MECP2 mutations account for most cases of typical forms of Rett syndrome

Rett syndrome (RTT) is a severe progressive neurological disorder that affe cts almost exclusively females, with an estimated prevalence of approximate ly one in 10 000-15 000 female births. Most cases are sporadic, but several reports about familial recurrence support X-linked dominant inheritance wi th male lethality. The gene responsible for this disorder, MECP2, was recen tly identified by candidate gene strategy. Mutations were detected in <25% of RTT cases in this first report. To characterize the spectrum of mutation s in the MECP2 gene in RTT patients, we selected 46 typical RTT patients an d performed mutation screening by denaturing gradient gel electrophoresis c ombined with direct sequencing. We identified 30 mutations, accounting for 65% of RTT patients. They include 12 novel mutations (11 located in exon 3 and one in exon 2). Mutations, such as R270X and frameshift deletions in a (CCACC)(n) rich region, have been found with multiple recurrences. Most of the mutations were de nova, except in one family where the non-affected tra nsmitter mother exhibited a bias of X inactivation. Although this study sho wed that MECP2 mutations account for most cases of typical forms of RTT (65 %) and mutations in non-coding regions cannot be excluded for the remaining cases, an alternative hypothesis that takes into account the homogeneous p henotype and exclusive involvement of females, could be the implication in RTT of a putative second X-linked gene.