Abstract

Background

Ile68Leu transthyretin-related amyloidosis (ATTR) is known as a mainly or exclusively cardiogenic variant. We hypothesized that an accurate specialized neurological evaluation could reveal a consistent frequency of mixed phenotypes.

Methods

Forty-six consecutive subjects with transthyretin (TTR) Ile68Leu (p.Ile88Leu) mutation (29 patients and 17 unaffected carriers) underwent an in-depth cardiac and neurologic evaluation at a single center.

Results

All 29 patients showed cardiac involvement. In 20 (69%) cases, it was associated with neurological abnormalities (i.e. a mixed phenotype): 10 (35% of the total) had signs and symptoms of neuropathy, 5 (17%) had abnormalities at the neurologic specialist examination but without symptoms, and 5 (17%) had abnormal nerve conduction study only. None of the asymptomatic carriers showed neurological abnormalities or cardiac involvement. The Neuropathy Impairment Score was > 5 in seven patients at baseline, and became >5 in six more patients during follow-up. The probability of experiencing a major adverse cardiac event (MACE) during follow-up was higher in the mixed than cardiologic phenotype (p = 0.026). Age and phenotype were independent prognostic predictors of MACE.

Conclusion

At least two-thirds of patients with Ile68Leu ATTR and amyloidotic cardiomyopathy show an associated – definite or probable – neurologic impairment of variable degree if accurately evaluated in a neurologic setting. This proportion can rise during follow-up. The mixed phenotype carries a worse prognosis compared to the exclusively cardiologic one. These observations show that more patients could be eligible for treatment with gene silencers than currently indicated and highlight the need for an in-depth and continuous multidisciplinary evaluation of Ile68Leu ATTR patients.

中文翻译：

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Ile68Leu (p.Ile88Leu) ATTR 淀粉样变性的神经系统受累：不仅是心源性突变

摘要

背景

Ile68Leu 转甲状腺素蛋白相关淀粉样变性 (ATTR) 被称为主要或唯一的心源性变体。我们假设准确的专业神经学评估可以揭示混合表型的一致频率。

方法

连续 46 名患有转甲状腺素蛋白 (TTR) Ile68Leu (p.Ile88Leu) 突变的受试者（29 名患者和 17 名未受影响的携带者）在一个中心接受了深入的心脏和神经系统评估。

结果

所有 29 名患者均表现出心脏受累。在 20 例 (69%) 病例中，它与神经系统异常（即混合表型）有关：10 例（占总数的 35%）有神经病变的体征和症状，5 例（17%）在神经科专家检查中有异常但没有症状，5 (17%) 只进行了异常的神经传导研究。无症状携带者均未表现出神经异常或心脏受累。基线时有 7 名患者的神经病变损伤评分 > 5，在随访期间有 6 名患者的神经病变评分 > 5。在随访期间发生重大心脏不良事件 (MACE) 的概率在混合表型中高于心脏表型 ( p  = 0.026)。年龄和表型是 MACE 的独立预后预测因子。

结论

如果在神经系统环境中准确评估，至少三分之二的 Ile68Leu ATTR 和淀粉样变性心肌病患者显示出相关的 - 确定的或可能的 - 不同程度的神经系统损伤。这一比例在随访期间可能会上升。与单纯的心脏病表型相比，混合表型的预后更差。这些观察结果表明，与目前表明的相比，更多的患者可能有资格接受基因沉​​默剂的治疗，并强调需要对 Ile68Leu ATTR 患者进行深入和持续的多学科评估。