Paroxysmal itch caused by gain-of-function Nav1.7 mutation

Area of Science:

• Genetics
• Neurology
• Dermatology

Background:

• Itch is a common symptom linked to systemic diseases, allergies, or somatosensory pathway disorders.
• The genetic underpinnings of paroxysmal itch, particularly those involving the somatosensory system, remain incompletely understood.

Purpose of the Study:

• To investigate the genetic basis of a familial paroxysmal itch disorder.
• To characterize the clinical and somatosensory phenotype associated with the identified genetic variant.

Main Methods:

• Clinical assessment, quantitative sensory testing, nerve conduction studies, autonomic function tests, skin biopsy for nerve fiber density, and SCN9A gene sequencing.
• Analysis of a kindred presenting with stereotypical itch attacks.

Main Results:

• A novel SCN9A gene variant (I739V) co-segregated with paroxysmal itch attacks in affected family members.
• Patients exhibited increased cold/pain thresholds and paradoxical heat sensations, with reduced intraepidermal nerve fiber density in some.
• Pregabalin effectively reduced itch intensity and frequency.

Conclusions:

• This study provides the first evidence linking a mutation in the SCN9A sodium channel gene to paroxysmal itch.
• The findings highlight the role of Nav1.7 sodium channels in itch pathophysiology and suggest potential therapeutic targets.