Neonatal Encephalopathy in Two Boys in Families With Recurrent Rett Syndrome
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Rett syndrome (RTT) has been described in its classic form only in females. Although the majority of cases are sporadic, familial cases give valuable insight into the genetic basis and phenotypic variability of the disorder. The exclusive occurrence of classic Rett syndrome in females led to the hypothesis that the Rett syndrome locus is likely to be X-linked and mutations are lethal in hemizygous males. We identified two boys in families with recurrent Rett syndrome who had encephalopathies with neonatal onset and who may represent the phenotype of males harboring Rett syndrome muta tions. The difference in severity of disease in these males and their female relatives supports the location of Rett syndrome locus on the X-chromosome. (J Child Neurol 1998;13:229-231).Keywords:
Rett Syndrome
MeCP2
Neurodevelopmental disorder
Rett syndrome (RTT) is a neurodevelopmental disorder predominantly occurring in females with an incidence of 1:10,000 births and caused by sporadic mutations in the MECP2 gene, which encodes methyl-CpG-binding protein-2, an epigenetic transcription factor that binds methylated DNA. The clinical hallmarks include a period of apparently normal early development followed by a plateau and then subsequent frank regression. Impaired visual and aural contact often lead to an initial diagnosis of autism. The characterization of experimental models based on the loss-of-function of the mouse Mecp2 gene revealed that subtle changes in the morphology and function of brain cells and synapses have profound consequences on network activities that underlie critical brain functions. Furthermore, these experimental models have been used for successful reversals of RTT-like symptoms by genetic, pharmacological and environmental manipulations, raising hope for novel therapeutic strategies to improve the quality of life of RTT individuals.
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Rett Syndrome
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Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.
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Rett syndrome is a leading cause of postnatal neurodevelopmental regression. Rett syndrome is caused by mutations in MECP2, the gene encoding methyl-CpG binding protein 2. In up to 96% of all classic cases, Rett syndrome cases are caused by mutations or deletions in MECP2. The phenotypic spectrum of MECP2 mutations is broad and includes mental retardation with or without seizures, Angelman syndrome—like phenotype, and autism. Mecp 308/Y mice carry a truncating mutation and display many of the features seen in Rett syndrome. Social behavior abnormalities and impaired social interactions in Mecp 308/Y mice suggest that MeCP2 plays a role in modulating the activity of genes and neurons important for social interactions. Mice that overexpress MeCP2 at twice the endogenous levels develop a progressive neurologic disorder, demonstrating that MeCP2 levels are tightly regulated and raising the possibility that duplications or gain-of-function mutations of MECP2 might underlie some cases of neurodevelopmental X-linked disorders. ( J Child Neurol 2005;20:736—740).
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Rett Syndrome
MeCP2
Neurodevelopmental disorder
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Rett syndrome is an X-linked dominant neurodevelopmental disorder. Mutation of the methyl-CpG-binding protein 2 gene (MECP2) is present in up to 96% of patients with Rett syndrome. Eight mutations represent the hotspot of MECP2 mutations (R106W, R133C, T158M, R168X, R255X, R270X, R294X, and R306C) in patients with classic Rett syndrome. The prevalence and survival rate of Rett syndrome among Chinese women was investigated. The 8 hotspot mutations and the A140V mutation were also studied in 4 cohorts of Chinese children (n = 144) actively followed up in our university neurodevelopmental center with classic Rett syndrome (n = 5), autism spectrum disorder (n = 94), epileptic encephalopathy of unknown cause (n = 22), and nonsyndromal mental retardation (n = 23). The prevalence of Rett syndrome among female Chinese younger than 35 years in Hong Kong West is 0.57 (95% confidence interval, 0.15-0.98) per 10 000. Survival is 100.0% at 10 years and 87.5% at 25 years. Three hotspot mutations (R106W, R255X, and R306C) were found in 3 girls with classic Rett syndrome. No hotspot MECP2 mutations were found in the other 3 cohorts. Screening of MECP2 mutations is not worthwhile in Chinese children with pure cognitive, autistic, or unexplained epileptic disorders without other signs of Rett syndrome. In the early stage of developmental arrest before developmental regression, MECP2 screening might be useful for girls with unexplained epileptic encephalopathy before full-blown classic Rett syndrome is evident.
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Rett syndrome (RTT) is a rare genetic neurodevelopmental disarray in which children are mostly effected with relapse of previously acquired skills after a period of normal development. Rett syndrome is usually identified in children age between 6to 18 months as they begin to lose the abilities they gained.it is caused by the mutation on the x chromosome on a gene MECP2.There are about 900 different mutations found on MECP2 gene. It is not a degenerative disorder. The course and severity of Rett syndrome is determined by the location, type and severity of the mutation and X-inactivation. In more than 99 percent of people with Rett syndrome, there is no history of the disorder in their family.
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Rett Syndrome
MeCP2
Neurodevelopmental disorder
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Rett syndrome (RTT, MIM#312750) is a neurodevelopmental disorder that is classified as an autism spectrum disorder. Clinically, RTT is characterized by psychomotor regression with loss of volitional hand use and spoken language, the development of repetitive hand stereotypies, and gait impairment. The majority of people with RTT have mutations in Methyl-CpG-binding Protein 2 (MECP2), a transcriptional regulator. Interestingly, alterations in the function of the protein product produced by MECP2, MeCP2, have been identified in a number of other clinical conditions. The many clinical features found in RTT and the various clinical problems that result from alteration in MeCP2 function have led to the belief that understanding RTT will provide insight into a number of other neurological disorders. Excitingly, RTT is reversible in a mouse model, providing inspiration and hope that such a goal may be achieved for RTT and potentially for many neurodevelopmental disorders.
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Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder typically affecting females, resulting in a range of symptoms including autistic features, intellectual impairment, motor deterioration, and autonomic abnormalities. RTT is primarily caused by the genetic mutation of the Mecp2 gene. Initially considered a neuronal disease, recent research shows that glial dysfunction contributes to the RTT disease phenotype. In the following manuscript, we review the evidence regarding glial dysfunction and its effects on disease etiology.
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Rett syndrome, one of the leading causes of mental retardation and developmental regression in girls, is the first pervasive developmental disorder with a known genetic cause. The majority of cases of sporadic Rett syndrome are caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 binds methylated DNA and likely regulates gene expression and chromatin structure. Genotype/phenotype analysis revealed that the phenotypic spectrum of MECP2 mutations in humans is broader than initially suspected: Mutations have been discovered in Rett syndrome variants, mentally retarded males, and autistic children. A variety of in vivo and in vitro models has been developed that allow analysis of MeCP2 function and pathogenic studies of Rett syndrome. Because the neuropathology of Rett syndrome shares certain features with other neurodevelopmental disorders, a common pathogenic process may underlie these disorders. Thus, Rett syndrome is a prototype for the genetic, molecular, and neurobiological analysis of neurodevelopmental disorders.
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Angelman Syndrome
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