Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted SPG7 sequencing was done in a cohort of 214 European ALS patients. The consequences of a splice site variant were analyzed on the mRNA level. The resulting protein alterations were visualized in a crystal structure model. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization. In 9 of 214 (4.2%) ALS cases, we identified five different rare heterozygous SPG7 variants, all of which were previously reported in patients with HSP or ALS. All detected SPG7 variants affect the AAA+ domain of the encoded mitochondrial metalloprotease paraplegin and impair its stability or function according to predictions from mRNA analysis or crystal structure modeling. ALS patients with SPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without SPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in SPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that SPG7 acts as a genetic risk factor for ALS. ALS patients carrying SPG7 mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings.

中文翻译：

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肌萎缩侧索硬化症中的 SPG7 突变：与遗传性痉挛性截瘫的遗传联系。

肌萎缩侧索硬化症 (ALS) 和遗传性痉挛性截瘫 (HSP) 是具有临床、病理和遗传相似性的运动神经元疾病。虽然已知双等位基因 SPG7 突变会导致隐性遗传的 HSP，但杂合 SPG7 突变已在 HSP 中反复发现，最近也在 ALS 病例中发现。然而，尚未在更大的 ALS 队列中研究罕见 SPG7 变体的频率和临床影响。在这里，对 214 名欧洲 ALS 患者的队列进行了全外显子组 (WES) 或靶向 SPG7 测序。在 mRNA 水平上分析了剪接位点变异的后果。由此产生的蛋白质改变在晶体结构模型中可视化。所有患者均接受临床、电生理学和神经放射学表征。在 214 例中的 9 例 (4.2%) ALS 病例中，我们确定了五种不同的罕见杂合 SPG7 变体，所有这些变体以前都在 HSP 或 ALS 患者中报道过。根据 mRNA 分析或晶体结构建模的预测，所有检测到的 SPG7 变体都会影响编码的线粒体金属蛋白酶 paraplegin 的 AAA+ 结构域并损害其稳定性或功能。与没有 SPG7 突变的患者相比，具有 SPG7 突变的 ALS 患者更常出现小脑症状、连枷臂或腿综合征，并显示出与 HSP 的部分临床重叠。SPG7 突变携带者的脑 MRI 发现包括小脑萎缩和提示额颞叶痴呆的模式。总的来说，我们的研究结果表明 SPG7 是 ALS 的遗传风险因素。携带 SPG7 突变的 ALS 患者具有与 HSP 重叠的不同特征，