Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome

Abstract

Background: Rett syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterised by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress. More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. Surprisingly, although the disorder is caused by mutations in a single gene, disease severity in affected individuals can be quite variable. To explore the source of this phenotypic variability, we propose that specific MECP2 mutations lead to different degrees of disease severity.

Methods: Using a database of 1052 participants assessed over 4940 unique visits, the largest cohort of both typical and atypical RTT patients studied to date, we examined the relationship between MECP2 mutation status and various phenotypic measures over time.

Results: In general agreement with previous studies, we found that particular mutations, such as p.Arg133Cys, p.Arg294X, p.Arg306Cys, 3° truncations and other point mutations, were relatively less severe in both typical and atypical RTT. In contrast, p.Arg106Trp, p.Arg168X, p.Arg255X, p.Arg270X, splice sites, deletions, insertions and deletions were significantly more severe. We also demonstrated that, for most mutation types, clinical severity increases with age. Furthermore, of the clinical features of RTT, ambulation, hand use and age at onset of stereotypies are strongly linked to overall disease severity.

Conclusions: We have confirmed that MECP2 mutation type is a strong predictor of disease severity. These data also indicate that clinical severity continues to become progressively worse regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

Keywords: MeCP2; RTT; Rett syndrome; genotype-phenotype.

Figure 1. Clinical severity score is dependent on MECP2 mutation status in participants with typical RTT

A) Matrix of p-values for comparisons of all MECP2 mutation groups. All significant differences (p < 0.05) are in green, and non-significant differences are in red. B-C) Clinical severity scores subdivided by age for each mutation type. The five age groups are 0–4, 5–8, 9–15, 16–20, and > 20 years.

Figure 2. Clinical features for typical RTT

Blue is least severe and red is most severe. Scales are normalized for each clinical measure. Values represent the average score. All statistically significant differences are listed in Supplementary Table 1.

Figure 3. Clinical severity score is dependent on MECP2 mutation status in participants with atypical RTT

A) Matrix of p-values for comparisons of all MECP2 mutation groups. All significant differences (p < 0.05) are in green, and non-significant differences are in red.

Figure 4. Clinical features for atypical RTT

Blue is least severe and red is most severe. Scales are normalized for each clinical measure. Values represent the average score. All statistically significant differences are listed in Supplementary Table 2.