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Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4\/\n                      <jats:italic>SPAST<\/jats:italic>\n                      gene in patients with HSP.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4\/\n                      <jats:italic>SPAST<\/jats:italic>\n                      variants were identified using direct and next\u2010generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4\/\n                      <jats:italic>SPAST<\/jats:italic>\n                      mutations in 284 patients, including four novel variants. Several mutations were population\u2010specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP\u2010SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4\/\n                      <jats:italic>SPAST<\/jats:italic>\n                      mutations presented with thin\n                      <jats:italic>corpus callosum<\/jats:italic>\n                      and intellectual disability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      In this study, we investigated pathogenic SPG4\/\n                      <jats:italic>SPAST<\/jats:italic>\n                      variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP\u2010SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype\u2013phenotype relationships offers insights into patient counseling and future research planning.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70371","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T11:05:25Z","timestamp":1774523125000},"page":"2002-2016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SPG4 and Dementia: Expanding the Clinical Spectrum"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2338-1139","authenticated-orcid":false,"given":"Emanuele","family":"Panza","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences University of Bologna  Bologna Italy"},{"name":"Medical Genetics Unit IRCCS Azienda Ospedaliero\u2010Universitaria di Bologna  Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1934-3906","authenticated-orcid":false,"given":"Arun","family":"Meyyazhagan","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2524-9764","authenticated-orcid":false,"given":"Eliseo","family":"Picchi","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1997-0552","authenticated-orcid":false,"given":"Gustavo","family":"Ribas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Federal University of Paran\u00e1 (UFPR)  Curitiba PR Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1293-3583","authenticated-orcid":false,"given":"Ingrid","family":"Faber","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Bras\u00edlia  Bras\u00edlia DF Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6434-9541","authenticated-orcid":false,"given":"Ryosuke","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Neurology Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7097-2276","authenticated-orcid":false,"given":"Preethi","family":"Basavaraju","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Molecular Biology Bharathiar University  Coimbatore TN India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0715-6396","authenticated-orcid":false,"given":"Paolo","family":"Eusebi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9997-6454","authenticated-orcid":false,"given":"Haripriya","family":"Kuchi Bhotla","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8706-3139","authenticated-orcid":false,"given":"Mario","family":"Stasi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2497-7495","authenticated-orcid":false,"given":"Fabrizio","family":"Gaudiello","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Imaging Guidonia Radiology Studio  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6923-0846","authenticated-orcid":false,"given":"Francesco","family":"Patti","sequence":"additional","affiliation":[{"name":"Department G.F. 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