- 學位論文
肢端紅痛症的基因型與表現型研究
The genotype and phenotype in patients with erythromelalgia
摘要
肢端紅痛症是一種以患者肢體會陣發性紅熱及燒灼痛為主要特徵的少見疾病。肢端紅痛症可以分為原發性及繼發性。家族性原發性肢端紅痛症通常是顯性遺傳。原發性肢端紅痛症病因尚未十分清楚。引起繼發性肢端紅痛症的原因包括有自體免疫疾病如修格連氏症候群，骨髓增生性疾病如紅血球增多症、糖尿病及神經病變如法布瑞氏症及酒精性神經病變。連鎖分析研究定位原發性肢端紅痛症基因位置於染色體2q24.2–q24.3，進一步序列分析發現一個載譯Nav1.7電壓門控鈉離子通道的SCN9A基因產生錯義突變。本研究的目的是分析肢端紅痛症的基因型與表現型。本研究收集13名肢端紅痛症患者。臨床上這些患者都有陣發性紅熱及厲害燒灼痛，特別是在炎熱的天氣。遇冷和浸泡冰水只能部分改善症狀。神經傳導檢查的結果無特別異常。基因分析人類SCN9A基因，結果在一個顯性遺傳的原發性肢端紅痛症家族發現錯義突變(I136V)，影響Nav1.7電壓門控鈉離子通道第一穿膜區段(D1S1)。另外在兩個偶發性病例發現兩個內含子序列變異。雷射都卜勒影像掃描測量皮膚灌注，發現在原發性肢端紅痛症組，無論是年輕及年長且特別是在年輕患者，在停止局部加熱10分鐘後皮膚灌注是顯著低於對照組。皮膚交感神經反應在兩個年輕原發性肢端紅痛症患者的手掌或腳掌呈現異常。且I136V突變患者的皮膚切片呈現顯著減少小纖維神經的密度。這結果顯示在原發性肢端紅痛症有血管收縮傾向，可能是Nav1.7鈉離子通道突變導致減少皮膚交感神經活性，產生對兒茶酚胺的去神經增敏狀態。證據顯示因「功能獲得」，在家族性肢端紅痛症，鈉離子通道產生動作電位有較低的閥值及增加產生動作電位的頻率，已經被報告過。更進一步的研究，如何使缺陷的鈉離子通道導致同時陣發性皮膚變紅和引起因為小纖維神經病變的痛，對於探討肢端紅痛症的病理機轉將會是有幫忙的。
並列摘要
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.