{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:10:49Z","timestamp":1790345449935,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["220600\/Z\/20\/Z"],"award-info":[{"award-number":["220600\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1001931"],"award-info":[{"award-number":["G1001931"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1002279"],"award-info":[{"award-number":["G1002279"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_15054"],"award-info":[{"award-number":["MC_PC_15054"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_15047"],"award-info":[{"award-number":["MC_PC_15047"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_18047"],"award-info":[{"award-number":["MC_PC_18047"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as \u2018pure\u2019 when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and \u2018complex\u2019 when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally.<\/jats:p>","DOI":"10.3390\/brainsci11050614","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T10:20:36Z","timestamp":1620728436000},"page":"614","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia"],"prefix":"10.3390","volume":"11","author":[{"given":"Reham","family":"Khalaf-Nazzal","sequence":"first","affiliation":[{"name":"Biomedical Sciences Department, Faculty of Medicine, Arab American University of Palestine, Jenin P227, Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7614-9202","authenticated-orcid":false,"given":"James","family":"Fasham","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"},{"name":"Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Gladstone Road, Exeter EX1 2ED, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishanka","family":"Ubeyratna","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Evans","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter EX2 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Leslie","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas T.","family":"Warner","sequence":"additional","affiliation":[{"name":"Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fida\u2019","family":"Al-Hijawi","sequence":"additional","affiliation":[{"name":"Paediatrics\u2019 Community Outpatient Clinics, Palestinian Ministry of Health, Jenin P200, Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shurouq","family":"Alshaer","sequence":"additional","affiliation":[{"name":"Faculty of Graduate Studies, Arab American University, Ramallah P622, Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wisam","family":"Baker","sequence":"additional","affiliation":[{"name":"Paediatrics Department, Dr. Khalil Suleiman Government Hospital, Jenin P200, Palestine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Turnpenny","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"},{"name":"Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Gladstone Road, Exeter EX1 2ED, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Baple","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"},{"name":"Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Gladstone Road, Exeter EX1 2ED, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Crosby","sequence":"additional","affiliation":[{"name":"College of Medicine and Health, RILD Wellcome Wolfson Centre, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/S0140-6736(83)92879-9","article-title":"Classification of the hereditary ataxias and paraplegias","volume":"1","author":"Harding","year":"1983","journal-title":"Lancet"},{"key":"ref_3","unstructured":"Genomics England (2021, April 11). 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