Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Department of Diagnostic Center, Ascension Seton Medical Center Austin, Austin, TX, USA.
Brain Behav. 2020 Jun;10(6):e01625. doi: 10.1002/brb3.1625. Epub 2020 Apr 19.
Mutations in the fused in sarcoma (FUS) gene have been associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor. Among the FUS mutations, p.P525L as a hot spot variant has been reported in more than 20 patients with ALS. Apart from the typical ALS phenotype, patients with p.P525L mutation exhibit some atypical symptoms. However, movement disorders related to p.P525L mutation have not been emphasized currently.
Two unrelated patients with ALS were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through next-generation sequencing. Muscle biopsies were performed on the 2 patients. Muscle samples were stained according to standard histological and immunohistochemical procedures.
The first patient presented with juvenile-onset neurogenic weakness and wasting and simultaneously had dropped head, ophthalmoplegia, tremor, involuntary movements, and cognitive impairments. The second patient showed a typical ALS phenotype and prominent adventitious movements. Genetic screening disclosed de novo p.P525L FUS mutation in the 2 patients by family cosegregation analysis. Muscle biopsy showed neurogenic patterns and numerous lipid droplets aggregating in the fibers.
Apart from the typical ALS phenotype, patients with p.P525L mutation in the FUS gene can present with great clinical heterogeneity including multiple movement disorders. Numerous lipid droplets in muscle fibers indicate that skeletal muscle is likely an important therapeutic target for ALS.
融合肉瘤（FUS）基因突变与肌萎缩侧索硬化症（ALS）、额颞叶变性和原发性震颤有关。在 FUS 突变中，p.P525L 作为热点变异已在 20 多名 ALS 患者中报道。除了典型的 ALS 表型外，p.P525L 突变的患者还表现出一些非典型症状。然而，目前尚未强调与 p.P525L 突变相关的运动障碍。
通过一系列临床和实验室检查评估了 2 名无关的 ALS 患者。通过下一代测序进行基因筛查。对 2 名患者进行了肌肉活检。肌肉样本按照标准的组织学和免疫组织化学程序进行染色。
第一个患者表现为青少年起病的神经源性无力和萎缩，同时伴有垂头、眼肌麻痹、震颤、不自主运动和认知障碍。第二个患者表现为典型的 ALS 表型和明显的意外运动。通过家系共分离分析，基因筛查在 2 名患者中发现了新发的 p.P525L FUS 突变。肌肉活检显示神经源性模式和纤维中聚集的大量脂滴。
除了典型的 ALS 表型外，FUS 基因中 p.P525L 突变的患者还可能表现出很大的临床异质性，包括多种运动障碍。肌肉纤维中大量的脂滴表明骨骼肌可能是 ALS 的一个重要治疗靶点。
