Abstract
Hereditary erythermalgia is a painful and debilitating genetic disorder associated with mutations in voltage-gated sodium channel Nav1.7. We have previously reported a Canadian family segregating erythermalgia consistently with a dominant genetic etiology. Molecular analysis of the proband from the family detected two different missense mutations in Nav1.7. In the present study we have performed a long-term follow-up clinical study of disease progression in three affected family members. A more extensive molecular study has also been completed, analyzing the segregation of the two missense variants in the family. The two variants (P610T, L858F) segregate independently with respect to clinical presentation. Detailed genotype/phenotype correlation suggests that one of the two variants (L858F) is causal for erythermalgia. The second variant (P610T) may modify the phenotype in the proband. This is the second reported study of potential compound heterozygosity for coding polymorphisms in Nav1.7, the first being in a patient with paroxysmal extreme pain disorder.
Highlights
The family was subsequently included in a cohort of families used to map a locus for erythermalgia to chromosome 2q31-32[3], and eventually molecular analysis of the proband identified two missense variants in voltage-gated sodium channel Nav1.7, amino acids P610T and L858F[4]
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Summary
A Canadian family segregating erythermalgia as an apparent dominant genetic trait was originally ascertained and reported in 1979[1]. The family was subsequently included in a cohort of families used to map a locus for erythermalgia to chromosome 2q31-32[3], and eventually molecular analysis of the proband identified two missense variants in voltage-gated sodium channel Nav1.7, amino acids P610T and L858F[4] Segregation of these two variants in the remaining affected and unaffected family members was not feasible at that time. Brother (III/2): The second brother is age 48 He reports having symptoms from birth, with reddened and burning painful hands, feet, and ears. PEPD alleles of Nav1.7 are likewise missense variants, suggesting that they have aberrant function (gof) They cause spontaneous rectal, ocular or submandibular pain with reddening. There are clearly many additional questions to answer about the role of Nav1.7 in sporadic and provoked pain sensation
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