Phenotypic manifestations of MECP2 mutations in classical and atypical rett syndrome

Abstract

Since the identification of mutations in MECP2 in girls and women with apparent Rett syndrome, numerous efforts have been made to develop phenotype-genotype correlations. These studies have produced conflicting results in part related to use of different clinical severity scales, different diagnostic criteria, and different stratification by age and mutation group as well as the possible effects of unbalanced X-chromosome inactivation. The present study applied a revised ordinal scoring system that allowed for correction for patient ages. We analyzed 85 patients with mutation in MECP2. Sixty-five (76%) had one of eight common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the methyl-binding domain (MBD) and the transcriptional repression domain (TRD). However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation including better overall score, later regression, and better language with less motoric impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. Thus, the impact of specific mutations coupled with possible variation in X-chromosome inactivation must be considered carefully in the derivation of phenotype-genotype correlations. These results emphasize the limitations of such analyses in larger mutation groups, either by type or position.

Clinical Stringency Greatly Improves Mutation Detection in Rett Syndrome

“…From a scientific and socio-economic point of view, the use of efficient and well defined clinical criteria is very important for many reasons: (1) In order to replicate research findings, such as mutation gene screening, it is essential to use the same phenotypic selection method. (2) In heterogeneous genetic disorders, where more than one gene locus might be involved, it is important to be able to discriminate those who harbour a mutation in order to only focus on those who do not have mutations to better homogenize the search of the unknown locus. (3) The more the diagnostic procedure is precise; the more appropriate treatments can be applied to the affected child.…”

“…1 However, depending on mutation location and extent of X-inactivation skewing, individuals with RTT may also exhibit milder phenotypes with preserved speech and ambulation, mild learning disability, or a clinical picture more similar to autism than to classical RTT. [2][3][4] Because of X-linkage, mutations causing classical RTT in girls are generally embryonic-lethal in boys, although some rare mild mutations allow survival and a variety of neurodevelopmental phenotypes in males. [5][6][7] Following mapping of the RTT candidate locus to Xq27-28, the use of a candidate gene approach allowed identification of ABSTRACT: Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder of girls, caused by mutations in the X-linked MECP2 gene.…”

The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome

“…2,3 The severity of the RTT phenotype varies considerably depending on the MECP2 mutation type and location. [4][5][6][7][8] The degree of X chromosome inactivation skewing has also been shown to affect phenotypic variability in Mecp2-null mice, 9 and in RTT females. 10 However, these two mechanisms only partially explain this variability.…”

“…Clinical severity was assessed using what we have coined the Percy scale, 6,29 which takes into account early developmental characteristics as well as current clinical features and has been shown to be an appropriate measure. Severity scales provide quantitative estimates of clinical severity.…”

Rett Syndrome: Reaching for Clinical Trials

“…Owing to a premature STOP codon, a nonsense mutation (e.g., R168X, R255X) observed in approximately one-third of RTT individuals causes the termination of translation and may destabilize mRNA molecules [70,71]. These individuals may have a more severe clinical presentation than those with missense MECP2 mutations that result in single amino acid substitutions, except, perhaps, for the R294X allele.…”