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

Abstract

Rett Syndrome (RTT), a neurodevelopmental disorder that primarily affects girls, is characterized by a period of apparently normal development until 6–18 months of age, when motor and communication abilities regress. More than 95% of people 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. 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 measures of growth, motor coordination, communicative abilities, respiratory function, autonomic symptoms, scoliosis, and seizures over time. 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, Large 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. Thus, we have confirmed that MECP2 mutation type is a strong predictor of disease severity. However, clinical severity continues to become progressively worse with advancing age regardless of initial severity. These findings will allow clinicians and families to anticipate and prepare better for the needs of individuals with RTT.

The eye-tracking of social stimuli in patients with Rett syndrome and autism spectrum disorders: a pilot study

“…The empirical observation of RS patients points to a relative preservation of social domain, as they have a very intense look and somehow respond to social stimuli. The etiology of RS has strongly been associated with mutations in MECP2 gene 2,3,4 , and more recently with alterations in CDKL5 and FOGX1 in some cases 5,6 . Although it has been ABSTRACT Objective: To compare visual fixation at social stimuli in Rett syndrome (RT) and autism spectrum disorders (ASD) patients.…”

Rett Syndrome: Reaching for Clinical Trials

“…Presently, up to 96% of individuals in the US Natural History Study (NHS) have such mutations [42,43]. Nevertheless, a MECP2 mutation does not indicate the clinical diagnosis of RTT.…”

“…Individuals with mutations may not have features of RTT syndrome. Conversely, up to 4% have RTT but do not have a MECP2 mutation [43]. More than 200 pathologic mutations have been identified.…”

“…Deletions and insertions account for nearly 20%, such that a large number of the remaining mutations occur privately or in only a few individuals. Among the most common mutations, definite phenotype-genotype correlations have been established [42][43][44]. Based on the Clinical Severity Score employed in the NHS, individuals with R133C, R294X, R306C, and 3'-truncations are significantly less involved than those with the 5 other common point mutations and with deletions of whole exons.…”

Building the repertoire of measures of walking in Rett syndrome

“…Mutations in the gene encoding Methyl-CpG-binding protein 2 (MECP2) has been identified as the cause of RTT in the majority of cases [6]. For most mutations, clinical severity increases with age [7]. Whilst mortality is increased, many live into adulthood and some into older age [8,9].…”