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Here we illustrate a translational approach to the case of an 18\u2010year\u2010old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound\u2010heterozygous missense variants in <jats:italic>CAPN1<\/jats:italic> (NM_001198868.2: c.1712A&gt;G (p.Asn571Ser)\/c.1991C&gt;T (p.Ser664Leu)) and a previously reported heterozygous stop\u2010gain variant in <jats:italic>RCL1<\/jats:italic>. In silico analyses of the <jats:italic>CAPN1<\/jats:italic> variants predicted a deleterious effect and in\u00a0vitro functional studies confirmed reduced calpain\u20101 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.<\/jats:p>","DOI":"10.1002\/acn3.51531","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T06:47:20Z","timestamp":1647499640000},"page":"570-576","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel <scp><i>CAPN1<\/i><\/scp> missense variants in complex hereditary spastic paraplegia with early\u2010onset psychosis"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1420-9775","authenticated-orcid":false,"given":"Julian E.","family":"Alecu","sequence":"first","affiliation":[{"name":"Department of Neurology and F.M. 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Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center Boston Children's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine A.","family":"Brownstein","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Gonzalez\u2010Heydrich","sequence":"additional","affiliation":[{"name":"The Manton Center for Orphan Disease Research Boston Children's Hospital Boston Massachusetts USA"},{"name":"Department of Psychiatry and Behavioral Sciences Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lance H.","family":"Rodan","sequence":"additional","affiliation":[{"name":"Department of Neurology and F.M. 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