Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M. Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H. Serap Sivri, Sven F. Garbade, Àngels García-Cazorla, Thomas Opladen
{"title":"琥珀酸半醛脱氢酶缺乏症不断演变的表型。","authors":"Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M. Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H. Serap Sivri, Sven F. Garbade, Àngels García-Cazorla, Thomas Opladen","doi":"10.1002/jimd.12723","DOIUrl":null,"url":null,"abstract":"<p>The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. 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 <i>ALDH5A1</i> 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 years, range 1.8–33.4 years) showed a diversifying course in follow-up: 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.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12723","citationCount":"0","resultStr":"{\"title\":\"The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency\",\"authors\":\"Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M. Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H. Serap Sivri, Sven F. Garbade, Àngels García-Cazorla, Thomas Opladen\",\"doi\":\"10.1002/jimd.12723\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. 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 <i>ALDH5A1</i> 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 years, range 1.8–33.4 years) showed a diversifying course in follow-up: 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. 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The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency
The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. 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 ALDH5A1 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 years, range 1.8–33.4 years) showed a diversifying course in follow-up: 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.
期刊介绍:
The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).