Rett Syndrome

Introduction

Rett syndrome (RTT) is a neurodevelopmental disorder observed first in 1977. Recently, it is recognized that it mainly affects females with loss of hand use. In addition to typical RTT, some individuals with variant or atypical RTT have been found to cluster in some distinct clinical groupings. They present with many clinical features, such as regression, but do not necessarily have all the features of RTT. The significant morphologic change in the RTT brain is a decrease in the size of the brain and of individual neurons, which show less dendritic arborization and spines than the non-Rett syndrome neurons. There is no apparent atrophy or degeneration, so the neuropathologic process in RTT is hypothesized to be a failure of development.

Genetic Basis of RTT

In 1999, researchers discovered that mutations in the MECP2 gene were associated with rare familial cases of RTT and the sporadic occurrences of typical RTT. Mutations in the MECP2 gene can be found in 95% of classic RTT cases using a battery of modern mutation detection assays.

• RTT with MECP2 Mutations

Mutations in the widely expressed MECP2 are at the root of RTT. This gene, located in the Xq28 region, codes for the prototype of the family of proteins sharing a methyl-binding domain. Mutations in MECP2 in exons 1-4 or DNA deletions are identified in almost all RTT cases. The spectrum of mutation types contains missense, nonsense, frameshift mutations, and deletions encompassing whole exons. Missense mutations seem to cluster in the methyl-CpG- binding domain. In contrast, nonsense or frame-shift mutations truncate the protein beyond this domain, affecting the transcription repression domain and C-terminal segment of the gene.

• CDKL5 Mutations Explain a Congenital RTT-like Disorder

Mutations in other genes have also been found in some individuals that are labeled as atypical RTT. For example, mutations in the CDKL5 gene are found in individuals with what has been characterized as the early-seizure onset variant of RTT with intractable early-onset seizures often accompanied by RTT-like features. Although most patients with CDKL5 mutations are female, there are rare occurrences in males suffering from severe mental retardation, infantile spasms, or early-onset epilepsy.

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