Nomura Toshiya, Misumi Yohei, Tasaki Masayoshi, Yamakawa Shiori, Taguchi Tomoaki, Obayashi Konen, Yamashita Taro, Ando Yukio, Ueda Mitsuharu
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.
Amyloidosis center, Kumamoto University Hospital, Kumamoto, Japan.
Orphanet J Rare Dis. 2025 Sep 2;20(1):474. doi: 10.1186/s13023-025-04006-6.
Hereditary transthyretin (ATTRv) amyloidosis is a rare, intractable genetic disorder caused by mutations in the transthyretin (TTR) gene. More than 150 TTR mutations have been identified, along with genotype-phenotype correlations. Early diagnosis is critical to facilitate the timely initiation of disease-modifying therapies.
To characterize the genetic and clinical features of ATTRv amyloidosis at our referral center.
A total of 6,201 TTR genetic tests were conducted at Kumamoto University Hospital over a ten-year period and revealed 289 mutations, including 235 symptomatic cases, which were analyzed in this study.
In a cohort of 235 patients with symptomatic ATTRv amyloidosis, 46 TTR mutations were identified. The genotypes were distributed as follows: V30M in endemic areas (7.7%), V30M in non-endemic areas (48.5%), and non-V30M mutations (43.8%). The mean age of onset was lowest for patients with V30M in endemic areas (42.4 ± 15.6 years) and higher for those with non-V30M mutations (60.6 ± 14.6 years) and V30M in non-endemic areas (64.5 ± 11.9 years). Family history was present in 93.3% of V30M cases in endemic areas but absent in 42.0% of V30M cases in non-endemic areas and 57.5% of non-V30M cases. Polyneuropathy was the predominant initial symptom, affecting 73.7% of endemic V30M cases, 54.3% of non-endemic V30M cases, and 34.6% of non-V30M cases. Diagnosis occurred earlier in patients with V30M in endemic areas than in other groups. Notably, delayed diagnosis has been observed in patients presenting with carpal tunnel syndrome or polyneuropathy.
These findings demonstrate that patients with V30M in non-endemic areas and those with non-V30M mutations are more prevalent than previously recognized and that their genetic and clinical characteristics exhibit considerable diversity.
遗传性转甲状腺素蛋白（ATTRv）淀粉样变性是一种由转甲状腺素蛋白（TTR）基因突变引起的罕见、难治性遗传性疾病。已鉴定出150多种TTR突变，以及基因型与表型的相关性。早期诊断对于及时启动疾病修饰疗法至关重要。
在我们的转诊中心描述ATTRv淀粉样变性的遗传和临床特征。
熊本大学医院在十年期间共进行了6201次TTR基因检测，发现289种突变，其中包括235例有症状的病例，本研究对这些病例进行了分析。
在235例有症状的ATTRv淀粉样变性患者队列中，鉴定出46种TTR突变。基因型分布如下：流行地区的V30M（7.7%）、非流行地区的V30M（48.5%）和非V30M突变（43.8%）。流行地区V30M患者的平均发病年龄最低（42.4±15.6岁），非V30M突变患者（60.6±14.6岁）和非流行地区V30M患者（64.5±11.9岁）的平均发病年龄较高。流行地区93.3%的V30M病例有家族史，而非流行地区42.0%的V30M病例和57.5%的非V30M病例无家族史。多发性神经病是主要的初始症状，影响73.7%的流行地区V30M病例、54.3%的非流行地区V30M病例和34.6%的非V30M病例。流行地区V30M患者的诊断比其他组更早。值得注意的是，在表现为腕管综合征或多发性神经病的患者中观察到诊断延迟。
这些发现表明，非流行地区的V30M患者和非V30M突变患者比以前认识到的更为普遍，并且他们的遗传和临床特征表现出相当大的多样性。
