Refining the phenotype of common mutations in Rett syndrome

Rett syndrome (RTT; MIM No 312750) is a neurodevelopmental disorder mainly affecting girls, with an incidence of 1:10 000 female births.1 The clinical features of the syndrome were first described in a series of publications2–5 during the decade after it was first reported in English language journals.6 At that time, in the absence of a biological marker, criteria to assist with the diagnosis were developed by an international working group.7 These criteria relate to the typical characteristics which are: normal prenatal and perinatal period and apparently normal development for the first six months of life; deceleration in head growth; loss of hand and communication skills between six and 30 months; apparent severe psychomotor retardation; acquisition of stereotypical hand movements; and evidence of gait or truncal apraxia between one and four years. These necessary criteria were supplemented by a set of supportive but not mandatory criteria, which help to delineate the phenotype further. These include breathing dysfunction, EEG abnormalities, seizures, spasticity, peripheral vasomotor disturbance, scoliosis, growth retardation, and hypotrophic small feet. In 1999 the association between Rett syndrome and mutations in the methyl-CpG binding protein 2 (MECP2; MIM No 300005) located on Xq28 was first identified.8 In the last decade there had already been much commentary about the expanding clinical spectrum of Rett syndrome and the occurrence of atypical forms.9 This culminated in 2001 in a meeting to revise the existing diagnostic criteria.10 It is now clear that, although this condition must be considered a severe neurodevelopmental disorder, there is still considerable variation in both functioning and associated morbidity, even in those cases with confirmed MECP2 mutations. We have been able to demonstrate this variability11 using a tool to measure functional ability12 and three clinical scales. The first was developed by …