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Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder and affects mainly females. The prevalence is 1 in 10,000 girls by the age of 12,1 making it one of the most common genetic causes of severe cognitive impairment in girls. RTT is caused by mutations in the MECP2 gene located at Xq28. MECP2 encodes a nuclear protein (MeCP2) that binds methylated DNA. The function of MeCP2 protein has not been fully elucidated; it is thought to mediate transcriptional silencing and epigenetic regulation of genes in regions of methylated DNA through its association with 5-methylcytosine–rich heterochromatin and may play a role in modulation of RNA splicing as well.2 There are different levels of expression depending on the tissue and developmental stage. Mutations in MECP2 can result in a similar constellation of neuropsychiatric abnormalities with either gain or loss of protein function. For example, MECP2 duplications have been reported in males with severe cognitive impairment.

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Approximately 99% of Rett syndrome cases are sporadic, resulting from a de novo mutation in most of the affected children or from inheritance of the mutation from 1 parent with germline mosaicism. In rare cases, it can be inherited from an unaffected or mildly affected mother with a favorably skewed X chromosome inactivation.

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Clinical Presentation

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Clinically, MECP2-related disorders present a spectrum of phenotypes, including classic RTT, variant RTT, and very mild learning disabilities in females. This variability may be related to the pattern of the X-chromosome inactivation, and depending on a favorable X skewing, some patients can be mildly affected or even asymptomatic. Another source of variability may be somatic mosaicism for the MECP2 mutations.

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In males, MECP2 mutations have a range of effects from syndromic or nonsyndromic cognitive impairment to a severe neonatal encephalopathy.3 Mutations leading to a classic RTT in females cause severe encephalopathy and breathing anomalies in males, and these patients usually die before the age of 1 year. A classic RTT phenotype can be seen in patients with 47,XXY karyotype or somatic mosaicism. Some mutations with no phenotypic effect in females can cause severe cognitive impairment or psychiatric disorders.

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Classical RTT symptoms appear in stages (eFig. 575.1).4-6 Girls are characterized by an apparent normal prenatal, perinatal, and early infancy period. At 6 to 18 months of age, they start a developmental stagnation period characterized by hypotonia and slow head and general growth. This is followed by regression in language and motor skills; social interaction and cognitive functioning; loss of purposeful hand use, which is replaced with stereotyped hand-wringing or “washing” movements; autistic-like behavior; disturbed sleep; breathing abnormalities; vasomotor changes; limb spasticity and gait ataxia/apraxia. This regression is followed by a pseudostationary stage characterized by amelioration of autistic-like behaviors, weight loss, osteopenia, scoliosis, motor problems, dystonia, rigidity, and foot and hand deformities. About 90% of patients develop seizures. In the late stage, motor deterioration continues, scoliosis is more ...

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