Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan
Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan
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DOI：
10.1136/jnnp-2022-330769
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发表时间：
2023-03
期刊：
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通讯作者：
M. Ando;Y. Higuchi;Junhui Yuan;A. Yoshimura;M. Dozono;Takahiro Hobara;Fumika Kojima;Yutaka Noguchi;Mika Takeuchi;Jun Takei;Y. Hiramatsu;S. Nozuma;Tomonori Nakamura;Y. Sakiyama;A. Hashiguchi;E. Matsuura;Y. Okamoto;J. Sone;H. Takashima
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作者：
M. Ando;Y. Higuchi;Junhui Yuan;A. Yoshimura;M. Dozono;Takahiro Hobara;Fumika Kojima;Yutaka Noguchi;Mika Takeuchi;Jun Takei;Y. Hiramatsu;S. Nozuma;Tomonori Nakamura;Y. Sakiyama;A. Hashiguchi;E. Matsuura;Y. Okamoto;J. Sone;H. Takashima
背景NOTCH 2 NLC GGC重复序列扩增与多种神经退行性疾病相关，包括神经元核内包涵体病和遗传性周围神经病（IPN）。然而，只有少数NOTCH 2NLC相关疾病的研究报告，在IPN，临床和遗传谱仍不清楚。因此，本研究旨在描述NOTCH 2NLC相关IPN的临床和遗传表现。方法在2692例临床诊断为IPN/Charcot-Marie-Tooth病（CMT）的日本患者中，我们分析了1783例无遗传学诊断的无关患者的NOTCH 2NLC重复扩增。使用重复引物PCR和荧光扩增子长度分析PCR进行NOTCH 2NLC重复扩增的筛选和重复大小测定。结果在22个家系中的26例IPN/CMT中发现NOTCH 2NLC重复扩增。正中运动神经传导速度平均为41 m/s（30.8-59.4），中度CMT 18例（69%）。平均发病年龄为32.7岁（范围：7-61岁）。除了运动感觉神经病变症状外，自主神经功能障碍和不自主运动也很常见（44%和29%）。此外，发病年龄或临床症状与重复次数之间的相关性仍不清楚。结论本研究有助于我们了解NOTCH 2 NLC相关疾病的临床异质性，如非长度依赖性运动优势表型和显著的自主神经受累。这项研究还强调了遗传筛查的重要性，无论CMT的发病年龄和类型如何，特别是在亚洲起源的患者中，表现为中间传导速度和自主神经功能障碍。
Background NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. Method Among 2692 Japanese patients clinically diagnosed with IPN/Charcot–Marie–Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. Results NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8–59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7–61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. Conclusions These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.