Khani Marzieh, Shamshiri Hosein, Taheri Hanieh, Hardy John, Bras Jose Tomas, Carmona Susana, Moazzeni Hamidreza, Alavi Afagh, Heshmati Ali, Taghizadeh Peyman, Nilipour Yalda, Ghazanfari Tooba, Shahabi Majid, Okhovat Ali Asghar, Rohani Mohammad, Valle Giorgio, Boostani Reza, Abdi Siamak, Eshghi Shaghayegh, Nafissi Shahriar, Elahi Elahe
School of Biology, College of Science, University of Tehran, Tehran, Iran.
Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Neurobiol Aging. 2021 Mar;99:102.e1-102.e10. doi: 10.1016/j.neurobiolaging.2020.09.021. Epub 2020 Oct 5.
Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.
布朗 - 维亚莱托 - 范莱尔（Brown-Vialetto-Van Laere，BVVL）病和法齐奥 - 隆德（Fazio-Londe）病是具有肌萎缩侧索硬化样特征的疾病，通常为隐性遗传。我们旨在鉴定10名先证者中的致病突变。进行了神经学检查、基因分析、听力测定、磁共振成像、生化和免疫检测以及/或者肌肉组织病理学检查。在7名先证者中发现了已知致病基因SLC52A3的突变。更重要的是，在几名患者中仅观察到1个突变等位基因，并且明显注意到了可变表达和不完全外显。环境损伤可能导致表现各异。在3名先证者中鉴定出其他基因的推定致病突变。其中两个基因，WDFY4和TNFSF13B，具有免疫相关功能。携带WDFY4突变的患者存在炎症反应。携带TNFSF13B突变的患者出现免疫系统功能障碍和线粒体异常。首次报道了杂合SLC52A3 BVVL致病突变的患病率以及纯合和杂合基因型表达的显著变异性。将WDFY4和TNFSF13B鉴定为候选致病基因支持了免疫系统参与BVVL病和肌萎缩侧索硬化的推测。
