{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:21:59Z","timestamp":1792642919522,"version":"4.5.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Hum. Neurosci."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>To investigate the genetic etiology of a familial case with spastic paraplegia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Neurological examination, clinical and genetic work-up, including exome sequencing (ES), followed by targeted testing, were performed to determine the underlying etiology of the patients\u2019 phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A 45-year-old man was initially diagnosed with spastic diplegic cerebral palsy in early childhood. He underwent multiple orthopedic interventions for lower extremities spasticity and progressive gait disturbance. His son developed similar neurological symptoms at 2-years of age. Despite unremarkable initial work-up, their relatively similar slowly progressive phenotype was suggestive of hereditary spastic paraplegia (HSP). ES was performed for the son at age 11\u202fyears, followed by cascade single testing for the father, which revealed a heterozygous (monoallelic) likely pathogenic variant [NM_001244008.2: c.947G\u202f&amp;gt;\u202fA (p.Arg316Gln); chr2-240775862] in exon 10 of the <jats:italic>KIF1A<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p><jats:italic>KIF1A<\/jats:italic> codes for a kinesin-3 motor protein involved in neuronal axon vesicular transport. <jats:italic>KIF1A<\/jats:italic> pathogenic variants are associated with several neurological phenotypes, most commonly HSP. The rare likely pathogenic variant (p.Arg316Gln) reported here was associated with an autosomal dominant HSP with few complications.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnhum.2025.1568511","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T05:15:09Z","timestamp":1747631709000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Hereditary spastic paraplegia associated with monoallelic variant in the motor domain of KIF1A"],"prefix":"10.3389","volume":"19","author":[{"given":"Kathryn","family":"Sine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brodie-Mends","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafae","family":"Chouhani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Massingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saud","family":"Alhusaini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2684","DOI":"10.1007\/s00415-015-7899-9","article-title":"Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis","volume":"262","author":"Citterio","year":"2015","journal-title":"J. Neurol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13024-018-0269-1","article-title":"Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China","volume":"13","author":"Dong","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1101\/gr.117143.110","article-title":"Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis","volume":"21","author":"Erlich","year":"2011","journal-title":"Genome Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1002\/acn3.198","article-title":"De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy","volume":"2","author":"Esmaeeli Nieh","year":"2015","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"419","DOI":"10.3389\/fncel.2019.00419","article-title":"Going too far is the same as falling short(\u2020): Kinesin-3 family members in hereditary spastic paraplegia","volume":"13","author":"Gabrych","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.parkreldis.2022.09.001","article-title":"Investigating KIF1A mutations in a Taiwanese cohort with hereditary spastic paraplegia","volume":"103","author":"Hsu","year":"2022","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e0174667","DOI":"10.1371\/journal.pone.0174667","article-title":"Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia","volume":"12","author":"Iqbal","year":"2017","journal-title":"PLoS One"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"Var some: the human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1111\/ene.13279","article-title":"Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene","volume":"24","author":"Krenn","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1083\/jcb.200408113","article-title":"A standardized kinesin nomenclature","volume":"167","author":"Lawrence","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/humu.22709","article-title":"De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy","volume":"36","author":"Lee","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.expneurol.2014.06.011","article-title":"Hereditary spastic paraplegia: clinical-genetic characteristics and evolving molecular mechanisms","volume":"261","author":"Lo Giudice","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1093\/brain\/awab386","article-title":"Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia","volume":"145","author":"M\u00e9reaux","year":"2022","journal-title":"Brain"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"7665","DOI":"10.3390\/ijms23147665","article-title":"The puzzle of hereditary spastic paraplegia: from epidemiology to treatment","volume":"23","author":"Meyyazhagan","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1002\/humu.24118","article-title":"Phenotypic expansion in KIF1A-related dominant disorders: a description of novel variants and review of published cases","volume":"41","author":"Montenegro-Garreaud","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1038\/ejhg.2017.124","article-title":"Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias","volume":"25","author":"Morais","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1136\/jmedgenet-2020-107007","article-title":"Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders","volume":"58","author":"Nicita","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1038\/jhg.2015.108","article-title":"De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance","volume":"60","author":"Ohba","year":"2015","journal-title":"J. Hum. Genet."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"972","DOI":"10.3390\/genes14050972","article-title":"Expanding the knowledge of KIF1A-dependent disorders to a Group of Polish Patients","volume":"14","author":"Paprocka","year":"2023","journal-title":"Genes (Basel)"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41431-019-0497-z","article-title":"KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia","volume":"28","author":"Pennings","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/s1474-4422(19)30235-2","article-title":"Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches","volume":"18","author":"Shribman","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s00415-021-10792-3","article-title":"Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review","volume":"269","author":"Vecchia","year":"2022","journal-title":"J. Neurol."}],"container-title":["Frontiers in Human Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnhum.2025.1568511\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T05:15:09Z","timestamp":1747631709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnhum.2025.1568511\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,19]]},"references-count":22,"alternative-id":["10.3389\/fnhum.2025.1568511"],"URL":"https:\/\/doi.org\/10.3389\/fnhum.2025.1568511","relation":{},"ISSN":["1662-5161"],"issn-type":[{"value":"1662-5161","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,19]]},"article-number":"1568511"}}