SCN9A – Paroxysmal Extreme Pain Disorder

Paroxysmal extreme pain disorder (PEPD) is a rare autosomal dominant sodium channelopathy characterized by episodic severe burning pain in the rectal, ocular, or mandibular regions often accompanied by cutaneous flushing or harlequin color change. The disease is caused by heterozygous gain‐of‐function variants in SCN9A, encoding the voltage‐gated sodium channel NaV1.7, leading to neuronal hyperexcitability and persistent sodium currents.

Genetic studies have identified at least ~30 unrelated PEPD probands harboring heterozygous SCN9A missense mutations (PMID:17145499; PMID:21079636; PMID:25903274). Segregation analysis across multiple pedigrees demonstrates variant co‐segregation with disease in ~12 additional affected relatives (PMID:24817410; PMID:25285947). Commonly reported variants include c.4852G>C (p.Gly1618Arg), c.554G>A (p.Arg185His), and c.5251G>T (p.Val1751Leu), which cluster in the domain IV voltage‐sensor and fast‐inactivation linker regions.

Inheritance is autosomal dominant with high penetrance. A representative variant, c.4852G>C (p.Gly1618Arg), was first described in a neonate with tonic body contractions and harlequin color change (PMID:21079636). Family‐based studies include a multigenerational pedigree with 6 affected members bearing c.5218G>C (p.Val1740Leu) (PMID:25903274) and a 4‐generation kindred with c.4837T>C (p.Leu1623Pro) exhibiting temperature‐sensitive attacks (PMID:25285947).

Electrophysiological assays in heterologous cells and dorsal root ganglion neurons uniformly reveal impaired fast inactivation, depolarized voltage dependence of inactivation, increased ramp currents, and accelerated recovery from inactivation, resulting in NaV1.7 hyperactivity and neuronal hyperexcitability (PMID:17145499; PMID:25285947). Carbamazepine selectively blocks persistent current and often provides symptom relief in PEPD patients.

No compelling contradictory reports have emerged; however, intrafamilial phenotypic variability has been noted with some carriers exhibiting only autonomic signs without full‐blown pain episodes. The concordance among genetic, segregation, and functional data over nearly two decades firmly establishes a definitive gene‐disease relationship.

Key Take-home: Heterozygous gain‐of‐function SCN9A variants are definitively causal for autosomal dominant PEPD, and genetic testing informs diagnosis, prognosis, and therapeutic decisions including sodium channel blockade.

References

• Neuron • 2006 • SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. PMID:17145499
• Nature reviews. Neurology • 2011 • Paroxysmal extreme pain disorder: a molecular lesion of peripheral neurons. PMID:21079636
• Pediatric nephrology (Berlin, Germany) • 2014 • Painful micturition in a small child: an unusual clinical picture of paroxysmal extreme pain disorder. PMID:24817410
• The journal of headache and pain • 2015 • Short-lasting unilateral neuralgiform headache attacks with ispilateral facial flushing is a new variant of paroxysmal extreme pain disorder. PMID:25903274
• Anesthesiology • 2015 • p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder. PMID:25285947
• BMC neurology • 2020 • Paroxysmal extreme pain disorder in family with c.3892G > T (p.Val1298Phe) in the SCN9A gene mutation - case report. PMID:32404070

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