Rett Syndrome: North American Database

Percy, Alan K.; Lane, Jane; Childers, Jerry; Skinner, Steve A.; Annese, Fran; Barrish, James P.; Caeg, Erwin; Glaze, Daniel G.; MacLeod, Patrick

doi:10.1177/0883073807308715

Cited by 89 publications

(77 citation statements)

References 15 publications

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“…Despite this phenotypic variability, greater than 95% of those with typical RTT and approximately 75% of cases with atypical RTT have a mutation in a single gene: methyl-CpG-binding protein 2 ( MECP2 ) 6 7. MeCP2 binds to methylated cytosines in DNA to either activate or repress transcription8 and contains three functional domains: (1) a methyl-binding domain (MBD) on the N-terminus allowing binding to DNA,9 (2) a nuclear localisation sequence allowing trafficking of MeCP2 to the nucleus10 and (3) a transcriptional repression domain (TRD), which modulates gene transcription.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…This research has been able to link a number of the more common mutations to milder or more severe clinical features or to specific Rett syndrome variants 3–5. In addition to the common point mutations (p.R106W, p.R133C, p.R168X, p.R255X, p.R270X, p.R294X, p.R306C and p.T158M) of MECP2 that are present in between 60% and 70% of cases with pathogenic MECP2 mutations,3 4 6 7 deletions in the C-terminal region have been reported in approximately 6–14% of cases 3 4 7 8. In one study, the phenotype of 10 cases with C-terminal deletions has been examined in detail,9 but in no other study would they appear to have been specifically examined as a separate group.…”

mentioning

confidence: 99%

Updating the profile of C-terminal MECP2 deletions in Rett syndrome

Bebbington

Percy

Christodoulou

et al. 2009

Journal of Medical Genetics

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Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region. Conclusion In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome.

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“…According to data in the literature, common point mutations of MECP2 (R106W, R133C, R168X, R255X, R270X, R294X, R306C and T158M) are present in B60-70% of cases with pathogenic MECP2 mutations. [21][22][23] Interestingly, we have only detected MECP2 mutations in 27.6% of the Rett patients studied, a ratio that is likely not only because of the limitations of direct sequencing method used for mutation analysis, but possibly attributable to a high percentage of gross rearrangements of the MECP2 gene that are not detectable by sequencing. Such rearrangements may account for 37.8% of classic RTT and 7.5% of atypical RTT patients according to recent literature.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations

et al. 2010

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Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C4T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G4T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G4T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.

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Rett Syndrome: North American Database

Cited by 89 publications

References 15 publications

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

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

Updating the profile of C-terminal MECP2 deletions in Rett syndrome

Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations

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