Preserved speech variant is allelic of classic Rett syndrome

Abstract

Rett syndrome is a neurological disorder affecting predominantly females with regression loss of speech and purposeful hand use, after a few months of almost normal development. Postnatal microcephaly, hand dispraxia, stereotypic 'hand-washing' activities, ataxia, and abnormal breathing are among its most characteristic features. Another aspect of this disorder is growth failure. The preserved speech variant (PSV) shares with Rett syndrome the same course and the stereotypic hand-washing activities but it differs in that patients typically recover some degree of speech and hand use and usually do not show growth failure. Progressive scoliosis, epilepsy and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech 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 with the preserved speech variant. Among the Rett syndrome group, two novel mutational hot spots (R270X and R294X), four novel mutations, two novel small deletions, as well as the previously reported 806delG, R168X and R255X mutations, were identified in 20/25 patients. Of note, among the preserved speech variants, two patients carry deletions of 41 bp and 44 bp each, which are strikingly similar to those observed in classic Rett syndrome. Our results confirm the presence of mutational hot spots in MECP2, broaden the spectrum of mutations, pinpoint additional mutational hot spots and establish that the preserved speech variant is indeed allelic of the classic form. Phenotype variability is only partially dependent on the kind of MECP2 mutation and other mechanisms such as skewed X-inactivation, and/or modifier gene effects should be investigated to explain the variable recovery in speech and hand use.

Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband

“…It is quite remarkable that the breakpoints of these large multi-kilobase deletions are restricted to a common B150-bp region; interestingly, this region is also the hotspot for the smaller deletions (20 -500 bp) confined within exon 4. Several explanations have been proposed to account for the intrinsic instability of this region; these include the presence of direct and inverted repeats, 8 the abundance of polypurine residues in the antisense strand 31 and the presence of a so-called w sequence, 15 which has been found to be highly recombinogenic in the Escherichia coli genome. 32 However, the w sequence is found in an additional four locations in the AF030876 genomic clone, none of which have been reported to be recombination hotspots.…”

“…7 Other groups speculated that larger deletions might occur, but would be missed by the routine non-quantitative PCR-based screening strategies because of exclusive amplification of the normal allele. 8,9 Accordingly, several groups have developed techniques to screen apparently mutationnegative RTT patients for the presence of large multiexonic deletions. 10 -21 These groups have detected large MECP2 deletions in 56/202 (27.7%) classical RTT patients in whom prior analysis of coding sequences revealed a seemingly wild-type result.…”

Clinical and biological progress over 50 years in Rett syndrome

“…2). 116 However, by additionally describing the forme fruste, late regression and male variants, Hagberg had already provided the best delineation of the full spectrum of clinical presentations. 117 As we reflect today on these early descriptors we can see how well they fit with our current understanding of the relationships between genotype and phenotype.…”

Prevalence of hearing loss in Rett syndrome

“…De Bona et al (2000), Nielsen et al (2001), Uchino et al (2001) and Yamashita et al (2001) have identified patients with preserved speech variant and mutations in MeCP2. In the present investigation, of the 22 patients with mutations in the MeCP2 gene, hearing loss was found in 10 and was absent in all of the tested mutation-negative patients.…”