Episodic Pain Syndrome, Familial, 3

A number sign (#) is used with this entry because of evidence that familial episodic pain syndrome-3 (FEPS3) is caused by heterozygous mutation in the SCN11A gene (604385) on chromosome 3p22.

Description

Familial episodic pain syndrome is an autosomal dominant disorder characterized by early childhood onset of intense episodic pain mainly affecting the distal lower extremities, but sometimes affecting the upper extremities as well. The pain comes in cycles lasting several days, is exacerbated by fatigue, may be accompanied by sweating, and can be relieved by antiinflammatory medication. Severe episodic pain tends to diminish with age (summary by Zhang et al., 2013).

For a discussion of the genetic heterogeneity of familial episodic pain syndrome, see FEPS1 (615040).

Clinical Features

Zhang et al. (2013) reported 2 unrelated large multigenerational Chinese families with a similar episodic pain syndrome with onset in early childhood. Intense pain was localized primarily to the distal lower extremities and occasionally in the upper body, especially in the joints of fingers and arms. Episodic pain appeared late in the day and occurred in cycles. The pain was exacerbated with fatigue, such as catching a cold or performing hard exercise, and was relieved by oral administration of antiinflammatory analgesic medicines. Episodes of pain were usually accompanied by sweating. The feeling of the pain region was extremely cold and the pain could be mitigated by a hot compress. All affected individuals reported that the severe pain episodes diminished with age. Neurologic examinations of 2 probands showed retained and intact sensitivities to joint position, light touch, and pinprick.

Clinical Variability

Small nerve fiber neuropathy (SFNP) is a clinical diagnosis that refers to a relatively common disorder characterized by adult onset of neuropathic pain, often of a burning quality, and autonomic symptoms. Affected individuals have reduced intraepidermal nerve fiber density affecting the thinly myelinated and unmyelinated small diameter nerve fibers; large diameter fibers are spared (summary by Faber et al., 2012). Huang et al. (2014) reported 12 unrelated patients with a clinical diagnosis of painful small fiber peripheral neuropathy associated with a heterozygous missense mutation in the SCN11A gene (see MOLECULAR GENETICS). Clinical features of 4 of these patients were described in detail. All 4 had onset of symptoms between 40 and 71 years of age. Symptoms were slightly variable, but mainly included numbness, tingling and burning sensations, and pain in the feet and hands. Two patients had intermittent foot or leg cramps, 1 patient reported pain triggered by low temperatures, and 1 reported involvement of the pubic region, ears, and tip of the tongue. Only 1 patient reported pain triggered by low temperature, although sensory testing showed abnormal cold and warm temperature thresholds in all patients. Physical examination showed decreased distal vibratory sensation in 2 patients, who were also diagnosed with large fiber involvement. Only 1 of the 4 patients had evidence of a peripheral neuropathy on nerve conduction studies. Skin biopsies showed normal intraepidermal nerve fiber densities in 3 patients and slightly decreased density in 1. All patients had additional features suggesting autonomic dysfunction, including hyperhidrosis, diarrhea, dry mouth, dry eyes, palpitations, and hot flushes. Three of the patients had significant comorbid medical problems, including Alport syndrome (203780), primary biliary cirrhosis, and colorectal cancer that was not treated with chemotherapy.

Inheritance

The transmission pattern of FEPS3 in the families reported by Zhang et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 unrelated Chinese families with autosomal dominant familial episodic pain syndrome-3, Zhang et al. (2013) identified 2 different missense mutations in the SCN11A gene (R225C, 604385.0002; A808G, 604385.0003). The mutation in the first family was found by genomewide linkage analysis combined with whole-exome sequencing. Electrophysiologic studies in mouse dorsal root ganglia neurons showed that both mutations had higher peak current densities compared to wildtype, indicating higher electrical activity. Mutant channels also showed increased spontaneous firing compared to wildtype. However, voltage-dependence for activation and inactivation kinetics of mutant channels were similar to wildtype. Neurons expressing the A808G mutation fired more action potentials than those expressing the R225C mutation, which was consistent with the increased number of episodic pain episodes in the family carrying the A808G mutation. Zhang et al. (2013) noted that the SCN11A channel is not directly responsible for action potential generation, but suggested that higher electrical activities of the mutant channels may induce the opening of other sodium channels, such as SCN10A (604427), and thus cause dorsal root ganglion neurons to be hyperexcitable, which would contribute to the episodic pain syndrome.

In 12 of 345 unrelated patients with painful small fiber peripheral neuropathy, Huang et al. (2014) identified 7 different heterozygous missense mutations in the SCN11A gene (see, e.g., L1158P, 604385.0004 and I381T, 604385.0005). Four of the mutations affected residues in membrane-spanning segments of the channel. Electrophysiologic studies showed that the L1158P and I381T mutations conferred a gain of function by depolarizing the resting membrane potential of dorsal root ganglion neurons, enhancing spontaneous firing, and increasing evoked firing of these neurons.