The genotype and phenotype in patients with erythromelalgia
|Keywords:||肢端紅痛症;SCN9A;Nav1.7;雷射都卜勒影像掃描;Erythromelalgia;SCN9A;Nav1.7;Laser Doppler imaging scan||Issue Date:||2008||Abstract:||
Erythromelalgia is a rare disease characterized by episodes of redness, heat, and severe burning pain in the extremities. Erythromelalgia can be either primary or secondary. Familial primary erythromelalgia is often inherited in an autosomal dominant manner. The etiology for the primary erythromelalgia is unknown. The causes for the secondary erythromelalgia include autoimmune diseases such as Sjögren''s syndrome, myeloproliferative diseases such as polycythemia vera, diabetes mellitus and neuropathies such as Fabry diseases and alcoholic neuropathy. Genetic linkage mapped the disease locus of primary erythromelalgia to human chromosome 2q24.2–q24.3, and further sequence analysis identified missense mutations in the SCN9A gene which encodes the alpha subunit of the voltage-gated sodium channel Nav1.7. The aim of this study is to analyze the genotypes and phenotypes of Taiwanese patients with erythromelalgia. In total, 13 index patients fulfilled the diagnostic criteria for erythromelalgia were recruited. Clinically these patients suffered from episodic attacks of severe redness, hot and severe burning pain especially at hot weather. Cold exposure or even immersing at ice-cold water can only partially relieve the pain. The nerve conduction studies were unremarkable. Genetic analysis revealed a missense mutation, I136V in the SCN9A gene, located at the first transmembrane domain (D1S1) of the voltage-gated sodium channel, Nav1.7 in an erythromelalgia family with autosomal dominant transmission pattern. Another two sequence variants at introns (IVS13+17 G>A, IVS5 +13 T>C) from two sporadic cases were also identified. Laser-Doppler skin perfusion study demonstrated that after post the local heat provocation for 10 minutes the skin perfusion in the affected patients was significantly lower than normal controls. The phenomenon occurred in both young and aged patients with primary erythromelalgia, especially the young adult. The sympathetic skin responses showed abnormal in either palms or soles in each of the two patients. Skin biopsy of the patient with I136V mutation revealed a marked reduced small fiber density in the affected patient than the normal controls. The results indicated that there is an increased vasoconstrictor activity in primary erythromelalgia which is probably due to reduced skin sympathetic activity with denervation hypersensitivity to circulating catecholamines by Nav1.7 mutations in primary erythromelalgia. Evidences of reduced the sodium channel firing threshold associated with increased frequency of firing electric potentials with a gain of function was reported in the familial erythromelalgia. Further studies on the mechanisms how the defective sodium channel induced both the episodic skin erythematous change and the pain triggered by the small fiber neuropathy would be helpful in elucidating the pathogenesis mechanisms.
|Appears in Collections:||分子醫學研究所|
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