Rett syndrome: Expanding the phenotype

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For most of the four decades since its original description, Rett syndrome was considered a somewhat rare form of developmental disability, mainly affecting girls, characterized by stereotypical hand movements and gradual neurologic deterioration. In 1999, the association between Rett syndrome and mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) was first reported. This rapidly led to the capability of molecular diagnosis for the disease, which is now widely available.

As is often the case, the availability of molecular diagnosis has somewhat confused the literature on Rett syndrome. The reported large series of the disorder were all accumulated and studied before genetic analysis became available. Thus, the reported patients all displayed a defined clinical phenotype. The experience with other disorders (Williams syndrome is a good example) suggests that, once a molecular diagnosis is possible, the phenotype and natural history of the disorder broadens.

Laurvick et al update the literature on Rett syndrome by reporting on a large cohort of children in an Australian database. This manuscript has something for everyone. For the generalist, it serves as an up-to-date review of the condition, illustrating when it should be suspected and explaining the molecular diagnosis. For the developmental pediatrician or neurologist, it provides the most current information on natural history, life expectancy, and complications, which will be invaluable in following children and counseling families. Finally, researchers will find herein the first attempt at establishing phenotype-genotype correlations in this disease.