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.