Rett Syndrome and MeCP2

Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.     

Congenital variant of Rett syndrome due to an intragenic large deletion in MECP2

Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6 months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.     

The Role of MeCP2 in Brain Development and Neurodevelopmental Disorders

Methyl CpG binding protein-2 (MeCP2) is an essential epigenetic regulator in human brain development. Rett syndrome, the primary disorder caused by mutations in the X-linked MECP2 gene, is characterized by a period of cognitive decline and development of hand stereotypies and seizures following an apparently normal early infancy. In addition, MECP2 mutations and duplications are observed in a spectrum of neurodevelopmental disorders, including severe neonatal encephalopathy, X-linked mental retardation, and autism, implicating MeCP2 as an essential regulator of postnatal brain development. In this review, we compare the mutation types and inheritance patterns of the human disorders associated with MECP2. In addition, we summarize the current understanding of MeCP2 as a central epigenetic regulator of activity-dependent synaptic maturation. As MeCP2 occupies a central role in the pathogenesis of multiple neurodevelopmental disorders, continued investigation into MeCP2 function and regulatory pathways may show promise for developing broad-spectrum therapies.     

MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders

Background: Mutations in the MECP2 gene (methyl-CpG-binding protein-2) are responsible for 60–95% of cases of Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder affecting mostly girls. Classic RTT is characterized by normal early development followed by psychomotor regression and onset of microcephaly, although variant forms are also observed. MECP2 has also been implicated in variable mental retardation (MR) phenotypes, including X-linked Mental Retardation (XLMR), Fragile-X-like Syndrome (FXS) and Angelman-like (AS) phenotypes. Aim: The aim of the study was: (a) to evaluate the incidence and spectrum of MECP2 mutations in children with RTT and variant MR; (b) to evaluate phenotype-genotype correlations. Methods: Exons 3–4 were analyzed for mutations in 281 MR patients (aged 13 months–27 years old, 144 males–137 females) consisting of 88 patients referred for RTT and 193 patients referred for AS-like and FXS-like types of MR. Statistical analysis included correlation between classic MECP2-positive and MECP2-negative and variant RTT patients, and frequency of MECP2 mutations in the various categories. Results: Mutations were detected in ≈70% of classic and ≈21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. MECP2-positive females had more problems in ambulation, muscle tone, tremor and ataxia, respiratory disturbances, head growth, hand use and stereotypies. Classic RTT-positive versus negative had significant respiratory and sitting problems and versus variant RTT-positive females ambulatory, hand and stereotypies problems. Conclusion: The analysis of the MECP2 gene could provide a diagnostic tool for RTT and non-specific MR research.     

Brief Report: MECP2 Mutations in People Without Rett Syndrome

Mutations in Methyl-CpG-Binding protein 2 (MECP2) are commonly associated with the neurodevelopmental disorder Rett syndrome (RTT). However, some people with RTT do not have mutations in MECP2, and interestingly there have been people identified with MECP2 mutations that do not have the clinical features of RTT. In this report we present four people with neurodevelopmental abnormalities and clear RTT-disease causing MECP2 mutation but lacking the characteristic clinical features of RTT. One patient’s symptoms suggest an extension of the known spectrum of MECP2 associated phenotypes to include global developmental delay with obsessive compulsive disorder and attention deficit hyperactivity disorder. These results reemphasize that RTT should remain a clinical diagnosis, based on the recent consensus criteria.     

Rett syndrome

PURPOSE OF REVIEW: Nearly 70 reports on Rett syndrome were published in 2004. We have selected 51 articles, including clinical reports, on pathophysiology, genotype-phenotype correlation, and clinical and basic molecular biology studies. These articles explain how mutation of the gene (MECP2) for methyl-CpG-binding protein 2 causes the particular disorders of Rett syndrome, and also induces other neurodevelopmental disorders, clarifying the situation for future studies. RECENT FINDINGS: The role of X-chromosome inactivation has been clarified in animal experiments. New isoforms of MeCP2 have been discovered and its functional characteristics are under research. Understanding of the influence of the MECP2 mutation on other neurodevelopmental disorders has increased. However, there is no apparent progress in neurophysiological studies. SUMMARY: Clinical studies included the pathophysiology of stereotyped movement, and cardiac and respiratory disturbances, and there were four therapeutic trials including one for epilepsy. For genotype-phenotype correlation the role of X-chromosome inactivation was looked at and its basic mechanisms were studied extensively in animals. Characteristics of mutations in the C-terminus and the biological function of the new isoform, exon 1, were introduced. In studies on related neurodevelopmental disorders, a relationship is suggested between the MECP2 gene and autism-related gene, with overlapping pathways, but this is not common to other neurodevelopmental disorders. Developmental studies suggest an important role for MeCP2 in the formation and/or maintenance of synapses, and clarify the molecular biological aspects of Rett syndrome. However, early involvement of the aminergic neurons, suggested as the basic, pathognomonic lesion of Rett syndrome, has unfortunately not been investigated with the MECP2 mutation.     

The spectrum of phenotypes in females with Rett Syndrome

Since the discovery of mutations in the methyl-CpG binding protein-2 (MECP2) gene in Rett Syndrome (RTT) a large number of females have been diagnosed worldwide. In this article we present the clinical and developmental data of 120 RTT females with mutations in the MECP2 gene and individually describe typical and atypical cases. We found a broad spectrum of phenotypes in females. At the severest end we have females with primary developmental delay who never learned to turn, sit or walk and who developed severe epilepsy. At the mildest end of the spectrum, there are females with only minor neurological symptoms who have good gross motor function, speak and have relatively well-preserved hand function. A number of girls either do not fulfil all the necessary diagnostic criteria or present with symptoms that have not been described in RTT before. Comparing our data with the normal population we found that girls with RTT have a smaller occipito-frontal circumference, shorter length and lower weight at birth. As a result of molecular genetic analysis a broad spectrum of phenotypes in RTT females has evolved. We found evidence that the defect in MeCP2 influences the somatic growth before birth.     

A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3?years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation.     

Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.     

Mutation spectrum and genotype-phenotype correlation of MECP2 in patients with Rett syndrome

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder characterized by regression in cognition and adaptability with autistic behavior, stereotypical hand movements, epilepsy and ataxia. Over 120 different mutations in the methyl-CpG binding protein 2 gene (MECP2) have been reported in patients with RTT, but a genotype-phenotype correlation has not been established. We have studied MECP2 mutations in 142 Japanese sporadic patients diagnosed clinically as having RTT. Forty different mutations in MECP2 have been detected in 103 female patients. Common mutations were four missense mutations (T158M,P152R, R133C and R306C) observed in 34 cases and four nonsense mutations (R168X, R255X, R270X and R294X) detected in 38 cases. Among these, R133C, R306C, and R294X were associated with atypical RTT including the preserved speech variant type, T158M and R168X with typical clinical features of RTT, and P152R, R255X, and R270X with severe developmental delay. These results suggest a genotype-phenotype correlation RTT. However, a large scale study of adult RTT patients is required to determine more precisely the influence of MECP2 mutation types on the natural history and clinical phenotypes of RTT.     

Altered methylation pattern of the G6 PD promoter in Rett syndrome

Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects girls. Recently mutations in MECP2, that encodes the methyl CpG binding protein 2 (MeCP2), have been found to cause RTT. MeCP2 has a role in gene silencing. It binds to methylated cytosine in the DNA and recruits histone deacetylases. We studied the methylation pattern of the promoters of two X chromosomal genes, G6 PD and SYBL1, in patients with RTT and in a control group. Both genes undergo X inactivation which correlates with promoter methylation. A 1 : 1 ratio of methylated versus non-methylated alleles was expected. In the control group a median ratio of 47 : 53 of methylated to non-methylated alleles was found at the G6 PD promoter locus. In 22 patients with RTT the median ratio was significantly different, 33 : 67 (p < 0.0001). Analysis of the SYBL1 promoter revealed an almost identical median ratio of methylated versus non-methylated alleles (RTT 47 : 53; control 49 : 51), however, the range was wider in the RTT group (RTT 23 : 77 to 56 : 44; control 43 : 57 to 55 : 45). There was no apparent correlation between G6 PD promoter methylation status and mutations in the MeCP2 gene or the severity of the clinical phenotype in our patient group. The finding of reduced methylation at the G6 PD promoter is an interesting finding and suggests that there could be widespread dysregulation of X chromosomal genes in Rett syndrome.     

MeCP2 Phosphorylation Is Required for Modulating Synaptic Scaling through mGluR5

MeCP2 (methyl CpG binding protein 2) is a key player in recognizing methylated DNA and interpreting the epigenetic information encoded in different DNA methylation patterns. The functional significance of MeCP2 to the mammalian nervous system is highlighted by the discovery that mutations in the MECP2 gene cause Rett syndrome (RTT), a devastating neurological disease that shares many features with autism. Synaptic scaling is a form of non-Hebbian homeostatic plasticity that allows neurons to regulate overall excitability in response to changes in network neuronal activity levels. While it is known that neuronal activity can induce phosphorylation of MeCP2 and that MeCP2 can regulate synaptic scaling, the molecular link between MeCP2 phosphorylation and synaptic scaling remains undefined. We show here that MeCP2 phosphorylation is specifically required for bicuculline-induced synaptic scaling down in mouse hippocampal neurons and this phenotype is mediated by mGluR5 (metabotropic glutamate receptor 5). Our results reveal an important function of MeCP2 in regulating neuronal homeostasis and may eventually help us understand how MECP2 mutations cause RTT.