GuidelinesGuidelines for reporting clinical features in cases with MECP2 mutations
Introduction
Investigation of Rett Syndrome (RS) [1] entered a new phase with the discovery in 1999 of mutations in the MECP2 gene [2]. MECP2 is thought to control expression of several genes including some involved in brain development [3]. Many mutations have recently been identified in MECP2 and the percentage of Rett cases with mutations is rising steadily [4], [5], [6] - over 80% for classic RS in large studies, however it is clear that the absence of a demonstrable MECP2 mutation does not negate the clinical diagnosis of RS. Boys may be affected, probably less frequently than girls [7], [8]. Atypical/variant forms have been described with and without mutations and the pattern of X-chromosome inactivation influences severity [9]. Phenotype may also be influenced by the position and nature of the mutation and this requires further investigation [9]. Other genetic and non-genetic factors may also contribute to the presentation. Range of severity is wider than was initially apparent and clinical features not characteristically associated with Rett syndrome have been reported with MECP2 mutations [8], [9]. It is therefore clear that mutations in MECP2 underlie both RS and other phenotypes.
Important new questions have thus emerged for clinicians.
- 1.
Who should be tested for MECP2 mutations?
- 2.
Which clinical features will be of value in comparing different phenotypes?
To these the authors offer collective advice based on extensive clinical, epidemiological and genetic experience.
Publications on genotype-phenotype correlation should indicate diagnostic tests, giving the methodology of the MECP2 mutational analysis, describing mutations in standard nomenclature [10] and reporting concomitant genetic rearrangements such as chromosomal translocation or deletion elsewhere in the genome. The pattern of X-chromosome inactivation influences severity of the clinical disease in females and measurement in more than one tissue is desirable.
Section snippets
Who should be tested for MECP2 mutations?
Since disorders caused by MECP2 mutations may present in girls or boys as developmental delay, hypotonia, tremulous movement, poor feeding, poor mobility, fall-off in the growth of the head circumference and onset of epileptic seizures or non-epileptic vacant spells [1], [7], [8], [9], [11], mutation testing should be considered in screening infants with combinations of these problems although the value of screening awaits further confirmation. Testing now seems appropriate in later childhood
Clinical features for comparison of phenotypes associated with MECP2 mutations
It is essential to state age at clinical assessment and source of the clinical information
Discussion
Here we have drawn on international experience of RS surveys to provide a simple scoring system, completion of which provides a profile of commonly encountered, readily ascertained clinical features, to ease comparison between the various profiles associated with MECP2 mutations. The system may help in evaluation of effects of intervention, however for such studies specific objective measures should also be selected to match the problems under consideration. The fluctuating nature of the
Acknowledgements
We acknowledge our indebtedness to our many colleagues and the families and individuals with RS and especially to Andreas Rett for his initial observations, to Bengt Hagberg and his collaborators who championed the cause of Rett Syndrome research in English speaking countries and Kathy Hunter whose commitment laid a foundation for recent successes.
References (20)
- et al.
MECP2 is a transcriptional repressor with abundant binding sites in genomic chromatin
Cell
(1997) - et al.
A mutation in the Rett Syndrome gene MECP2 causes x-linked mental retardation and progressive spasticity in males
Am J Hum Genet
(2000) - et al.
Rett variations a suggested model for inclusion criteria
Pediatr Neurol
(1994) - et al.
Clinical features of the early stage of the Rett Syndrome
Brain Dev
(1990) Über ein Eigenartiges hirnatrophisches Syndrome bei Hyperammonämie in Kindsalter
Wiener Medizinische Wochenschrift
(1966)- et al.
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Nat Genet
(1999) - et al.
Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location
Hum Mol Genet
(2000) - et al.
Mutation analysis of the methyl-CpG binding protein 2 gene (MECP2) in patients with Rett syndrome
J Med Genet
(2000) - et al.
Mutation analysis of the MECP2 gene in British and Italian Rett syndrome families
J Mol Med
(2000) - et al.
Somatic mutation in MECP2 as a non-fatal neurodevelopmental disorder in males
Lancet
(2000)
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