title: Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene.
abstract: Centronuclear myopathy is a genetically heterogeneous congenital myopathy. Whilst mutations in the myotubularin (MTM1) gene are implicated in the X-linked variant, mutations in the dynamin 2 (DNM2) gene have been recently associated with dominant inheritance. We report a 16-year-old girl with clinical features of a congenital myopathy and external ophthalmoplegia. Multiple central nuclei affecting up to 50% of fibres and central accumulation of oxidative enzyme stains were the most prominent findings on muscle biopsy obtained at 1 year. However, some core-like areas appeared on repeat biopsy 8 years later; in addition, muscle MRI was compatible with the pattern we previously reported in patients with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Mutational analysis identified a de novo dominant RYR1 missense mutation (c.12335C>T; Ser4112Leu) affecting a highly conserved domain of the protein. Our findings expand the phenotypical spectrum associated with RYR1 mutations and indicate that RYR1 screening should be considered in centronuclear myopathy patients without MTM1 or DNM2 mutations; muscle MRI may aid selection of appropriate genetic testing.
authors: Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. h.jungbluth@imperial.ac.uk
authors: Heinz
authors: H
authors: Jungbluth
authors: Haiyan
authors: H
authors: Zhou
authors: Caroline A
authors: CA
authors: Sewry
authors: Stephanie
authors: S
authors: Robb
authors: Susan
authors: S
authors: Treves
authors: Marc
authors: M
authors: Bitoun
authors: Pascale
authors: P
authors: Guicheney
authors: Anna
authors: A
authors: Buj-Bello
authors: Carsten
authors: C
authors: Bönnemann
authors: Francesco
authors: F
authors: Muntoni
mesh_terms: D000293:Adolescent; D002118:Calcium / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology; D004252:DNA Mutational Analysis / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D006801:Humans; D007930:Leucine / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011189:Potassium Chloride / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012694:Serine / Q000235:genetics
chemical_list: D003408:Cresols; D019837:Ryanodine Receptor Calcium Release Channel; C006984:chlorocresol; D012694:Serine; D011189:Potassium Chloride; D007930:Leucine; D002118:Calcium