It has been fourteen years since Huda Zoghbi discovered that mutations in the MECP2 gene cause Rett Syndrome. During that time it has become clear that mutations in this complex gene cause symptoms that extend well beyond Rett Syndrome.
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 chromosome inactivation. However, when skewing is normal and a mutation known to produce severe symptoms results in a very mild phenotype, we must assume that modifier gene(s) have 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, cognitive challenges of varying degrees, with or without seizures.
In males, mutations have been seen in childhood onset schizophrenia, infantile encephalopathy, bipolar disease and intellectual disability 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 severe progressive disorder with Rett-like symptoms in males.
Impaired mitochondrial function, involvement of glial cells, abnormal neurotransmitter levels, Parkinsonian features, anxiety and the range of physical and psychiatric problems associated with MECP2 mutations, 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.
The work that RSRT is funding is clinically relevant not only to Rett Syndrome but to all disorders that are caused by MECP2 dysfunction.