Abstract

Background

Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimotor and autonomic polyneuropathy (ATTRv-PN) leading to severe disability. While most prospective studies have focussed on endemic ATTRv-PN, real-world data on non-endemic, mostly late-onset ATTRv-PN are limited.

Methods

This retrospective study investigated ATTRv-PN patients treated at the Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020. Clinical symptoms, survival, prognostic factors and efficacy of treatment with tafamidis were analysed. Neurologic outcome was assessed using the Coutinho ATTRv-PN stages, and the Peripheral Neuropathy Disability (PND) score.

Results

Of 346 subjects with genetic TTR variants, 168 patients had symptomatic ATTRv-PN with 32 different TTR variants identified. Of these, 81.6% had the late-onset type of ATTRv-PN. Within a mean follow-up period of 4.1 ± 2.8 years, 40.5% of patients died. Baseline plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥900 ng/l (HR 3.259 [1.421–7.476]; p = .005) was the main predictor of mortality in multivariable analysis. 64 patients were treated with tafamidis and presented for regular follow-up examinations. The therapeutic benefit of tafamidis was more pronounced when treatment was started early in ATTRv-PN stage 1 (PND scores II vs. I; HR 2.718 [1.258–5.873]; p = .011).

Conclusions

In non-endemic, mostly late-onset ATTRv-PN, cardiac involvement assessed by NT-proBNP is a strong prognosticator for overall survival. Long-term treatment with tafamidis is safe and efficacious. Neurologic disease severity at the start of treatment is the main predictor for ATTRv-PN progression on tafamidis.

中文翻译：

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非地方性遗传性甲状腺素转运蛋白淀粉样变性病与多发性神经病的现实结果：20年德国单诊中心经验

摘要

背景

遗传性甲状腺素转运蛋白淀粉样变性病是由TTR基因中的致病性变异引起的，通常与心脏和其他器官功能障碍一起表现为快速进行性感觉运动和自主神经性多发性神经病（ATTRv-PN），导致严重的残疾。虽然大多数前瞻性研究都集中在地方性ATTRv-PN，但有关非地方性，主要是晚发的ATTRv-PN的真实数据有限。

方法

这项回顾性研究调查了1999年11月至2020年7月在海德堡大学医院淀粉样变性中心治疗的ATTRv-PN患者。分析了临床症状，生存率，预后因素和他法米西治疗的疗效。使用Coutinho ATTRv-PN分期和周围神经病变残疾（PND）评分评估神经系统结局。

结果

在346个具有遗传性TTR变异体的受试者中，有168例患者出现了症状性ATTRv-PN，并鉴定出32种不同的TTR变异体。其中81.6％的患者为ATTRv-PN的晚发型。在4.1±2.8年的平均随访期内，有40.5％的患者死亡。脑利钠肽（NT-proBNP）≥900 ng / l的基线血浆N端激素激素（HR 3.259 [1.421–7.476]；p  = .005）是多变量分析中死亡率的主要预测指标。64例患者接受了他法米地治疗，并接受定期随访检查。当在ATTRv-PN阶段1早期开始治疗时，他法米地的治疗益处更加明显（PND评分II vs. I； HR 2.718 [1.258-5.873]；p  = .011）。

结论

在非地方性，主要是晚发型的ATTRv-PN中，NT-proBNP评估的心脏受累是整体生存的强有力的预后指标。用他法米第长期治疗是安全有效的。开始治疗时神经系统疾病的严重程度是他法米特上ATTRv-PN进展的主要预测因子。