By Joshua Weaver, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College.

Dr. Weaver reports no financial relationships relevant to this field of study.

SYNOPSIS: A detailed non-interventional clinical study of patients with inherited erythromelalgia who carry gain-of-function mutations of voltage-gated sodium channel Nav1.7 further characterized pain phenotypes in this disorder and showed wide variability of pain symptoms.

SOURCE: McDonnell A, Schulman B, Ali Z, et al. Inherited erythromelalgia due to mutations in SCN9A: Natural history, clinical phenotype and somatosensory profile. Brain 2016;139:1052-1065.

Inherited erythromelalgia (IEM) is a rare pain syndrome genetically linked to dominant gain-of-function mutations of the SCN9A gene encoding the voltage-gated sodium channel Nav1.7. Patients with IEM experience episodic pain, erythema, and swelling of the distal extremities and face, and attacks often are triggered by exertion and exposure to heat.

From a database of IEM subjects maintained at the Yale University Department of Neurology, 13 patients with clinical erythromelalgia who carried one of four distinct gain-of-function mutations of Nav1.7 were consented and enrolled in this study. Information was obtained regarding pain and psychological symptoms, family history, and treatments. Quantitative sensory testing (QST) was performed in one affected and one unaffected body site. Since there are known links between Nav1.7 and odor perception, olfaction threshold testing was obtained. Subjects then completed a 12-week diary recording pain symptoms during and between pain attacks.

All subjects reported IEM signs and symptoms by the second decade of life, with the majority of subjects reporting onset in the first decade. A clinical diagnosis was obtained anywhere from one to 20 years after the onset of pain symptoms. The most common symptoms included reddening, swelling, and heat in the distal extremities. Four subjects reported facial pain. Disease progression was split almost evenly among the subjects, with five reporting worsening, four reporting improvement, and four reporting stable symptoms over time.

There was considerable variability noted in pain symptoms across all subjects and between subjects with the same genetic mutation. The severity of pain ranged from 1 to 10 on a numerical rating scale, generally with more severe pain noted during an attack (mean 5.7 across subjects) compared to pain felt between attacks (mean 2.69). The mean number of attacks ranged from 0.9 to 15.3 per week. This variability also was seen within family groups having the same mutation type. The duration of pain attacks ranged from 5 minutes to 17 hours.

Many pharmacologic therapies were reported, usually with modest results at best. Acetylsalicylic acid was tried by 11 of 13 subjects, with six reporting a positive (“some” to “good”) response and five reporting no response. Two subjects reported a modestly beneficial response to carbamazepine in terms of reduction of severity and frequency of pain attacks. Non-pharmacological treatments were used most often and included ice, cold air, or immersion of affected extremities in cold water; most patients reported this to be the most effective form of treatment. Pain triggered by heat and exercise was reported by all subjects, but two also reported worsening of pain with exposure to cold. No trigger was identified for about one-third of all attacks recorded.

Based on psychometric questionnaire scoring, seven subjects had anxiety and four had depression; these scores correlated with pain severity between attacks. Pain catastrophizing was seen in only three of 13 subjects. Olfaction threshold testing was normal. QST profiles showed reduced detection of temperature in affected sites and hyperalgesia in unaffected sites, suggesting small fiber nerve dysfunction.

COMMENTARY

Prior to the discovery of the link between IEM and Nav1.7 mutations about a decade ago, patients with clinical erythromelalgia symptoms were studied, but no verification of genetic mutation status was possible. In the last decade, multiple mutations have been described and partially clinically characterized. This study is the first systematic review of patients with IEM and known sodium channel gain-of-function mutations.

Faber et al reported a link between gain of function mutations in Nav1.7 and small fiber neuropathy.1 This study also suggested an association between small fiber neuropathy and erythromelalgia based on QST results. Analyzing intraepidermal nerve fiber density via skin biopsy in patients with IEM may help better characterize these findings.

There was substantial variability reported in the number, duration, and severity of pain attacks both between and within mutation subtypes. Careful characterization of pain phenotype will be important in pursuing clinical trials for therapeutic agents in this disorder. Future trials assessing the efficacy of sodium channel blockers as well as gene therapy will be of particular interest.

REFERENCE

  1. Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012;71:26-39.