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Abstract
Background: Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype–phenotype relationships and compares these with previous findings in a population-based cohort.
Method: The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272).
Results: Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language.
Conclusions: This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype–phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders.
GLOSSARY: ANOVA = analysis of variance; ARSD = Australian Rett Syndrome Database; IQR = interquartile range.
Footnotes
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Received June 8, 2007. Accepted in final form October 22, 2007.
Supplemental data at www.neurology.org
Supported by a grant from the International Rett Syndrome Association. The Australian Rett Syndrome Database is supported by NIH grant HD43100 (H.L.). H.L. is funded by National Health and Medical Research Council program grant 35314, and W.E.K. is funded by NIH grant HD24448. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.
Disclosure: The authors report no conflicts of interest.
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