Describing the phenotype in Rett syndrome using a population database

Colvin, Lyn; Fyfe, Sue; Leonard, Seonaid; Schiavello, T; Ellaway, Carolyn; Klerk, Nicholas de; Christodoulou, John; Msall, Michael E.; Leonard, Helen

doi:10.1136/adc.88.1.38

Cited by 98 publications

(118 citation statements)

References 50 publications

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“…Data for items contained in the Kerr, Percy and Pineda severity scores were coded and summed to calculate severity scores (in which higher scores denote greater severity) as previously described. 17 Data from the Spanish cohort were used to calculate the Pineda scale scores but not the Kerr or Percy scale scores, because of differences in questionnaire design (and therefore data collection), but were used in analyses on the individual aspects of Rett syndrome severity where this data was collected on the Spanish cohort.…”

Section: Methodsmentioning

confidence: 99%

The phenotype associated with a large deletion on MECP2

et al. 2012

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Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22-0.79, P¼0.007) and to be currently walking (OR 0.53, 95% CI: 0.26-1.10, P¼0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98-3.48, P¼0.057) and epilepsy (OR 2.72, 95% CI: 1.38-5.37, P¼0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected.

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Section: Methodsmentioning

confidence: 99%

The phenotype associated with a large deletion on MECP2

et al. 2012

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“…10 By early 2005, 278 individuals with verified Rett syndrome (23 of whom were known to have died) were registered with the ARSD. Among these, a pathogenic molecular abnormality has been identified in 175 (62.9%).…”

Section: Case Recruitmentmentioning

confidence: 99%

p.R270X MECP2 mutation and mortality in Rett syndrome

et al. 2005

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Among cases in the Australian Rett Syndrome Database, the nonsense mutation p.R270X is one of the most commonly occurring single pathogenic MECP2 mutations. In two recent published reports of the MECP2 mutational spectrum the p.R270X appeared to be under represented. We hypothesised that increased mortality arising from this mutation may underlie this apparent discrepancy. We investigated our hypothesis in two independent study groups from Australia and the UK with prospective data collections (total n ¼ 524). Only females with Rett syndrome and an identified MECP2 mutation were included. Significant differences in survival were detected among Rett syndrome cases grouped for the eight most frequent mutations (log-rank v 2 (7) ¼ 15.71, P ¼ 0.03). Moreover, survival among cases with p.R270X, when compared with survival among cases with all the other mutations was reduced (log-rank v 2 (2) ¼ 6.94, P ¼ 0.01). Our observation of a reduced survival associated with the p.R270X mutation offers an explanation for the under representation of p.R270X in older subjects with Rett syndrome.

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“…We chose to use the Percy scale, which has 15 items with maximum possible score of 45, because of its reasonable balance between current functioning and developmental characteristics. 29 Data used to determine the scores were derived from information for ARSD cases that were provided to the ARSD in the 2004 follow-up questionnaire and coded for previous analyses. 30 Information for Israeli cases was extracted from case records and coded in the same way as the Australian cases.…”

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confidence: 99%

“…Cases in the ARSD (n ϭ 131) represent 42.8% of all cases known to the ARSD in December 2006. The ARSD is a population-based database of RTT subjects born since 1976, 29 so that ages ranged from 2.9 to 28.9 years at the 2004 follow-up. Israeli cases were identified from those cases seen at Sheba Medical Centre, with ages ranging from 3.5-42 years.…”

mentioning

confidence: 99%