Preserved speech variant is allelic of classic Rett syndrome

Rett syndrome is a neurological disorder affecting predominantly females wi th regression loss of speech and purposeful hand use, after a few months of almost normal development. Postnatal microcephaly, hand dispraxia, stereot ypic 'hand-washing' activities, ataxia, and abnormal breathing are among it s most characteristic features. Another aspect of this disorder is growth f ailure. The preserved speech variant (PSV) shares with Rett syndrome the sa me course and the stereotypic hand-washing activities but it differs in tha t patients typically recover some degree of speech and hand use and usually do not show growth failure. Progressive scoliosis, epilepsy and other mino r handicaps, usually present in Rett syndrome, are rare in the preserved sp eech variant. Here we explore the spectrum of mutations affecting the MECP2 gene in a group of 25 classic Rett syndrome girls and in three patients wi th the preserved speech variant. Among the Rett syndrome group, two novel m utational hot spots (R270X and R294X), four novel mutations, two novel smal l deletions, as well as the previously reported 806delG, R168X and R255X mu tations, were identified in 20/25 patients. Of note, among the preserved sp eech variants, two patients carry deletions of 41 bp and 44 bp each, which are strikingly similar to those observed in classic Rett syndrome. Our resu lts confirm the presence of mutational hot spots in MECP2, broaden the spec trum of mutations, pinpoint additional mutational hot spots and establish t hat the preserved speech variant is indeed allelic of the classic form. Phe notype variability is only partially dependent on the kind of MECP2 mutatio n and other mechanisms such as skewed X-inactivation, and/or modifier gene effects should be investigated to explain the variable recovery in speech a nd hand use.