 25 years was regulated by one of these microRNAs that is known to be housed on chromosome 21.

A key role of RNA in a cell is to make protein, and proteins are the building blocks of all life. But the process has many steps. MicroRNAs are small pieces of RNA that bind to messenger RNA, which contains the actual set of instructions for building proteins. When that connection is made, however, the microRNA inhibits the building of the protein. Why that occurs is not completely understood, but increasingly microRNAs are considered tiny molecules that have a big impact in a number of physiological processes.

For his cardiovascular disease research, Elton found that a genetic trait in some people caused one specific microRNA to be bad at its job, leading to high protein levels that contribute to cardiovascular disease. This malfunctioning molecule is called microRNA-155, or miR-155.

"So we became interested in miR-155, and it is on chromosome 21. That's how we jumped to Down syndrome," Elton said.

There is also a strong link between the heart and Down syndrome. About half of those with the syndrome are born with congenital heart defects – problems with the heart's anatomy, not coronary arteries. But they do not experience cardiovascular disease or high blood pressure.

The advent of biomedical informatics has allowed scientists to use supercomputers to explore the human genome in a search for genes and their various relationships in the context of human disease. Elton consulted a bioinformatic database and found that five microRNAs sit on chromosome 21, and he and colleagues demonstrated in previous research that all five of them are overexpressed in the tissues, brains and hearts of Down syndrome patients.

"That means that whatever proteins these microRNAs work with are underexpressed," Elton said.

Further database exploration suggested that these five microRNAs target 1,695 proteins, all of which could cause problems in Down syndrome because they are underexpressed. To narrow that to a more manageable number, Elton's group had to make an educated guess based on a variety of data, including which proteins that are connected to these microRNAs are made by cells in the brain and heart – two areas most commonly affected by Down syndrome.

A protein surfaced as an attractive target to study: methyl-CpG-binding protein 2, known as MeCP2. Among the reasons it seemed important: A mutation in this protein is already known to lead to Rett syndrome, a cognitive disorder.

"So we thought that it was more than a coincidence that this protein plays a role in normal brain development, and if the protein doesn't function right, you're going to have cognitive impairment. Maybe this is the connection," Elton said. "We still don't know if this is the most important protein related to Down syndrome. But we were able to go on and prove scientifically that MeCP2 is a target of these microRNAs on chromosome 21."

The researchers used just two of the five microRNAs on chromosome 21 for the experiments in this study, miR-155 and miR-802, to match the only microRNAs available in the genetically engineered mouse model of Down syndrome.

First, the researchers made copies of the relevant microRNAs. In human brain cell lines, they manipulated levels of those two molecules to show the inverse relationship with the protein. If the microRNAs were more active, the level of the MeCP2 protein went down. When the microRNAs were underexpressed, the protein levels went up.

Next, the researchers examined adult and fetal human brain tissue from healthy and Down syndrome samples obtained from a national tissue bank.

"In both adult and fetal Down syndrome brain samples, it didn't matter which area of the brain we were looking at, the MeCP2 proteins were down. These are just observations with no manipulation on our part, and the MeCP2 is almost non-existent in the Down syndrome brain," Elton said. "We marked the protein with a fluorescent molecule, and by comparison, we could visualize and appreciate how much MeCP2 was being made by neurons in the control samples."

MeCP2 is a transcription factor, meaning it turns genes on and off. If its levels are too low in the brain, this suggests that genes influenced by its presence should be malfunctioning, too. Based on previous research by another group, Elton and colleagues focused on two genes affected by the MeCP2 protein for their next set of experiments.

Looking again at the human brain tissue samples, they found that the genes were indeed affected by the lowered protein level in Down syndrome brains – one gene that MeCP2 normally silences was in abundance, and the gene that should have been activated was underexpressed. Because the two genes examined have known roles in neural development, Elton said the results suggested even more strongly that the lowered protein's effects on the genes likely contribute to cognitive problems associated with Down syndrome.

Finally, the researchers tested an experimental drug called an antagomir on mice that serve as models for Down syndrome research. Antagomirs are relatively new agents that render microRNAs inactive. The scientists injected an antagomir into the brains of these mice to silence the miR-155 with the intent to increase levels of the MeCP2 protein. Seven days after the injection, the level of the protein in the treated mouse brains resembled levels in normal mouse brains.

"We showed that we can fix the protein abnormality in mice that model Down syndrome. But we can't undo the pathology that has already occurred," Elton said. "It's a starting point, but it appears that we have new therapeutic targets to consider."

###This work was supported by grants from the National Institutes of Health and the Foundation Jerome Lejeune.

Co-authors of the study were Donald Kuhn, Gerard Nuovo, Mickey Martin, Geraldine Malana, Sarah Sansom, Adam Pleister and David Feldman of Ohio State's Davis Heart and Lung Research Institute; Alvin Terry Jr. and Wayne Beck of Medical College of Georgia's Department of Pharmacology and Toxicology; and Elizabeth Head of the Institute for Brain Aging and Dementia, Department of Neurology, University of California, Irvine.

Contact: Terry Elton, (614) 292-1400; terry.elton@osumc.edu

Written by Emily Caldwell, (614) 292-8310; caldwell.151@osu.edu

MeCP2 Goes Global: Redefining the Function of the Rett Syndrome Protein

FEBRUARY 25, 2010


A paper published online today in Molecular Cell proposes that Methyl CpG binding protein 2 (MeCP2) impacts the entire genome in neurons, rather than acting as a regulator of specific genes. Mutations in MeCP2 cause the autism spectrum disorder Rett Syndrome as well as some cases of neuropsychiatric problems including autism, schizophrenia and learning disabilities.

The discovery of MeCP2’s global reach was made in the laboratory of Adrian Bird, Ph.D. of the University of Edinburgh. Bird’s seminal contributions in the Rett Syndrome field include cloning the MeCP2 protein in the early 1990’s and the dramatic reversal of severe symptoms in fully mature mice models of the disease published in Science in 2007. He is a Trustee and Scientific Advisor of the Rett Syndrome Research Trust, a 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.

Historically, MeCP2 has been viewed as a classic transcription factor, but Bird’s data establishes MeCP2 as one of the most abundant neuronal nuclear proteins, with levels 100 to 1,000 times higher than typical transcription factors. In fact, there are nearly as many molecules of MeCP2 in the nucleus as there are nucleosomes, the fundamental repeating structural units of chromatin which in turn make up chromosomes. To put this in perspective, there is enough MeCP2 to cover nearly the entire genome.

Peter Skene, a post-doctoral fellow in the Bird lab and first author of the paper confirmed via chromatin immunoprecipitation and high throughput sequencing that this huge abundance of MeCP2 meticulously tracks the DNA methylation pattern of the cell. As a result, Skene observed that most regions of the genome bind to MeCP2, calling into question the previously assigned role of this protein as a target-specific transcription factor. This may explain why few clear gene targets for MeCP2 have been identified in the last decade.

“The brain contains many types of neurons with different functions, but interestingly it appears that the pattern of MeCP2 binding to chromosomes is broadly similar in all of them. This raises the possibility that the neuronal defect brought about by mutations in this gene affect all neurons in a similar way. If there really is a generic defect shared by many neurons, then the causes of Rett Syndrome may be less complicated than we feared. This idea now needs to be tested by further work,” said Professor Bird.

In line with its genome-wide distribution, the scientists found that MeCP2 globally impacts the packaging of the DNA in the cell. Histones are proteins which act as spools around which DNA is wound. This winding, or compaction, allows the 1.8 meters of DNA material to fit inside each of our cells. There are two classes of histones – core histones and linker histones. Core histones form the spool around which DNA winds - resembling beads on a string. The linker histones, such as histone H1, seal the DNA onto the spool formed by the core histones. In this way linker histones act as a padlock to hold the DNA in this structure and stop inappropriate access to the DNA outside of genes. In the absence of MeCP2, the amount of linker histone H1 doubles, suggesting an attempt to compensate for the lack of MeCP2.

The Bird lab also found an increase in histone acetylation in MeCP2-deficient neurons, but not in glia. These chemical modifications lead to an unwinding of the chromatin spools and potentially leave the DNA open for inappropriate expression. This suggests that the role of MeCP2 is to globally suppress the genome.

“Consistent with MeCP2 coating the entire genome, we observed global changes in the chromatin composition and activity. In the absence of MeCP2, we discovered an increase in the spurious transcription of the so-called ‘junk DNA’ which lies between genes. This suggests to us that rather than targeting specific genes, MeCP2 functions on a genome-wide level and may act as the watchdog of the neuronal genome,” said Skene.

“RSRT is pursuing two parallel approaches to interventions for Rett Syndrome. One is to find assays for MeCP2 function and then screen for anything that fixes the defect. The other is to understand as much as possible about what MeCP2 does in the brain and then design rational treatments. Understanding that MeCP2 acts in a global manner rather than as a gene-specific regulator gives us a new perspective on the molecular basis of Rett Syndrome that will aid in guiding drug development and other treatment modalities,” comments Monica Coenraads, Executive Director of RSRT and parent of a child with the disorder.

For an in-depth interview with Adrian Bird please visit the RSRT Blog, http://rettsyndrome.wordpress.com/

Source: Rett Syndrome Research Trust

Rett Search: International consortium of clinical researchers

Click on the title to go to Rett Search

Misguided neurons play role in Autism spectrum disorders

In a newly developing nervous system, there is a constant jumble of activity: Cells are growing and dividing, chemical signals are diffusing through tissues, and neurons are trying to reach their targets and maintain connections that will be used and strengthened later in the developmental process.


All of these things are happening in the same space, at roughly the same time, and it can get a bit confusing for the neurons.

The confusion is usually kept under control when cells match: One gives off a chemical signal that will help sustain the growing axons of new neurons; the chemical attracts and promotes the growth of the target neurons. This chemically-released signal is called a neurotrophic factor, and its presence is essential for the organization and proper functioning of the developing brain.

However, if this process of matching goes awry, the developing brain can run into problems: Neurons will grow wild, connections that should be made don't get made and connections that should be weeded out thrive. Chaos can ensue, and the end product is usually malfunction.

Now there is some evidence that exactly this process might be to blame for some part of the malfunctioning seen in some Autism spectrum disorders. Autism and related disorders, which comprise a highly varied spectrum of symptoms and severity, are generally characterized by impaired social abilities, as well as demonstrations of repetitive behaviors.

Scientists at Hopkins and the University Medical Center in the Netherlands have been trying to explain this varied and often debilitating spectrum of disorders at the cellular level by looking at how the brain's neurons grow and develop - as well as how they navigate through the brain to find the proper targets with which to make the proper connections that will be strengthened with use later in life.

As Alicia Degano, R. Jeroen Pasterkamp, and Gabriele Ronnett and others have begun to realize, in Autism spectrum disorders, including Rett Syndrome, which is on the spectrum, neurons aren't getting to where they need to go. They aren't making the right connections. They aren't coming together to form nerve tracts, and they aren't being guided to their proper target cells. These Hopkins researchers believe that this malfunction can be tied to a mistake in one gene, called MeCP2.

MeCP2 is involved in turning off gene expression when not needed in development. Degano and her colleagues believe that when MeCP2 doesn't work, or when it works improperly, neurons first will not develop their tips (which can become either dendrites or axons), and then later will not form the necessary connections with other neurons due to malfunctioning axon guidance. Both deficits are crippling to cells that depend on proper connections for both survival and function.


The team studied patients with Rett syndrome as well as mice with an analog disorder. In particular, they chose to study the olfactory system because neurons in the olfactory system can regenerate, which makes it easy to take one or two to study. And by being able to study neurons not just in the mouse model, but also in the actual human disorder, Degano and her fellow scientists have been able to make unparalleled comparisons of the two disorders.

Indeed, they have found out that the two models are highly similar, thereby proving the olfactory system to be an excellent site for the study of Rett syndrome and related disorders.

The similarities across species are dramatic: In both human olfactory neurons as well as in those of small mice, axons are seen to project wildly from their parent neurons outside of the bounds of normal neural tracts. This misguidance is due to the loss of chemical signaling that tells axons where to grow and how to get there.

Also, the team has observed that besides just leading to simple misguidance, MeCP2 malfunction actually alters the levels of chemical signals that are expressed in the developing brain; it is most likely due to these altered levels that targeting and connection goes so badly awry.

This study, while helpful in understanding the mechanism of Rett syndrome and of other Autism spectrum disorders, is merely a stepping stone for Degano and her fellow scientists. They plan to perform further studies to investigate which chemical signals in particular are implicated in the malfunction seen in Rett syndrome as well as to further develop their understanding of the present findings.

Source: The John Hopkins News-letter

Rett syndrome and DSM-V: Interview of Dr. Huda Zoghbi

As many parents may already know, the Diagnostic and Statistical Manual of Mental Disorders, known as the DSM, is in the process of reevaluating criteria for the new edition to be published in 2013, the DSM V. There is discussion among members of the Rett community and the Asperger’s community about the decisions to drop both diagnoses from the manual. How this change might impact services, particularly intensive educational intervention for Rett children, is unknown and will probably vary from state to state. People who would like to express their opinions to the DSM committee may do so until April 20, 2010.


RSRT scientific advisory board member and Rett Syndrome researcher Huda Zoghbi , M.D. discusses the DSM reclassification with Monica Coenraads.

Huda Zoghbi will be appearing on the Charlie Rose Show on Tuesday, February 23. The episode, entitled “The Developing Brain” is part of the “Charlie Rose Brain Series” hosted jointly with Nobel Laureate, Eric Kandel, Ph.D. of Columbia University.........................



To read more, Click on the title....

Source:

Rett Syndrome Research Trust Blog

Neuropathology of Rett syndrome

By Dr. D. Armstrong

Introduction

The features of the disorder that has become known as Rett syndrome were observed first in 1977 in Austria by Andres Rett^[1] and in 1983 in Sweden by Hagberg and his European colleagues.^[2] It is now recognized worldwide, usually presenting in a small girl with loss of speech and of purposeful hand use and the presence of stereotopies and ataxia. Some girls cannot walk, and many have epilepsy. Jellinger and Seitelberger made the first report of a series of eight Rett syndrome cases and observed decreased brain weight and decreased pigmentation of the substantia nigra pars compacta.^[3] Riederer and colleagues described the altered chemistry associated with Rett syndrome.^[4] Since these early reports, clinician-scientists have come to better understand this rare disorder in large part because the determination and encouragement of parents have prompted progress in the field. Even so, defining each aspect of the clinical-pathologic features of Rett syndrome has been difficult.

For example, it has been a challenge to determine that Rett syndrome is a genetic disorder. It affects girls and seems to be primarily a sporadic disease, with few familial cases. The identification of the X-linked MECP2 as the causative gene required careful collaborations among laboratories, extensive study, and sharing of data.^[5]Mutations in the MECP2 gene in exons 1 to 4 or DNA deletions have now been identified in more than 90% of Rett syndrome cases.^[5–8] Abnormalities in MECP2 have also been detected in some boys with an infantile encephalopathy,^[9] in some children with an Angelman syndrome phenotype,^[10] and in some boys with mental retardation.^[11] Three animal models are now being used to clarify the relationship of MECP2 to the pathogenesis of Rett syndrome ( Table 1 ).^[12–14]

The definition of the clinical features of Rett syndrome has also been evasive. Classic and variant forms have been defined. Genotype-phenotype correlations are now being made, and international data registries have been created to facilitate these associations.^[15]

The patient with Rett syndrome is small, and studies of growth have identified disorders of swallowing mechanisms.^[16] The characterization of motor problems, absence of speech, loss of hand use, stereotopies, ataxia, dystonia, and hypertonicity or hypotonicity has been problematic.^[17] The cognitive aspects of Rett syndrome have evaded definition because of problems in testing patients who have no speech or hand use. Girls display abnormalities of breathing, heart rate, peripheral circulation, and emotional hyperexcitability that have to be distinguished from autonomic dysfunction and seizures.^[18–20] These complex clinical features in aggregate define a unique and demanding clinical situation requiring complete daily care by parents and innovative assistance from physicians and support groups. The relatively healthy patients with Rett syndrome survive into the fourth and fifth decades, although there is an increased incidence of sudden death in the adolescent years.^[21]

Neurochemistry

The neurochemistry of Rett syndrome ( Table 2 ) has been difficult to determine in patients.^[22–41] Studies on cerebrospinal fluid and brain tissue have analyzed transmitters, their receptors, and additional trophic factors. Abnormalities have been reported in most systems, including in acetylcholine, dopamine, serotonin, glutamate substance P, and new nerve growth factor. The age of the patient with Rett syndrome^[29] and the severity of the symptoms^[31]influence measurements. Wenk concluded that the studies of neurotransmitters and peptides were variable except for acetylcholine, whose markers were consistently reduced.^[35]Kaufmann concluded in his review that dopamine is involved in the striatonigral system and in forebrain choline acetyltransferase expression, with a moderate reduction in cortical cholinergic innervation and an elevation of glutamate and of some glutamate receptor subtypes in younger subjects with Rett syndrome.^[32] The clearer documentation of the alterations in chemistry with relation to age is still needed. The changes in the neurotransmitters and other trophic factors are of great importance, early on for their role as neurotrophins in brain development and later for their role in normal functioning of the mature brain. It is hoped that animal models will allow for more controlled examinations of how these important chemicals are altered in Rett syndrome.

Pathology

In this article, I elaborate on the observations that have been made suggesting that neuronal maturation is defective in Rett syndrome and on the observations about MECP2 expression that coincide with these observations.

The infant girl with Rett syndrome is nondysmorphic, with a head circumference that is normal at birth but that begins to decelerate in its growth at 2 to 3 months of age. The other growth parameters (ie, height, weight, hand, foot size) decline later.^[42] Autopsies of patients with Rett syndrome of various ages reveal that all organs, except the adrenal gland, are small for the age of the patient but not for the height. The brain, however, is an exception. The average brain weight is 900 g, the brain weight of a 1-year-old infant. Thus, the weight of the Rett syndrome brain is significantly less than that of the brain of non–Rett syndrome controls for age and for height (Figure 1). The identification of this preferential involvement of the brain suggested that Rett syndrome was a disease of the nervous system. This has been endorsed by the observations that MECP2 is expressed primarily in neurons.^[43] The weight of the Rett syndrome brain does not decrease significantly with age, so atrophy does not account for the small size, an observation that has been confirmed by imaging studies of patients with Rett syndrome.^[32]

The decrease in brain weight is not generalized. The cerebral hemispheres are affected more than the cerebellum. The brainstem weights have not been compared with those of non–Rett syndrome brains because of the various techniques of brainstem dissection (Figure 2). Imaging studies define alterations in brain volumes in prefrontal, posterior frontal, and anterior temporal regions, with relative preservation in the posterior temporal and posterior occipital regions.^[44,45]

With routine examinations, the Rett syndrome brain reveals no obvious alteration in the blood vessels, cranial nerves, gyri, white matter, basal ganglia, cerebellum, brain stem, or spinal cord, although these have not been evaluated quantitatively in detail. Single reports of cerebellar and spinal cord neuronal loss with time have been recorded,^[46,47] and there have been no consistent reports of changes in glia or in the accumulation of lipofuschin. Kaufmann found some increase in glial fibrillary acidic protein expression but could not determine if this is a primary or a secondary phenomenon.^[32] It has been generally concluded that no recognizable degenerative, demyelinating, or gross malformative process explains the Rett syndrome phenotype.

Studies of the Cerebral Cortex

To study the decreased size of the Rett syndrome brain, the cerebral cortex was examined with the Golgi technique. Pyramidal neurons of layers III and V of the frontal, motor, occipital, superior temporal, and inferior temporal cortices and layers II and IV of the subicular cortex and the neurons of Ca1 of the hippocampus were evaluated using camera lucida drawings and the Scholl analysis. There was a significant decrease in the dendritic territories in Rett syndrome of the frontal, motor, and subicular cortices when compared with non–Rett syndrome cases and trisomy 21 cases.^[48,49] The decreased dendritic territories in selected regions of the Rett syndrome brain correlated with other observations that defined in the cortex, thalamus, basal ganglia, amygdala, and hippocampus a decreased neuronal size and in the hippocampus an increased neuronal packing density.^[50] Casanova and colleagues studied cortical minicolumns in areas 9, 21, and 22 in five Rett syndrome brains. The minicolumns are reduced in size, significantly so, in area 21. The minicolumn is defined as the smallest functional unit of the cerebral cortex, and its diminished size in Rett syndrome could reflect the decreased dendritic branching of neurons that was observed in the Golgi studies or other undefined associations.^[51] Belichenko and colleagues made quantitative studies observing a decreased number of neurons in layers II and III of the frontal and temporal cortices,^[52] and in the speech cortex a normal number of neurons, a preservation of the size differences between the dominant and nondominant hemispheres, and reduced numbers of parvalbumin-positive interneurons and synaptic sites.^[53] Belichenko and colleagues observed decreased numbers of dendritic spines and afferent axons in the frontal cortex of four patients with Rett syndrome.^[54,55]

Studies in Other Brain Regions

In the midbrain and substantia nigra, the large neurons of pars compacta have less melanin and tyrosine hydroxylase staining than controls.^[3] Imaging studies record decreased volumes of the midbrain, caudate, putamen, and thalamus.^[44] The neurons of the globus pallidus were observed on Golgi studies to have altered contours and appendages in the region of the upper extremity.^[56] In the cerebellum, a progressive loss of neurons with increasing age was observed in autopsy tissue,^[46] and by magnetic resonance imaging.^[57] In the spinal cord, there is a report of anterior horn neuronal loss and gliosis in the corticospinal tracts of two patients.^[47]

The clinical expression of breathing irregularities, heart rate variability, small cold feet, constipation, and difficulties in swallowing suggests autonomic impairment. Functional studies of the vagus nerve define an abnormality of vagal tone.^[58] Limited brainstem studies suggest abnormalities in serotonin receptors and in substance P content.^[41,59]

In the peripheral nerve, a mild distal axonal neuropathy was observed in 7 of 12 cases by Haas^[60] and in 4 of Jellinger and colleagues' cases.^[61] Muscle biopsies have shown variable Results, including type II atrophy, type I atrophy, myopathic changes (in a rare case), alterations in mitochondrial morphology, and a reduction in mitochondrial enzyme levels.^[61] Continuing reports of altered chemistry and mitochondrial enzymes suggest either primary or secondary involvement.^[62–64]

In summary, the major morphologic change in the Rett syndrome brain is a decrease in the size of the brain and of individual neurons, which show less dendritic arborization and spines than the non–Rett syndrome neurons. There is no obvious atrophy or degeneration, so the neuropathologic process in Rett syndrome has been hypothesized to be one of a failure of development.

Studies Related to MECP2

MECP2 modifies gene expression by inhibiting transcription, and this function would seem to be significant in the genetic control of brain development. The distribution of MECP2 protein has been studied in the developing human brain and in Rett syndrome.^[65] The earliest normal expression of MECP2 at 10 gestational weeks is in the nuclei of isolated cells of the cerebral subventricular zone, of the brain stem, and of the subcortical and Cajal-Retzius neurons of the cerebral cortex. The expression of MECP2 appears next in the thalamus, midbrain, and basal ganglia. The hippocampus and the cerebellum show less expression early in development, but with maturation, most neurons, but not glia, express MECP2. The cerebral cortical neurons continue to show increasing amounts of MECP2-immunopositive neurons into the adolescent years.^[43]

The interpretation of the immunochemical marking for MECP2 has been complicated by the availability of consistent antibodies, by antibodies that identify various epitopes, and by the observed variability of intensity of staining at various ages and within the same types of neurons. Most staining appears in the nucleus, but there is slight cytoplasmic staining in some neurons whose cytoplasm can be recognized by routine histology. LaSalle and colleagues, using laser scanning cytometry, were able to quantitate the expression of MECP2 in the human and murine brain and confirmed the presence of both a low and a high expression of MECP2 immunoreactivity.^[66]They studied the ontogeny of MECP2 in the developing mouse brain and showed that near the time of birth (E10–E19), MECP2 of the low expression type is abundant in the medulla and thalamus. The expression decreases after birth and then gradually increases (after 5 days) to increasing levels of high MECP2 expression in all neurons in the brain (3–40 weeks).^[67] The Ronnet laboratory showed a similar pattern of variable MECP2 expression in the neurons of the olfactory epithelium and identified MECP2 expression in the immature and mature olfactory receptor neurons prior to synaptogenesis in those neurons. They demonstrated in the mouse olfactory epithelium that when synaptogenesis was blocked by axonotomy, the expression of MECP2 was decreased.^[68] These observations draw attention to the role of MECP2 in synaptogenesis. Kaufmann's study on the location of MECP2 revealed that it is present not only in the nucleus but also in the postsynaptic compartment of the neuron, where it is available to react in response to neuronal activity.^[69] Ronnett's continuing examination of the effect of MECP2 deficiency on the olfactory epithelium in the MECP2-null mouse,^[70] and in the olfactory epithelium of patients with Rett syndrome showed that their olfactory receptor neurons exhibit a delay in maturation. In addition, the axonal projections of the MECP2-null animals are disorganized, resulting in a reduced size of the olfactory glomeruli.^[71]

LaSalle studied the expression of MECP2 in female mice heterozygous for MECP2. The MECP2-negative cells were found to be uniformly distributed, and using tissue microarrays, she observed that the percentage of MECP2-negative cells was less than the expected 50%, in the range of 20% to 39%. This was interpreted to mean that an unbalanced X-chromosome inactivation pattern favors inactivation of the mutant allele. The MECP2 expression pattern in the cells that do express MECP2, however, differed from the Wt expression of MECP2, exhibiting more cells of the low expression type and suggesting that mutant MECP2 can influence the Rett syndrome phenotype by both cell-autonomous and non–cell-autonomous mechanisms. Similar observations were made on tissue microarrays of frontal cortex of three patients with Rett syndrome.^[67]

Discussion of MECP2 in Neuronal Maturation and in Rett Syndrome

In Rett syndrome, there is a low brain weight, a reduced branching of dendrites, and a decrease in dendritic spines. The studies on the ontogeny of MECP2 expression reveal that MECP2 is a marker of the "maturing neuron"^[43,72,73] being expressed in neurons as they mature and take up critical locations for the continuing development of the brain. The increase in MECP2 expression in the brain after the prenatal period, when most apparent brain development occurs, suggests that MECP2 might also be required for neuronal maintenance and function.

On the basis of these observations, and the fact that the child with Rett syndrome has a deceleration in growth of the head circumference during the time that rapid synaptogenesis is occurring, it has been postulated that synaptogenesis is deficient in Rett syndrome. This is supported by the observations that in mice MECP2 is expressed prior to synaptogenesis so that, presumably, the MECP2-deficient Rett syndrome brain would have fewer synapses. The animal models suggest a hypothesis that addresses the deficiency of synapses.

In normal early embryonic life, MECP2 is expressed in two developmentally important regions: the medulla and the thalamus. In normal brain development, the neurons of the medulla express critical trophic catecholamines (noradrenaline and serotonin)^[74] and send nonspecific afferents to the developing cortex, where they influence migration and organization of neuronal systems. MECP2 deficiency in brainstem neurons, subplate, and Cajal-Retzius neurons (and all neurons required for critical stages of development) would alter the efficacy of these neurons by interfering with their maturation, causing a reduced production of trophic factors,^[74] receptors,^[75] early response genes,^[76] and structural proteins^[77] and disorganization of cortical columns,^[51] dendrite growth, and synapse formation.^[48]

Studies of MECP2 in the olfactory epithelium of mice have shown that MECP2 is expressed prior to synapse formation and that interfering with synapse formation reduces the amount of MECP2 expression.^[68,70] LaSalle's model suggests that in the normal maturation of neurons, the neurons that express a low level of MECP2 are modified by a non–cell-autonomous mechanism (possibly by synaptic stimuli from surrounding neurons) to express MECP2 at a high level. Thus, through cell-autonomous and non–cell-autonomous regulation, the availability of MECP2 in individual neurons will influence its role in the genetic regulation of maturation. In the Rett syndrome brain, with fewer synapses, the expression of MECP2 is less than optimum. This direct role of MECP2 in response to neuronal activity has been suggested by two other studies. Kaufmann and colleagues' identification ofMECP2 in the postsynaptic compartment of neurons places it in a site where it is available to respond to neuronal activity.^[78] Chen and colleagues also demonstrated that calcium entry into the cell causes phosphorylation of MECP2 and releases its inhibitory role, enabling the transcription of brain-derived neurotrophic factor.^[79]

The abnormalities that we have observed in the anatomy, chemistry, and clinical manifestations of Rett syndrome all suggest that MECP2 is essential for neuronal maturation. The signal for the initial expression of MECP2 in a neuronal precursor cell can be regulated by a cell-autonomous mechanism. Its increasing expression in fully mature neurons can then be regulated in part by external factors, such as synaptic input. Proteomic studies of olfactory epithelium at the age at which synaptogenesis is taking place demonstrate that MECP2 deficiency alters some of the proteins required for neuronal outgrowth, path finding, and cell connections. It is also required for proteins involved in mitochondrial activity and stress management.^[80] Thus, MECP2 appears to be required for both the structural and the functional maturity of neurons (Figure 3). To promote neuronal maturation in children with Rett syndrome, it will be necessary now to determine how MECP2 deficiency can be treated.

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Presented as part of the Rett Syndrome, Neurobiology of Disease in Children, National Institutes of Health Conference in Ottawa, ON, Canada, October 13–16, 2004, in conjunction with the 33rd annual meeting of the Child Neurology Society.Presented as part of the Rett Syndrome, Neurobiology of Disease in Children, National Institutes of Health Conference in Ottawa, ON, Canada, October 13–16, 2004, in conjunction with the 33rd annual meeting of the Child Neurology Society.

Indian Rett Syndrome Foundation Blog: Testing and Diagnosis of Rett syndrome in India

Indian Rett Syndrome Foundation Blog: Testing and Diagnosis of Rett syndrome in India

Testing and Diagnosis of Rett syndrome in India

Diagnosis of Rett syndrome is done in the presence of a team of doctors including Clinical geneticists, Neurologists and psychologists and is based on the worldwide accepted Diagnostic criteria of Rett syndrome (clinical diagnosis) and molecular diagnosis, which is done by testing the MECP2 and CDKL5 gene in these patients. If you have any queries regarding Rett syndrome and if  you want to get your child tested for Rett syndrome, then please contact the following Lab.

Molecular Genetics Lab,
Genetics Unit, Department of Pediatrics,
Old O.T Building, Room No.110, First floor,
All India Institute of Medical Sciences (AIIMS),
New Delhi-110029
India
Phone:- +919999343421
             +911126594585