Methyl-CpG binding protein 2 (MECP2)-related disorders include Rett syndrome (RTT), the variant forms of FOXG1 and CDKL5 syndromes, and MECP2 duplication syndrome. Despite overlap in presentation, FOXG1 and CDKL5 syndromes are increasingly recognized as separate entities. MECP2 duplication syndrome mainly affects boys and is also clinically distinct. This chapter focuses on RTT.
RTT is a severe neurodevelopmental disorder that is inherited in an X-linked dominant fashion. Its clinical presentation was initially described in 1966 by the Austrian pediatrician Andreas Rett, but it found recognition in English-language literature only in the 1980s. RTT occurs almost exclusively in girls. Boys with loss of function of MECP2 who survive postnatally typically present with severe neonatal encephalopathy and have a significantly shortened lifespan. The prevalence of RTT is estimated at approximately 1 per 10,000 live-born girls. RTT is the second most common cause of profound intellectual disability in girls after Down syndrome. RTT occurs at a similar frequency across all ethnic and racial groups.
Mutations in the MECP2 gene have been found to underlie most cases of RTT. Specifically, mutations in the MECP2 gene underlie 95% to 97% of cases of classic RTT, whereas only 50% to 70% of individuals with atypical RTT carry a mutation in MECP2. More than 200 different mutations in the MECP2 gene have been described. Mutations in MECP2 have also been found in a few children with other neurologic disorders, such as autism spectrum disorder or nonspecific X-linked mental retardation.
The MECP2 gene, which is located on the X chromosome at Xq28, codes for the MeCP2 protein, which functions as a genome-wide modifier of gene expression, including context-dependent transcriptional regulation. MeCP2 protein expression is developmentally regulated and is present in all postnatal tissues, particularly the brain. Disease-causing MECP2 mutations occur de novo in nearly all cases (> 99%) and almost always originate in the paternal germline. Girls with RTT tend to have random X inactivation with a significant proportion of cells expressing the normal allele. The varying degree of inactivation of the faulty allele contributes to the wide spectrum of RTT presentations. Although how the loss of MeCP2 function leads to RTT has yet to be clearly determined, it is believed that MeCP2 deficiency leads to altered synaptic maturation and maintenance in the brain.
Analysis of postmortem tissue indicates that RTT affects brain growth, as the brains of most individuals with RTT are smaller than those of age-matched controls. By contrast, other organs continue to grow at a normal rate until the end of the first decade. The lack of brain growth begins only after birth, with the absence of any indication of brain degeneration. On a microscopic level, the dendrites of pyramidal neurons appear abnormally short and less complex. Consistent with this observation, RTT is associated with the deficient expression of proteins that ...