類澱粉神經病變治療的新進展

Recent Progress in the Therapy for Tansthyretin Amyloidosis

家族型類澱粉神經病變(hereditary transthyretin amyloidosis, hATTR)，或是稱為familial amyloid polyneuropathy(FAP)，是一遺傳性之多發性神經病變，影響運動、感覺與自律神經，主要是運甲狀腺素蛋白(transthyretin, TTR)的基因突變所致。運甲狀腺蛋白主要以四聚體(tetramer)存在，突變的運甲狀腺素蛋白會造成蛋白結構變不穩定，成為單體(monomer)，因而聚集沉積(aggregate)，成為類澱粉(amyloid)沉積。類澱粉主要沉積在周變神經、心臟與內臟器官。在臺灣的家族型類澱粉神經病變，主要的突變點是Ala97Ser (p.Ala117Ser)，和國外常見的基因型Val30Met(p.Va150Met)不同。臺灣的Ala97Ser 病人通常在55至60歲左右發病。一般早期症狀為小纖維神經受損的神經痛與自律神經失調。經過2至5年，病人的運動神經退化，造成肌肉無力與行動障礙。臺大團隊應用小片皮膚切片(punch skin biopsy)可以診斷、評估早期的表皮神經及汗腺神經的退化。因為運甲狀腺素蛋白主要在肝臟製造，肝臟移植是在1990年代主要的治療方式。自2010 年代，最近10年來，新的科技使得家族型類澱粉神經病變的治療，有了很大進展。包括使用：（一）運甲狀腺素蛋白的穩定劑TTR stabilizer : tafamidis 與diflunisal，與（二）基因靜默化(gene silencing)治療，RNA干擾術(RNAi)與反義核苷酸(anti-sense)技術，都可以延緩疾病的進展。這些療效都已經在有安慰劑之隨機、雙盲3期臨床試驗，證實其減少神經學缺失的療效。對於家族型類澱粉神經病變的症狀，包括神經痛及自律神經障礙，都可以藥物治療緩解。對於病人的生育年齡子女，可以結合胚胎著床前基因診斷(pre-implantation genetic diagnosis)，和試管嬰兒的方式，生產出正常的下一代，終結這一遺傳疾病。整體而言，最近10年來，家族型類澱粉神經病變的治療，已有長足的進展，原來無助的疾病，已經看到曙光。

Hereditary transthyretin amyloidosis (hTTR) or familial amyloid polyneuropathy (FAP) is a devastating degeneration disorder affecting the motor, sensory and autonomic components of the peripheral nervous system. This disease is caused by mutations of the transthyretin (TTR) gene. In normal condition, TTR exists in tetramers; mutant TTR leads to instability of this molecule and becomes monomers which easily form aggregates. Hence amyloid deposition in the peripheral nerves, hearts, and visceral organs. The most common genotype worldwide is Val30Met (p.Vat50Met); in contrast, Ala97Ser (p. Ala117Ser) constitutes the major mutation in Taiwan, with a manifestation of late-onset pain-modality polyneuropathy. Liver is the major organ to synthesize TTR and liver transplantation was the predominant therapy in 1990s. Since 2010s, new technologies including TTR stabilizer (tafamidis and diflunisal) and gene silencing (RNAi and anti-sense therapy) have become the major therapies. The effects were confirmed by documenting the slowing of neurological declines in phase III randomized and placebo-controlled clinical trials. In addition, neurological symptoms of neuropathic pain and autonomic dysfunctions can be alleviated with appropriate treatments. Preimplantation genetic diagnosis can be offered for the offspring of these patients to deliver healthy babies. Overall, new therapies based on technological advancements have been emerging for this previously untreatable disease.