OBJECTIVE To determine the clinical and molecular features in patients with ALS4 and mutations in the senataxin (SETX) gene, and to develop tools for evaluating SETX variants. METHODS Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and one with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy X-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. RESULTS We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01, lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than the upper extremities (average fat Z-scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a gain of senataxin function and thus a decrease in R-loops. INTERPRETATION We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. This article is protected by copyright. All rights reserved.

中文翻译：

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ALS4 中 senataxin 突变的临床和分子方面

目的 确定 ALS4 和 senataxin (SETX) 基因突变患者的临床和分子特征，并开发评估 SETX 变异的工具。方法 我们的研究涉及 32 名患者，包括 31 名在 c.1166 T>C (p.Leu389Ser) 的 SETX 突变和 1 名在 c.1153 G>A (p.Glu385Lys) 的突变。患者的临床特征包括神经系统检查、血液检查、磁共振成像 (MRI) 和双能 X 射线吸收测定法 (DEXA)。获得成纤维细胞和运动神经元以模拟疾病并表征 senataxin 功能的分子改变。结果 我们报告了 ALS4 的关键临床特征。实验室分析显示 Leu389Ser ALS4 队列中血清肌酸激酶和肌酐发生改变。MRI 显示下肢肌肉脂肪分数增加，这与疾病持续时间相关（大腿脂肪分数 R2 = 0.35，p = 0.01，小腿脂肪分数 R2 = 0.49，p < 0.01）。DEXA 测量显示下肢比上肢更容易受到影响（平均脂肪 Z 值分别为 2.1 和 0.6）。SETX 功能的细胞测定证实，与 Leu389Ser 突变一样，Glu385Lys 变体导致 senataxin 功能的增加，从而导致 R 环的减少。解释 我们确定了 ALS4 的临床实验室和放射学特征，因此应监测它们的疾病进展。患者来源细胞中 R 环水平的分子表征提供了对疾病病理学和检测的深入了解，以评估 SETX 基因中候选突变的致病性。本文受版权保护。版权所有。