Congenital myopathy with "corona" fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Hernan D Gonorazky; Christian R Marshall; Maryam Al-Murshed; Lili-Naz Hazrati; Michael G Thor; Michael G Hanna; Roope Männikkö; Peter N Ray; Grace Yoon

doi:10.1016/j.nmd.2017.02.001

Congenital myopathy with "corona" fibres, selective muscle atrophy, and craniosynostosis associated with novel recessive mutations in SCN4A

Neuromuscul Disord. 2017 Jun;27(6):574-580. doi: 10.1016/j.nmd.2017.02.001. Epub 2017 Feb 8.

Authors

Hernan D Gonorazky¹, Christian R Marshall², Maryam Al-Murshed³, Lili-Naz Hazrati³, Michael G Thor⁴, Michael G Hanna⁴, Roope Männikkö⁴, Peter N Ray⁵, Grace Yoon⁶

Affiliations

¹ Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
² 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.
³ Division of Neuropathology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
⁴ MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, United Kingdom.
⁵ 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.
⁶ 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: [email protected].

PMID: 28262468
DOI: 10.1016/j.nmd.2017.02.001

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 Na_v1.4 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.

Keywords: Channelopathies; Congenital myopathy; Corona fibres; SCN4A.

Publication types

Case Reports

MeSH terms

Adolescent
Adult
Craniosynostoses / complications
Craniosynostoses / genetics*
Craniosynostoses / pathology*
Exome
Genes, Recessive
HEK293 Cells / physiology
Humans
Muscular Atrophy / genetics*
Mutation*
Myotonia Congenita / complications
Myotonia Congenita / genetics*
Myotonia Congenita / pathology*
NAV1.4 Voltage-Gated Sodium Channel / genetics*
Pedigree
Phenotype
Young Adult

Substances

NAV1.4 Voltage-Gated Sodium Channel
SCN4A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding