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Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome

From the Section of Neurology, Department of Pediatrics (J.L.N., E.O.S., H.Z., D.G.G.), Medical Genetics Laboratories (P.F.), and Department of Molecular and Human Genetics (H.Z.), Baylor College of Medicine, Houston, TX; Texas Children's Hospital (J.L.N., J.B., E.B.C., H.Z., D.G.G.); and University of Alabama (J.L., A.P.), Birmingham.

Address correspondence and reprint requests to Dr. Jeffrey L. Neul, Baylor College of Medicine, Room 319C, One Baylor Plaza, Houston, TX 77030 jneul{at}bcm.tmc.edu.

Objective: To determine if a relationship exists between the clinical features of Rett syndrome, an X-linked dominant neurodevelopmental disorder, and specific mutations in MECP2.

Method: Cross-sectional study of 245 girls and women with typical Rett syndrome seen between 1990 and 2004 in tertiary academic outpatient specialty clinics and who had complete MECP2 mutation analysis. A structured clinical evaluation was completed for each participant. The results were grouped by MECP2 mutation and compared.

Results: Participants with the R133C mutation are less severely affected than those with R168X or large DNA deletions (p < 0.05). Likewise, individuals with the R168X mutation are more severely affected than those with R294X and late carboxy-terminal truncating mutations (p < 0.05). Clinical differences are notable in ambulation, hand use, and language (p < 0.004), three cardinal features of Rett syndrome. Individuals with R168X are less likely to walk (p = 0.008), retain hand use (p = 0.002), or use words (p = 0.001). In contrast, those with carboxy-terminal truncations are more likely to walk (p = 0.007) and use words (p < 0.001). The R306C mutation, previously found to confer milder features, adversely affects only one clinical feature, language (p < 0.05).

Conclusions: Specific mutations in MECP2 confer different severity. These results allow the design of therapies targeted toward the amelioration of expected problems. Furthermore, the distinct effects of MECP2 mutations on clinical severity must be considered in clinical intervention trials.

Abbreviations: BCM = Baylor College of Medicine; CSS = Clinical Severity Score; MLPA = multiple ligation-dependent probe amplification; RTT = Rett syndrome; TCH = Texas Children's Hospital; UAB = University of Alabama–Birmingham; XCI = X-chromosome inactivation.

Supplemental data at www.neurology.org

Editorial, page 1302.

e-Pub ahead of print on March 12, 2008, at www.neurology.org.

Editorial Note: We draw your attention to this article highlighted with an editorial and accepted on September 11, 2007. Readers may want to cross-reference this paper with the paper by Bebbington et al. published in the March 11, 2008, issue, which was accepted on October 23, 2007.

Supported by NIH grants HD40301, RR019478, RR00188, NS057819, NS052240, NS43124, MRRC grant HD38985, the Blue Bird Circle, and Civitan International Research Center funds.

Disclosure: H.Y.Z. holds patent for diagnostic testing of MECP2 mutations.

Received May 25, 2007. Accepted in final form September 11, 2007.

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