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Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission.1 Clinical presentations range from predominant ptosis, ophthalmoparesis, facial and bulbar weakness, and generalised muscle weakness to predominant limb girdle weakness with sparing of the eye and face muscles. Symptoms may appear during the neonatal period, late childhood, adolescence or even adulthood. Clinical presentation and response to treatment may be influenced by the underlying molecular mechanism.Mutations in more than 30 genes have been identified as causing CMS.1 The primary pathogenic mechanism is defective neuromuscular junction (NMJ) transmission but may include central nervous system and skeletal muscle involvement. Biallelic loss-of-function (LOF) genetic mutations in SCN4A encoding skeletal muscle sodium channel NaV1.4 are a rare cause of CMS.2–6 Heterozygous carriers are asymptomatic, demonstrating recessive inheritance. NaV1.4 conducts the depolarising current of the skeletal muscle action potential that when reduced results in attenuated action potentials and muscle force.Biallelic SCN4A LOF mutations can also be found in patients diagnosed with congenital myopathy6–8 and occasionally hypokalaemic periodic paralysis (hypoPP).9 10 A common pathogenic mechanism can account for the notion that patients diagnosed with SCN4A -associated CMS may present with additional features of myopathy5 or hypoPP.4 The mutant NaV1.4 channels within SCN4A LOF clinical spectra show distinct functional defects. Mutations associated with congenital myopathy show a range of alterations on NaV1.4 channel function but one allele is often null.6–8 Hitherto reported CMS-associated mutations enhance channel inactivation2–5 and typically affect fourth voltage sensing domain (VSD) of NaV1.4, the key VSD implicated in control of …

Homozygous C-terminal loss-of-function NaV1.4 variant in a patient with congenital myasthenic syndrome

Homozygous C-terminal loss-of-function Na_V1.4 variant in a patient with congenital myasthenic syndrome