Elsevier

Research in Autism Spectrum Disorders

Volume 3, Issue 3, July–September 2009, Pages 639-659
Research in Autism Spectrum Disorders

InterRett, a model for international data collection in a rare genetic disorder

https://doi.org/10.1016/j.rasd.2008.12.004Get rights and content

Abstract

Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population-based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other studies. A literature review compared InterRett with RTT population-based and case-based studies of 30 or more cases that investigated genotype and/or phenotype relationships. Questionnaire data were used to determine case status and to investigate the comparability of InterRett and ARSD. Twenty-four case series, five population-based studies and a MECP2 mutation database were identified of which 21 (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of 1114 InterRett subjects, 935 born after 1976 could be verified as Rett cases and compared with the 295 ARSD subjects. Although more InterRett families had higher education and occupation levels and their children were marginally less severe, the distribution of MECP2 mutation types was similar.

The InterRett can be used with confidence to investigate genotype phenotype associations and clinical variation in RTT and provides an exemplary international model for other rare disorders.

Section snippets

Background

Rett syndrome (RTT) is characterised by severe intellectual and physical disability and affects 1 in 8500 females by the age of 15 years (Hagberg, 1985; Laurvick et al., 2006). In general, the most notable characteristics of RTT are the development of stereotypic hand movements and a regression in motor and cognitive function usually after a period of normal development (Trevathan, 1988). Other features include development of motor impairments including apraxia, epilepsy, scoliosis and

Literature review

A review of the literature identified studies published in English speaking journals investigating Rett syndrome genotypes and/or phenotypes. Articles published between 2000 and 2008 (inclusive) were selected from a Medline search using the search terms “Rett syndrome” and “phenotype” or “genotype”. A broad search of RTT population-based studies and case series was conducted for studies before 2000.

Parameters such as sample size, data source and case validation method were then compared.

Comparison of Rett syndrome studies

Twenty-four studies using case series, 5 studies using population-based data and 1 MECP2 mutation database met the inclusion criteria for the literature search (Table 3). Of the studies 1 (3.3%) provided only phenotypic information, 7 only genotypic information (23.3%) and 21 (70.0%) both phenotypic and genotypic information. Only for the population-based studies was there sufficient information to complete all the parameters with information generally poorly provided on case source and country

Discussion

Much research has attempted to investigate genotype and phenotype relationships with small studies, which consequently have been insufficiently powered to detect the real differences. Therefore findings have at times been conflicting (Charman et al., 2005, Cheadle et al., 2000; Nectoux et al., 2008). Often investigators, particularly in early studies, have attempted to group mutations to increase power. However, in the grouping, mutations with directly opposing characteristics (such as p.R294X

Competing interests

The authors report no conflicts of interest. The funding agencies for this study had no involvement in the study design nor the collection, analysis and interpretation of data.

Authors’ contributions

SL designed the study, organized the data, performed the statistical analysis and drafted the manuscript. SF was involved in study conception, participated in its design and made a major contribution to the drafting and revision of manuscript for important intellectual content. AB assisted with the analysis and interpretation of the data and participated in drafting the manuscript. NBB contributed to the provision of data and revised the manuscript critically for important intellectual content.

Acknowledgements

The authors would like to acknowledge the International Rett Syndrome Foundation (IRSF previously IRSA) for their ongoing support of the InterRett project and their continuous encouragement of this international collaboration. We would also like to express our special appreciation to all the families who have participated in the study and all the clinicians who have completed questionnaires. In particular we would like to thank Yael Petel Galil for her submission of clinical data on Israeli

References (55)

  • C.L. Laurvick et al.

    Rett syndrome in Australia: A review of the epidemiology

    Journal of Paediatrics

    (2006)
  • H. Leonard et al.

    Genotype and early development in Rett syndrome: The value of international data.

    Brain & Development

    (2005)
  • R.E. Amir et al.

    Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

    Annals of Neurology

    (2000)
  • R.E. Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nature Genetics

    (1999)
  • H. Archer et al.

    Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation

    Journal of Medical Genetics

    (2007)
  • Australian Bureau of Statistics. (2006). Australian and New Zealand standard classification of occupations. (From...
  • A. Bebbington et al.

    Investigating genotype-phenotype relationships in Rett syndrome using an international data set

    Neurology

    (2008)
  • T. Bienvenu et al.

    MECP2 mutations account for most cases of typical forms of Rett syndrome

    Human Molecular Genetics

    (2000)
  • J.H. Chae et al.

    Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype

    Journal of Child Neurology

    (2004)
  • T. Charman et al.

    Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome

    European Journal of Human Genetics

    (2005)
  • J.P. Cheadle et al.

    Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: Correlation of disease severity with mutation type and location

    Human Molecular Genetics

    (2000)
  • L. Colvin et al.

    Refining the phenotype of common mutations in Rett syndrome

    Journal of Medical Genetics

    (2004)
  • Downs, J., Young, D., de Klerk, N., Bebbington, A., Baikie, G., & Leonard, H. (in press). The impact of scoliosis...
  • S. Fyfe et al.

    InterRett and RettBASE: International Rett Syndrome Association databases for Rett syndrome

    Journal of Child Neurology

    (2003)
  • B. Hagberg

    Rett's syndrome: prevalence and impact on progressive severe mental retardation in girls

    Acta Paediatrica Scandinavica

    (1985)
  • B. Hagberg

    Clinical delineation of Rett syndrome variants

    Neuropediatrics

    (1995)
  • B. Hagberg

    Clinical manifestations and stages of Rett syndrome

    Mental Retardation and Developmental Disabilities Research Reviews

    (2002)

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