SCN4A – Potassium-Aggravated Myotonia

SCN4A encodes the Nav1.4 α-subunit of the skeletal muscle voltage-gated sodium channel and is implicated in potassium-aggravated myotonia (HGNC:10591; MONDO:0018959).

Autosomal dominant missense variants in SCN4A underlie a spectrum of non-dystrophic myotonias, including potassium-aggravated myotonia. Approximately 20 distinct point mutations were first catalogued in early linkage studies (PMID:10366610). Subsequent case series have identified over 25 probands across more than 20 unrelated families with segregating SCN4A variants and characteristic EMG myotonic discharges, often with cold or exercise aggravation (PMID:21664816; PMID:32411069).

The variant spectrum is dominated by missense changes clustering in S4–S5 linkers and pore-lining segments. Representative alleles include c.3917G>A (p.Gly1306Glu) ([PMID:36192135]), c.4307T>C (p.Leu1436Pro) ([PMID:21664816]), c.1333G>A (p.Val445Met) ([PMID:32276507]), and recurrent founder alleles such as c.644T>C (p.Ile215Thr) in Southern Italy (PMID:32411069).

Electrophysiological studies in heterologous systems (HEK293 cells, Xenopus oocytes) consistently demonstrate gain-of-function defects: hyperpolarizing shifts in voltage-dependent activation, impaired fast and/or slow inactivation, and enhanced persistent or window currents. The archetypal p.Gly1306Glu mutation produces a pronounced persistent Na⁺ current and slowed inactivation, correlating with severe myotonia (PMID:36192135).

Mechanistically, PAM arises from aberrant channel gating rather than haploinsufficiency. Altered inactivation kinetics prolong Na⁺ influx during depolarization, lowering excitation threshold and promoting repetitive firing and muscle stiffness. Pharmacological block with mexiletine or carbamazepine can mitigate symptoms by stabilizing inactivation.

No robust refuting or alternative gene associations have been reported for potassium-aggravated myotonia in these pedigrees. Occasional co-inheritance of CLCN1 variants may modulate phenotype but does not negate the primary SCN4A association.

In summary, the association between SCN4A and potassium-aggravated myotonia is definitive. Genetic testing for SCN4A missense variants is clinically actionable for diagnosis, prognosis, and guiding sodium-channel-blocking therapies.

References

• The Journal of neuroscience • 1999 • Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation. PMID:10366610
• Neuromuscular disorders : NMD • 2011 • Late onset painful cold-aggravated myotonia: three families with SCN4A L1436P mutation. PMID:21664816
• Frontiers in neurology • 2020 • Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4. PMID:32411069
• Practical neurology • 2023 • Acute myotonic reaction during succinylcholine anaesthesia. PMID:36192135
• International journal of molecular sciences • 2020 • Changes of Resurgent Na+ Currents in the Nav1.4 Channel Resulting from an SCN4A Mutation Contributing to Sodium Channel Myotonia. PMID:32276507

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