title: Congenital myopathy with "corona" fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A.
abstract: We describe two brothers with lower facial weakness, highly arched palate, scaphocephaly due to synostosis of the sagittal and metopic sutures, axial hypotonia, proximal muscle weakness, and mild scoliosis. The muscle MRI of the younger sibling revealed a selective pattern of atrophy of the gluteus maximus, adductor magnus and soleus muscles. Muscle biopsy of the younger sibling revealed myofibres with internalized nuclei, myofibrillar disarray, and "corona" fibres. Both affected siblings were found to be compound heterozygous for c.3425G>A (p.Arg1142Gln) and c.1123T>C (p.Cys375Arg) mutations in SCN4A on exome sequencing, and the parents were confirmed carriers of one of the mutations. Electrophysiological characterization of the mutations revealed the Cys375Arg confers full and Arg1142Gln mild partial loss-of-function. Loss of function of the Nav1.4 channel leads to a decrement of the action potential and subsequent reduction of muscle contraction. The unusual muscle biopsy features suggest a more complex pathomechanism, and broaden the phenotype associated with SCN4A mutations.
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hernan D
authors.initials: HD
authors.lastname: Gonorazky
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Division of Neuropathology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Al-Murshed
authors.affiliation: Division of Neuropathology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Lili-Naz
authors.initials: LN
authors.lastname: Hazrati
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Thor
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, United Kingdom.
authors.forename: Roope
authors.initials: R
authors.lastname: Männikkö
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, The University of Toronto, Toronto, Canada.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.affiliation: Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada. Electronic address: grace.yoon@utoronto.ca.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
mesh_terms: D000293:Adolescent; D000328:Adult; D003398:Craniosynostoses / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D059472:Exome; D005808:Genes, Recessive; D057809:HEK293 Cells / Q000502:physiology; D006801:Humans; D009133:Muscular Atrophy / Q000235:genetics*; D009154:Mutation; D009224:Myotonia Congenita / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human
keywords: Channelopathies; Congenital myopathy; Corona fibres; SCN4A