title: Genotype-phenotype correlations in X-linked myotubular myopathy.
abstract: X-linked myotubular myopathy is a severe congenital myopathy that presents in the neonatal period with profound hypotonia and an inability to establish spontaneous respiration. Usually death occurs in infancy from respiratory failure. However, there is phenotypic variability; a number of affected boys have achieved respiratory independence and become ambulatory. Disease-causing mutations have been identified throughout the MTM1 gene on Xq28. MTM1 encodes the protein myotubularin, which is expressed ubiquitously. The main objectives of this study were to establish whether the nature or site of the mutation in the MTM1 gene could predict severity of the disease and to investigate whether early intensive clinical intervention facilitated survival until spontaneous improvement occurred. An association was demonstrated between the presence of a non-truncating mutation of the MTM1 gene and the mild phenotype. However, many non-truncating mutations were also seen in association with the severe phenotype and these were not confined to recognized functional domains of the protein. This suggests that the use of mutation analysis to predict prognosis in the early period following diagnosis is limited. Unexpectedly, over 50 patients surviving for more than 1 year were identified in this study. Further information obtained on 40 of these cases revealed that 50% were receiving 24-h ventilatory support, while 27% were ventilated at night only. The high survival rate for this disorder therefore reflects intensive medical intervention without which the majority of these boys would not survive.
authors.affiliation: Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UK. mcentagart@yahoo.co.uk
authors.forename: Meriel
authors.initials: M
authors.lastname: McEntagart
authors.forename: Gretchen
authors.initials: G
authors.lastname: Parsons
authors.forename: Anna
authors.initials: A
authors.lastname: Buj-Bello
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Iain
authors.initials: I
authors.lastname: Fenton
authors.forename: Mark
authors.initials: M
authors.lastname: Little
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Nick
authors.initials: N
authors.lastname: Thomas
authors.forename: Gail
authors.initials: G
authors.lastname: Herman
authors.forename: Angus
authors.initials: A
authors.lastname: Clarke
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
mesh_terms: D016009:Chi-Square Distribution; D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D004303:Dosage Compensation, Genetic; D005091:Exons; D005192:Family Health; D005500:Follow-Up Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D005810:Multigene Family; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D017063:Outcome Assessment, Health Care; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D013223:Statistics as Topic; D016019:Survival Analysis; D013997:Time Factors; D012122:Ventilators, Mechanical / Q000706:statistics & numerical data / Q000600:supply & distribution
chemical_list: D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin