Phenotypic heterogeneity in skeletal muscle sodium channelopathies: A case report and literature review

Saleem, Rabia; Setty, Gururaj; Khan, Arif; Farrell, D.; Hussain, Nahin

doi:10.4103/1817-1745.117848

Cited by 4 publications

(1 citation statement)

References 8 publications

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“…The main symptoms of these channelopathies, i.e. muscle stiffness and myotonia, episodic weakness and cold sensitivity, may variably combine to result in one of the three phenotypes; however, there are several reports of mutations causing mild, incomplete, or overlapping phenotypes, as well as unusual heat sensitivity or warm-up phenomenon, a feature typical of chloride channel (CLCN1 gene) myotonia [3][4][5][6][7][8][9][10] but increasingly seen in sodium channel myotonia. The electrophysiological behavior of mutated channels has been analyzed in detail for a number of mutations [11][12][13][14][15], disclosing impaired inactivation and/or enhanced activation as the main gating mechanisms causing the channel overactivity that determines hyperexcitability and muscle stiffness.…”

Section: Introductionmentioning

confidence: 99%

A c.1775C > T Point Mutation of Sodium Channel Alfa Subunit Gene (SCN4A) in a Three-Generation Sardinian Family with Sodium Channel Myotonia

Campanale,

Laghetti,

Saltarella

et al. 2024

JND

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Background: The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. Methods: Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected. Results: A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude. Conclusions: The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.

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