Paroxysmal limb intolerable pain (infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome).

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Navl.9, a voltage-gated sodium channel sub- type, has been established as a genetic influence for certain peripheral pain syndromes. Herein, we performed a genetic study in six unrelated, multigenerational Japanese families with episodic pain syndrome. Affected participants were characterized by infantile recurrent pain episodes, with spontaneous mitigation around adolescence. The affected joints, in an in- creasing order of frequency, include those in the knees, ankles, wrists, and elbows. The pain typically lasts for 15-30 min and recurs several times a day. The pain is often induced by fa- tigue and is a prelude of bad weather. The affected regions feel cold in the patients, and warming the lesions relieves the symptoms. This unique phenotype was inherited in an autosomal-dominant mode. Two missense var- iants, p.R222S and p.R222H, were identified in SCN11A by linkage analysis and exome analy- sis. Next, we generated a knock-in mouse model harboring one of the mutations (p.R222S). Behavioral tests showed that p.R222S mice were significantly more hypersensitive to hot and cold stimuli. Electrophysiological studies using dorsal ganglion neurons showed significant increase of input impedance and firing frequency of evoked action potentials in p.R222S mice. These results suggest that the novel mutation reported herein is a gain-of-function mu- tation that causes infantile familial episodic pain.

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