Highly skewed X-inactivation leading to an extremely mild variant of Rett syndrome with predominantly psychiatric problems

Since the first mutations in the MECP2 gene were described in 1999, we have seen that the spectrum of possible clinical phenotypes is wider than previously thought. Patients with a mild phenotype can speak single words and have partially preserved hand function. It has been shown that the type and position of the MECP2 mutations only have a very limited influence on the severity of the disorder.

We describe here a patient with an extremely mild phenotype of Rett Syndrome. She is visiting a school for children with mild learning disabilities, can calculate numbers up to ten, speaks fluently, uses inline skates and has normal hand function. She has phases with uncontrolled aggression and requires repeated inpatient treatment in a psychiatric institution. Mutation analysis showed a deletion in position 1163–1207 of the MECP2 gene. Such deletions are normally associated with a classical Rett syndrome phenotype. Therefore we investigated the X-inactivation and found that it was highly skewed (84/16). The favoured inactivation of the defective X-chromosome has protected the patient from most of the functional consequences of this deletion. Our case shows that skewed X-inactivation can influence the phenotypic variability of Rett syndrome patients. Because we have never screened patients, with a phenotype in which psychiatric problems dominate, for mutations in the MECP2 gene, we do not know whether our case is a rare exception or a common clinical phenotype of Rett syndrome patients.