{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:26:41Z","timestamp":1779190001102,"version":"3.51.4"},"reference-count":40,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T00:00:00Z","timestamp":1688688000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V112C\u2010001"],"award-info":[{"award-number":["V112C\u2010001"]}],"id":[{"id":"10.13039\/501100011912","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":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by slowly progressive lower limb spasticity and weakness. HSP type 54 (SPG54) is autosomal recessively inherited and caused by mutations in the <jats:italic>DDHD2<\/jats:italic> gene. This study investigated the clinical characteristics and molecular features of <jats:italic>DDHD2<\/jats:italic> mutations in a cohort of Taiwanese patients with HSP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mutational analysis of <jats:italic>DDHD2<\/jats:italic> was performed for 242 unrelated Taiwanese patients with HSP. The clinical, neuroimaging, and genetic features of the patients with biallelic <jats:italic>DDHD2<\/jats:italic> mutations were characterized. A cell\u2010based study was performed to assess the effects of the <jats:italic>DDHD2<\/jats:italic> mutations on protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SPG54 was diagnosed in three patients. Among them, two patients carried compound heterozygous <jats:italic>DDHD2<\/jats:italic> mutations, p.[R112Q];[Y606*] and p.[R112Q];[p.D660H], and the other one was homozygous for the <jats:italic>DDHD2<\/jats:italic> p.R112Q mutation. <jats:italic>DDHD2<\/jats:italic> p.Y606* is a novel mutation, whereas <jats:italic>DDHD2<\/jats:italic> p.D660H and p.R112Q have been reported in the literature. All three patients manifested adult onset complex HSP with additional cerebellar ataxia, polyneuropathy, or cognitive impairment. Brain proton magnetic resonance spectroscopy revealed an abnormal lipid peak in thalamus of all three patients. In vitro studies demonstrated that all the three <jats:italic>DDHD2<\/jats:italic> mutations were associated with a considerably lower DDHD2 protein level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>SPG54 was detected in approximately 1.2% (3 of 242) of the Taiwanese HSP cohort. This study expands the known mutational spectrum of <jats:italic>DDHD2<\/jats:italic>, provides molecular evidence of the pathogenicity of the <jats:italic>DDHD2<\/jats:italic> mutations, and underlines the importance of considering SPG54 as a potential diagnosis of adult\u2010onset HSP.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51850","type":"journal-article","created":{"date-parts":[[2023,7,8]],"date-time":"2023-07-08T03:41:15Z","timestamp":1688787675000},"page":"1603-1612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Biallelic <scp><i>DDHD2<\/i><\/scp> mutations in patients with adult\u2010onset complex hereditary spastic paraplegia"],"prefix":"10.1002","volume":"10","author":[{"given":"Ying\u2010Tsen","family":"Chou","sequence":"first","affiliation":[{"name":"Department of Neurology Taipei Veterans General Hospital  Taipei 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