Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that afflicts females after 6 to 18 months of apparently normal development. Around this time, they enter a short period of developmental stagnation followed by rapid regression in language and motor development. A hallmark of RTT is the loss of purposeful hand use followed by repetitive, stereotyped hand movements. Additional features include autistic behavior, gait ataxia and apraxia, seizures, episodic apnea and/or hyperpnea, bruxism, and acquired microcephaly. After this period of rapid deterioration, the disease becomes relatively stable, but patients reaching the second or third decade may show additional neurologic abnormalities, such as seizures, dystonia, parkinsonism, spasticity, and kyphoscoliosis. X-linked inheritance explains the existence of a few males with severe neonatal encephalopathy born into families affected by RTT.
No laboratory findings have proven consistent enough to be diagnostically useful. The EEG is typically normal for the first 2 years of life, after which patients lose occipital dominant rhythm and background activity. CT and MRI show cortical atrophy and sometimes narrowing of the brain stem; PET reveals reduced cerebral blood flow in the prefrontal and temporoparietal association regions. Brains of RTT patients weigh less than age-matched controls; there is mild cortical and cerebellar atrophy but no evidence of neuronal loss. Select neuronal populations show reduced dendritic arborization, smaller neuronal size, and increased neuronal density.
Current effective management of RTT patients focuses on supportive and symptomatic therapy, for example, anticonvulsants for seizures, chloral hydrate for agitation, carbidopa/levodopa for rigidity, and melatonin for sleep disturbances. Nutritional management is important to ensure adequate caloric and fiber intake.
RTT is caused by any of various mutations in the the gene that encodes methyl CpG-binding protein 2 (MECP2) gene, which encodes the methyl CpG-binding protein 2. This ubiquitous protein assists in transcriptional silencing by binding to symmetrically methylated single CpGs in double-stranded DNA. The transcriptional repression domain binds to the corepressor Sin3A and recruits histone deacetylases and other proteins to the silencing complex. When lysine residues of the core histones H3 and H4 become deacetylated, the chromatin structure changes and renders the DNA inaccessible to the transcriptional machinery. The heritability of the repressed state depends on maintenance of CpG methylation through replication by the maintenance methylase that acts on hemimethylated DNA.
The severity of the RTT phenotype is determined primarily by the female's pattern of X inactivation (XCI), but the type of mutation could also have an influence. Individuals who meet the diagnostic criteria for RTT have more or less random XCI. Rare cases with skewed XCI might be severely affected and lack a period of normal early development if the mutant X is predominantly active. Patients with the normal X predominantly active have milder presentation. Extreme skewing can cause nonspecific learning deficits in women for whom a diagnosis of RTT would not have been considered; so far, such women have been identified only because of relation to individuals with classic RTT. Indications for mutation testing extend beyond individuals with the clinical diagnosis of RTT to include females with partial phenotypes who do not meet diagnostic criteria for RTT and males with unexplained encephalopathy in the neonatal period or death during infancy.