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Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of <jats:italic>ALDH5A1<\/jats:italic> variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12\u2009years, range 1.8\u201333.4\u2009years) showed a diversifying course in follow\u2010up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype\/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.<\/jats:p>","DOI":"10.1002\/jimd.12723","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T04:08:31Z","timestamp":1710821311000},"page":"447-462","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency"],"prefix":"10.1002","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2560-3970","authenticated-orcid":false,"given":"Natalia Alexandra","family":"Julia\u2010Palacios","sequence":"first","affiliation":[{"name":"Inborn Errors of Metabolism Unit, Department of Neurology Institut de Recerca Sant Joan de D\u00e9u and CIBERER\u2010ISCIII  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-6566","authenticated-orcid":false,"given":"Oya","family":"Kuseyri H\u00fcbschmann","sequence":"additional","affiliation":[{"name":"Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine Heidelberg University, Medical Faculty Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-3399","authenticated-orcid":false,"given":"Mireia","family":"Olivella","sequence":"additional","affiliation":[{"name":"Bioinfomatics and Medical Statistics Group University of Vic\u2010Central University of Catalonia  Vic Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6749-1906","authenticated-orcid":false,"given":"Roser","family":"Pons","sequence":"additional","affiliation":[{"name":"First Department of Pediatrics, Aghia Sofia Hospital University of Athens  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2573-2489","authenticated-orcid":false,"given":"Gabriella","family":"Horvath","sequence":"additional","affiliation":[{"name":"Division of Biochemical Genetics, Department of Pediatrics, BC Children's Hospital University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"L\u00fccke","sequence":"additional","affiliation":[{"name":"St. Josef\u2010Hospital, University Children's Hospital Ruhr\u2010University Bochum  Bochum Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0105-1673","authenticated-orcid":false,"given":"Cheuk\u2010Wing","family":"Fung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine The Hong Kong Children's Hospital  Hong Kong Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suet\u2010Na","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine The Hong Kong Children's Hospital  Hong Kong Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8604-2230","authenticated-orcid":false,"given":"Elisenda","family":"Cort\u00e8s\u2010Saladelafont","sequence":"additional","affiliation":[{"name":"Inborn Errors of Metabolism Unit, Department of Neurology Institut de Recerca Sant Joan de D\u00e9u and CIBERER\u2010ISCIII  Barcelona Spain"},{"name":"Unit of Inherited Metabolic Diseases and Child Neurology, Department of Pediatrics, Hospital Germans Trias i Pujol, Badalona and Faculty of Medicine Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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