Preserved speech variants of the Rett syndrome: Molecular and clinical analysis

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Abstract
Mutations in the MECP2 gene cause the severe neurodevelopmental disorder called Rett syndrome. Preliminary evidence suggests that MECP2 may be involved in a broader phenotype than classical Rett syndrome including preserved speech variants (PSV). Here we report clinical and mutation analysis of 18 PSV patients. Ten of them had a MECP2 mutation (55%). The clinical features of these girls have been characterized and two subgroups defined. All of them had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of two‐to‐three years, and were able to speak in sentences; four had normal weight, mental age not beyond one‐to‐two years, and spoke in single words and two‐word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand‐washing was present in the first years of life but often subsequently disappeared. Significantly, all mutations found in PSV are either missense or late truncating mutations. In particular, we did not find the four early truncating hot spots: R168X, R255X, R270X, R294X. These results suggest that early truncating mutations lead to a poor prognosis (classic Rett), while late truncating and missense mutations lead either to classic Rett or PSV. We hypothesize that a missense or late truncating mutation is necessary but not sufficient to produce a PSV, based on the presence of one (or more) modifier genes whose product may interact in a epistatic manner with MeCP2 protein.