Specific mutations in <i>Methyl-CpG-Binding Protein 2</i> confer different severity in Rett syndrome

TLDR

The study aims to assess whether specific MECP2 mutations correlate with clinical severity in Rett syndrome. The authors performed a cross‑sectional analysis of 245 Rett syndrome patients, conducting structured clinical evaluations and comprehensive MECP2 mutation testing. R133C mutations are associated with milder Rett symptoms compared to R168X or large deletions, whereas R168X carriers exhibit the greatest severity, especially in ambulation, hand use, and language, C‑terminal truncations predict better motor and speech function, and the R306C mutation mainly affects language, highlighting the need for mutation‑specific therapeutic strategies and consideration in clinical trials.

Abstract

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