Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
J Neurol. 2023 Aug;270(8):3970-3980. doi: 10.1007/s00415-023-11746-7. Epub 2023 May 3.
Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data.
We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association.
WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11).
In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS.
原发性侧索硬化症（PLS）是一种以运动神经元丧失为特征的运动神经元疾病。大多数患者表现为腿部进行性痉挛性无力，也可能扩散至手臂或延髓区域。区分 PLS、早期肌萎缩侧索硬化症（ALS）和遗传性痉挛性截瘫（HSP）具有挑战性。目前的诊断标准建议避免广泛的基因检测。然而，这一建议是基于有限的数据。
我们旨在通过全外显子组测序（WES）对与 ALS、HSP、共济失调和运动障碍（364 个基因）以及 C9orf72 重复扩增相关的基因对 PLS 队列进行基因特征分析。从正在进行的基于人群的流行病学研究中招募符合 Turner 等人确定的 PLS 标准且有足够质量 DNA 样本的患者。根据 ACMG 标准对遗传变异进行分类，并根据疾病相关性将其分组。
对 139 例患者进行了 WES，对 129 例患者分别分析了 C9orf72 中的重复扩增。这导致了 31 个变异，其中 11 个是（可能）致病性的。（可能）致病性变异根据疾病相关性分为 3 组：ALS-FTD（C9orf72、TBK1）、单纯 HSP（SPAST、SPG7）、“ALS-HSP-CMT 重叠”（FIG4、NEFL、SPG11）。
在 139 例 PLS 患者的队列中，基因分析导致 31 个变异（22%），其中 10 个（可能）致病性变异与不同疾病相关（主要是 ALS 和 HSP）。基于这些结果和文献，我们建议在 PLS 的诊断工作中考虑基因分析。
