调查肌萎缩性脊髓侧索硬化症中 MFN2 基因突变的发生率:来自意大利队列的启示。

IF 4.1 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae312
Elena Abati, Delia Gagliardi, Arianna Manini, Roberto Del Bo, Dario Ronchi, Megi Meneri, Francesca Beretta, Annalisa Sarno, Federica Rizzo, Edoardo Monfrini, Alessio Di Fonzo, Maria Teresa Pellecchia, Alberto Brusati, Vincenzo Silani, Giacomo Pietro Comi, Antonia Ratti, Federico Verde, Nicola Ticozzi, Stefania Corti
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引用次数: 0

摘要

MFN2 基因编码丝裂蛋白 2,它是线粒体融合、运输、维持和细胞通讯的关键蛋白。MFN2 基因突变主要与 Charcot-Marie-Tooth 病 2A 型有关。然而,之前也有一些同时伴有 MFN2 突变的肌萎缩侧索硬化症和肌萎缩侧索硬化症/颞前痴呆表型的病例报道。本研究考察了一组意大利肌萎缩性侧索硬化症患者的临床和遗传特征,这些患者均有罕见的非同义 MFN2 突变。一组于 2008 年至 2023 年期间在本院神经内科确诊为肌萎缩侧索硬化症的患者(n = 385)接受了包括 MFN2 在内的全面分子检测。在排除了肌萎缩侧索硬化症相关主要基因(即 C9orf72、SOD1、FUS 和 TARDBP)的致病突变后,根据美国医学遗传学和基因组学学院指南对 MFN2 变异进行了分类,并检索了 MFN2 变异患者的人口统计学和临床数据。我们在 19 人(4.9%)中发现了 12 个罕见、杂合、非同义的 MFN2 变异。根据美国医学遗传学和基因组学学院(American College of Medical Genetics and Genomics)的指南,9 名患者(2.3%)携带的这些变异中有 8 个是致病变异、可能致病变异或意义不明的变异。在这些患者中,有四名表现出家族遗传模式。观察到的表型包括典型肌萎缩侧索硬化症和球部肌萎缩侧索硬化症、肌萎缩侧索硬化症/颞前痴呆症、外翻臂、外翻腿和进行性肌萎缩。发病后的中位生存期差异极大,从不到 1 年到 13 年不等。本研究调查了意大利肌萎缩侧索硬化症患者队列中罕见、非同义的 MFN2 变异的发生率,这些患者已接受过广泛的调查,从而加深了我们对其潜在表型谱的了解。要了解 MFN2 基因突变是否会导致运动神经元疾病以及导致的程度,还需要进一步的研究。从诊断和治疗的角度来看,提高我们对肌萎缩侧索硬化症遗传基础的认识至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.

The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.

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