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While biallelic <jats:italic>SPG7<\/jats:italic> mutations are known to cause recessively inherited HSP, heterozygous <jats:italic>SPG7<\/jats:italic> mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare <jats:italic>SPG7<\/jats:italic> variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted <jats:italic>SPG7<\/jats:italic> 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 <jats:italic>SPG7<\/jats:italic> variants, all of which were previously reported in patients with HSP or ALS. All detected <jats:italic>SPG7<\/jats:italic> variants affect the AAA+\u2009domain 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 <jats:italic>SPG7<\/jats:italic> mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without <jats:italic>SPG7<\/jats:italic> mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in <jats:italic>SPG7<\/jats:italic> mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that <jats:italic>SPG7<\/jats:italic> acts as a genetic risk factor for ALS. ALS patients carrying <jats:italic>SPG7<\/jats:italic> mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings.<\/jats:p>","DOI":"10.1007\/s00415-020-09861-w","type":"journal-article","created":{"date-parts":[[2020,5,23]],"date-time":"2020-05-23T16:02:42Z","timestamp":1590249762000},"page":"2732-2743","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia"],"prefix":"10.1007","volume":"267","author":[{"given":"Alma","family":"Osmanovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maylin","family":"Widjaja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisa","family":"F\u00f6rster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Weder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike P.","family":"Wattjes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inken","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Sarikidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Auber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Raab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Christians","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Preller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Petri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruthild G.","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,23]]},"reference":[{"issue":"7","key":"9861_CR1","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1242\/dmm.015719","volume":"7","author":"SA Patten","year":"2014","unstructured":"Patten SA, Armstrong GA, Lissouba A, Kabashi E, Parker JA, Drapeau P (2014) Fishing for causes and cures of motor neuron disorders. 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