{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T12:41:33Z","timestamp":1780663293976,"version":"3.54.1"},"reference-count":33,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,8,29]],"date-time":"2020-08-29T00:00:00Z","timestamp":1598659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771230"],"award-info":[{"award-number":["81771230"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81801130"],"award-info":[{"award-number":["81801130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1905210"],"award-info":[{"award-number":["U1905210"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2019J05076"],"award-info":[{"award-number":["2019J05076"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Recessive mutations in the <jats:italic>CAPN1<\/jats:italic> gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia\u2010spasticity disease spectrum. This study aims to assess the influence of <jats:italic>CAPN1<\/jats:italic> variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened a cohort of 240 unrelated HSP families for variants in <jats:italic>CAPN1<\/jats:italic> using high\u2010throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six unreported <jats:italic>CAPN1<\/jats:italic>\u2010associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs<jats:sup>*<\/jats:sup>103, c.759+1G&gt;A, and p.R285<jats:sup>*<\/jats:sup>), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain\u20101 protein, encoded by <jats:italic>CAPN1,<\/jats:italic> with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.015).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study supports the clinically heterogeneous inter\u2010 and intra\u2010family variability of SPG76 patients, and demonstrates that gender and calpain\u20101 linker structure may contribute to clinical heterogeneity in SPG76 cases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51169","type":"journal-article","created":{"date-parts":[[2020,8,29]],"date-time":"2020-08-29T08:40:27Z","timestamp":1598690427000},"page":"1862-1869","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Novel <i>CAPN1<\/i> mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8481-9421","authenticated-orcid":false,"given":"Lu\u2010Lu","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Neurology and Institute of Neurology First Affiliated Hospital Institute of Neuroscience Fujian Medical University Fuzhou 350005 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology First Affiliated Hospital Institute of Neuroscience Fujian Medical University Fuzhou 350005 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Lu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology and Institute of Neurology First Affiliated Hospital Institute of Neuroscience Fujian Medical University Fuzhou 350005 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