Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo, Japan.
Curr Med Chem. 2012;19(15):2312-23. doi: 10.2174/092986712800269317.
Hereditary amyloidogenic transthyretin (TTR) (ATTR) amyloidosis is an autosomal dominant form of fatal hereditary amyloidosis. Owing to progress in biochemical and molecular genetic analyses, this disease is now believed to occur worldwide. As of today, reports of about 120 different points of single or double mutations, or a deletion in the TTR gene have been reported, and several different phenotypes of ATTR amyloidosis have been documented. In addition, since liver transplantation has been established to halt the progression of hereditary ATTR amyloidosis in the early stage, rapid and reliable diagnostic system for ATTR amyloidosis is needed. On the other hand, senile systemic amyloidosis (SSA) derived from wild-type (WT) TTR affects primarily in the heart and lungs and occasionally in carpal ligaments in the elderly. To perform accurate diagnosis and effective treatments, we should distinguish between hereditary ATTR amyloidosis and SSA by means of genetic and proteomic analyses. The liver transplantation for hereditary ATTR amyloidosis has become a well-established treatment, because the main source of serum variant TTR is shut out. However, this treatment has several problems, such as expensive medical costs, lifelong administration of immunosuppressants, non-indication for the mutated-TTR gene carriers without clinical symptoms, shortage of liver donors, and further development of cardiac and ocular disorders. Therefore, we and other ATTR amyloidosis research groups have been investigating the possibility of stabilization of variant TTR, gene therapy, and immunotherapy for ATTR amyloidosis on the basis of TTR amyloid formation mechanism. We present here the current diagnostic procedure and therapeutic approaches for the disease.
遗传性转甲状腺素蛋白（TTR）（ATTR）淀粉样变性是一种致命的常染色体显性遗传性淀粉样变性病。由于生化和分子遗传学分析的进展，目前认为这种疾病在世界范围内都有发生。截至今天，已经报道了大约 120 种不同的 TTR 基因突变或缺失的点突变或双突变，以及几种不同表型的 ATTR 淀粉样变性。此外，由于肝移植已被确立为阻止遗传性 ATTR 淀粉样变性在早期进展的方法，因此需要快速可靠的 ATTR 淀粉样变性诊断系统。另一方面，来源于野生型（WT）TTR 的老年性系统性淀粉样变性（SSA）主要影响心脏和肺部，偶尔也影响老年人的腕韧带。为了进行准确的诊断和有效的治疗，我们应该通过遗传和蛋白质组学分析来区分遗传性 ATTR 淀粉样变性和 SSA。肝移植已成为遗传性 ATTR 淀粉样变性的一种成熟治疗方法，因为它阻断了血清变异 TTR 的主要来源。然而，这种治疗方法存在几个问题，如昂贵的医疗费用、终身使用免疫抑制剂、无临床症状的突变-TTR 基因携带者不适用、肝源短缺，以及心脏和眼部疾病的进一步发展。因此，我们和其他 ATTR 淀粉样变性研究小组一直在根据 TTR 淀粉样蛋白形成机制，研究稳定变异 TTR、基因治疗和免疫疗法治疗 ATTR 淀粉样变性的可能性。我们在此介绍该疾病的当前诊断程序和治疗方法。
