SCN4A – Hyperkalemic Periodic Paralysis

Autosomal dominant hyperkalemic periodic paralysis (HyperPP) is caused by gain-of-function variants in the skeletal muscle sodium channel gene SCN4A (HGNC:10591) and is catalogued as Hyperkalemic Periodic Paralysis (MONDO:0008224).

Clinical validity for SCN4A–HyperPP is definitive: over 50 unrelated probands from >20 families exhibit classic episodic weakness with hyperkalemia, multi-family co-segregation of variants, and concordant functional data. The earliest evidence derived from seven unrelated patients showing a recurrent Thr704Met variant co-segregating in two pedigrees and arising de novo in a third (PMID:1659948). Subsequent molecular diagnosis across 12 families and linkage studies reinforced SCN4A as the causative locus (PMID:8385748).

Genetic evidence is strong: SCN4A variants follow autosomal dominant inheritance with >50 probands reported, including recurrent missense changes in conserved transmembrane segments. The spectrum includes Thr704Met, Met1592Val and novel pore-lining defects such as Val792Gly, each segregating with HyperPP in multiple families. Segregation analysis demonstrated ≥18 additional affected relatives across published pedigrees. A previously proposed Val781Ile variant was later shown to be a benign polymorphism (PMID:7695243; PMID:9266738).

Functional studies provide strong mechanistic evidence: heterologous expression and patch-clamp assays of Thr704Met and Met1592Val demonstrate hyperpolarizing shifts in activation, impaired slow inactivation, and increased persistent currents at −40 mV, consistent with episodic membrane depolarization (PMID:10366610; PMID:9886942). A novel V792G inner‐pore lesion further confirmed gain-of-function gating alterations correlating with family phenotypes (PMID:36628799).

No credible refuting studies for SCN4A in HyperPP have been reported beyond isolated benign polymorphisms. Animal models and rescue experiments remain limited but additional functional concordance across multiple channel domains exceeds ClinGen scoring maximum.

Key take-home: SCN4A testing enables definitive molecular diagnosis of HyperPP, guides management (e.g., acetazolamide, salbutamol), and informs genetic counselling in autosomal dominant families.

References

• Cell • 1991 • Identification of a mutation in the gene causing hyperkalemic periodic paralysis. PMID:1659948
• Neurology • 1993 • Hyperkalemic periodic paralysis: rapid molecular diagnosis and relationship of genotype to phenotype in 12 families. PMID:8385748
• Annals of Neurology • 1995 • Hyperkalemic periodic paralysis with cardiac dysrhythmia: a novel sodium channel mutation? PMID:7695243
• Annals of Neurology • 1997 • A proposed mutation, Val781Ile, associated with hyperkalemic periodic paralysis and cardiac dysrhythmia is a benign polymorphism. PMID:9266738
• 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
• The American Journal of Physiology • 1999 • Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel. PMID:9886942
• Brain & Development • 2023 • Hyperkalemic periodic paralysis associated with a novel missense variant located in the inner pore of Nav1.4. PMID:36628799

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