The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

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

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

J Inherit Metab Dis. 2024 May;47(3):447-462. doi: 10.1002/jimd.12723. Epub 2024 Mar 18.

Authors

Natalia Alexandra Julia-Palacios¹, Oya Kuseyri Hübschmann², Mireia Olivella³, Roser Pons⁴, Gabriella Horvath⁵, Thomas Lücke⁶, Cheuk-Wing Fung⁷, Suet-Na Wong⁷, Elisenda Cortès-Saladelafont^{1

8}, M Mar Rovira-Remisa⁸, Yılmaz Yıldız⁹, Saadet Mercimek-Andrews^{10

11}, Birgit Assmann², Galina Stevanović¹², Filippo Manti¹³, Heiko Brennenstuhl^{2

14}, Sabine Jung-Klawitter², Kathrin Jeltsch², H Serap Sivri⁹, Sven F Garbade², Àngels García-Cazorla¹, Thomas Opladen²

Affiliations

¹ Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.
² Center for Pediatric and Adolescent Medicine Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.
³ Bioinfomatics and Medical Statistics Group, University of Vic-Central University of Catalonia, Vic, Spain.
⁴ First Department of Pediatrics, Aghia Sofia Hospital, University of Athens, Athens, Greece.
⁵ Division of Biochemical Genetics, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ St. Josef-Hospital, University Children's Hospital, Ruhr-University Bochum, Bochum, Germany.
⁷ Department of Pediatrics and Adolescent Medicine, The Hong Kong Children's Hospital, Hong Kong, Hong Kong.
⁸ 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.
⁹ Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
¹⁰ The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ 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.
¹² Clinic of Neurology and Psychiatry for Children and Youth, School of Medicine, University of Belgrade, Belgrade, Serbia.
¹³ Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Università degli Studi di Roma La Sapienza, Rome, Italy.
¹⁴ Institute of Human Genetics, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany.

PMID: 38499966
DOI: 10.1002/jimd.12723

Abstract

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.

Keywords: SSADH deficiency; evolving phenotype; genetic spectrum; in silico analyses; long‐term follow‐up.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Amino Acid Metabolism, Inborn Errors* / genetics
Child
Child, Preschool
Developmental Disabilities / genetics
Female
Humans
Infant
Male
Movement Disorders / genetics
Muscle Hypotonia / genetics
Mutation
Phenotype*
Succinate-Semialdehyde Dehydrogenase* / deficiency
Succinate-Semialdehyde Dehydrogenase* / genetics
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding