The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency
Por:
Julià-Palacios NA, Kuseyri Hübschmann O, Olivella M, Pons R, Horvath G, Lücke T, Fung CW, Wong SN, Cortés-Saladelafont E, Rovira-Remisa MM, Yildiz Y, Mercimek-Andrews S, Assmann B, Stevanovic G, Manti F, Brennenstuhl H, Jung-Klawitter S, Jeltsch K, Sivri HS, Garbade SF, Garcia-Cazorla A and Opladen T
Publicada:
1 may 2024
Ahead of Print:
1 mar 2024
Resumen:
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.
Filiaciones:
Julià-Palacios NA:
Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain
Kuseyri Hübschmann O:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Olivella M:
Bioinfomatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Vic, Spain
Pons R:
First Department of Pediatrics, Aghia Sofia Hospital, University of Athens, Athens, Greece
Horvath G:
Division of Biochemical Genetics, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
Lücke T:
St. Josef-Hospital, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany
Fung CW:
Department of Pediatrics and Adolescent Medicine, The Hong Kong Children's Hospital, Hong Kong, Hong Kong
Wong SN:
Department of Pediatrics and Adolescent Medicine, The Hong Kong Children's Hospital, Hong Kong, Hong Kong
Cortés-Saladelafont E:
Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain
Unit of Inherited Metabolic Diseases and Child Neurology, Department of Pediatrics, Hospital Germans Trias i Pujol, Badalona and Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Rovira-Remisa MM:
Unit of Inherited Metabolic Diseases and Child Neurology, Department of Pediatrics, Hospital Germans Trias i Pujol, Badalona and Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
Yildiz Y:
Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
Mercimek-Andrews S:
The Hospital for Sick Children, Toronto, Ontario, Canada
Department of Medical Genetics, Faculty of Medicine and Dentistry, Women and Children's Health Research Institute, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada
Assmann B:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Stevanovic G:
Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia
Manti F:
Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Università degli Studi di Roma La Sapienza, Rome, Italy
Brennenstuhl H:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Institute of Human Genetics, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Jung-Klawitter S:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Jeltsch K:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Sivri HS:
Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
Garbade SF:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Garcia-Cazorla A:
Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain
Opladen T:
Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
Green Submitted, hybrid
|