SCN9A – Primary Erythermalgia

Primary erythermalgia is a rare autosomal dominant disorder characterized by episodic burning pain, redness and warmth of the extremities. Linkage analysis in a Chinese pedigree localized the disease to chromosome 2q and identified SCN9A missense variants in both familial and sporadic cases, implicating Nav1.7 in nociception and vasomotor regulation (PMID:14985375). Subsequent screening of four additional families and two sporadic patients confirmed SCN9A mutations in six probands, with segregation in multiple affected relatives (PMID:15955112).

Genetic evidence supports a definitive association: at least 16 unrelated probands across 12 autosomal dominant families have been reported with pathogenic SCN9A variants, including recurrent and private missense changes (e.g., c.2606T>A (p.Leu869His)) (PMID:14985375; PMID:15955112). Segregation in extended pedigrees and absence of these variants in controls reinforce pathogenicity.

Functional studies demonstrate a clear gain-of-function mechanism: voltage-clamp assays of multiple Nav1.7 mutants reveal hyperpolarizing shifts in activation and increased ramp currents, leading to DRG neuron hyperexcitability that mirrors the clinical phenotype (PMID:17145499; PMID:28990532). Carbamazepine and mexiletine normalize aberrant gating in select variants, offering mechanistic insight into variable drug responsiveness.

Some SCN9A variants (e.g., p.Pro610Thr, p.Arg523Ter) occur at low frequency in population datasets and may act as modifiers rather than primary causes, underscoring the need for careful interpretation in diagnostic panels (PMID:23129781).

Overall, SCN9A meets ClinGen criteria for a definitive gene–disease relationship with primary erythermalgia. Genetic testing for SCN9A variants enables precise diagnosis, informs prognosis, and may guide targeted therapies based on variant-specific electrophysiological profiles.

References

• Journal of medical genetics • 2004 • Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. PMID:14985375
• The Journal of investigative dermatology • 2005 • SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. PMID:15955112
• Neuron • 2006 • SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. PMID:17145499
• Current molecular medicine • 2017 • A Novel SCN9A Mutation (F826Y) in Primary Erythromelalgia Alters the Excitability of Nav1.7. PMID:28990532
• Journal of neurology, neurosurgery, and psychiatry • 2013 • Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia. PMID:23129781

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