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. Gonorazky et al. 3

Genetic Causes of Craniosynostosis: An Update

“…Muscle biopsy of the younger sibling revealed myofibers with internalized nuclei, myofibrillar disarray, and "corona" fibers [Gonorazky et al, 2017]. Electrophysiological characterization of the mutations revealed full and partial loss of function of the Na v 1.4 channel, which leads to a decrement of the action potential and subsequent reduction of muscle contraction [Gonorazky et al, 2017]. Previous reports of compound heterozygotes of mutations in SCN4A did not describe craniosynostosis [Ptácek et al, 1992;Jurkat-Rott et al, 2000;Tsujino et al, 2003;Vicart et al, 2004;Zaharieva et al, 2016], and the craniosynostosis phenotype cannot be explained by loss of function of the Na v 1.4 channel [Gonorazky et al, 2017].…”

“…They had lower facial weakness, high-arched palate, sagittal and metopic synostosis, axial hypotonia, proximal muscle weakness, and mild scoliosis [Gonorazky et al, 2017]. Also, atrophy of the gluteus maximus, adductor magnus, and soleus muscles was seen.…”

“…Also, atrophy of the gluteus maximus, adductor magnus, and soleus muscles was seen. Muscle biopsy of the younger sibling revealed myofibers with internalized nuclei, myofibrillar disarray, and "corona" fibers [Gonorazky et al, 2017]. Electrophysiological characterization of the mutations revealed full and partial loss of function of the Na v 1.4 channel, which leads to a decrement of the action potential and subsequent reduction of muscle contraction [Gonorazky et al, 2017].…”

Trouble at the junction: When myopathy and myasthenia overlap

“…In most patients, nonspecific myopathic findings were observed on muscle biopsy. One individual's biopsy was found to display multiple internal nuclei arranged in a crown‐like manner, which the authors named “corona” fibers . Several but not all affected individuals were found to harbor one full loss‐of‐function mutation and a second mutation leading to reduced channel conductance …”

Genotype–phenotype association in patients with SCN4A mutation – Authors' reply

“…However, the solutions can be found in the references to our previous work using this cell system. [2][3][4] Additionally, we cannot measure action potentials in a heterologous expression system, which is why any discussion of action potential waveforms is omitted.…”