Episodic Pain Syndrome, Familial, 1

A number sign (#) is used with this entry because of evidence that familial episodic pain syndrome-1 (FEPS1) is caused by heterozygous mutation in the TRPA1 gene (604775) on chromosome 8q13. One such family has been reported.

Description

Familial episodic pain syndrome-1 is an autosomal dominant neurologic disorder characterized by onset in infancy of episodic debilitating upper body pain triggered by fasting, cold, and physical stress (summary by Kremeyer et al., 2010).

Genetic Heterogeneity of Familial Episodic Pain Syndrome

See also FEPS2 (615551), caused by mutation in the SCN10A gene (604427) on chromosome 3p22, and FEPS3 (615552), caused by mutation in the SCN11A gene (604385) on chromosome 3p22.

Clinical Features

Kremeyer et al. (2010) reported a large 4-generation family from Colombia, South America, in which 21 individuals had an episodic pain syndrome. The disorder was characterized by onset in infancy of episodic debilitating upper body pain usually triggered by fasting, fatigue, cold, illness, and/or physical exertion. The episodes typically lasted about 1.5 hours, had a prodromal phase during which the episode could sometimes be aborted, and were followed by a period of exhaustion and deep sleep. The episodes of intense pain were accompanied by breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. However, affected individuals reported no altered pain sensitivity outside the episodes, and neurologic examination was normal. Skin biopsies of affected individuals showed no abnormalities of intraepidermal nerve fibers, and quantitative sensory testing in affected individuals was similar to unaffected individuals. Tests with mustard oil, known to activate TRPA1 receptors, showed that some affected individuals had higher flare responses and secondary hyperalgesia compared to unaffected individuals.

Inheritance

The transmission pattern of FEPS in the family reported by Kremeyer et al. (2010) was consistent with autosomal dominant inheritance.

Mapping

By linkage and haplotype analysis, Kremeyer et al. (2010) mapped the episodic pain syndrome in a large Colombian family to chromosome 8q12-q13. A maximum multipoint lod score of 5.36 was obtained at 8q13.

Molecular Genetics

By linkage analysis followed by candidate gene sequencing in a large Colombian family with episodic pain syndrome, Kremeyer et al. (2010) identified a heterozygous missense mutation in the TRPA1 gene (N855S; 604775.0001). The mutation completely segregated with the disorder. In vitro functional expression studies indicated that the mutation resulted in a gain of function of channel activity.