The power of a single gene: MECP2 spectrum disorders

Because MECP2 affects the expression of many genes involved with neurological development and function, the emerging picture of MECP2 disorders extends well beyond Rett Syndrome and has become increasingly broad and complex.

The clinical presentation of patients with MECP2 mutations ranges from severe physical and neuropsychiatric problems to a normal phenotype. This variability is sometimes based on favorable X-inactivation. However, when skewing is normal and a mutation known to produce severe symptoms results in a very mild phenotype, we must assume that an as yet unidentified modifier gene, or set of genes, has intervened to prevent the damage that would be expected. 

MECP2 mutations in females have been identified in patients diagnosed with anxiety, learning disabilities, autism, Angelman-like syndrome, mental retardation of varying degrees, with or without seizures.

In males, mutations have been seen in childhood schizophrenia, infantile encephalopathy, bipolar disease and mental retardation that may be accompanied by tremors and other motor deficits and psychiatric symptoms.

Duplication of MECP2 has been documented in both males and females; this overexpression can result in a variety of phenotypes, including autism, a preserved speech variant of Rett Syndrome in females, and retardation with Rett-like symptoms in males.

The Parkinsonian features, anxiety and range of physical and psychiatric problems associated with MECP2 abnormalities, together with the extreme autonomic nervous system imbalances manifested in Rett Syndrome, reflect the scope of this gene's influence and the potential of MECP2 research to benefit a diverse patient population.

Impaired mitochondrial function, involvement of glial cells, and abnormal neurotransmitter levels may lead to connections with more disorders as our understanding of epigenetics continues to expand.

Banner image - The Mecp2 protein is indicated by the bright blue staining in cultured wildtype mouse cells. Photography courtesy of Adrian Bird.