Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Itay Tokatly Latzer; Mariarita Bertoldi; Nenad Blau; Melissa L DiBacco; Sarah H Elsea; Àngels García-Cazorla; K Michael Gibson; Andrea L Gropman; Ellen Hanson; Carolyn Hoffman; Kathrin Jeltsch; Natalia Juliá-Palacios; Ina Knerr; Henry H C Lee; Patrizia Malaspina; Alice McConnell; Thomas Opladen; Mari Oppebøen; Alexander Rotenberg; Mark Walterfang; Lee Wang-Tso; Ron A Wevers; Jean-Baptiste Roullet; Phillip L Pearl

doi:10.1016/j.ymgme.2024.108363

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

Mol Genet Metab. 2024 May;142(1):108363. doi: 10.1016/j.ymgme.2024.108363. Epub 2024 Mar 4.

Authors

Itay Tokatly Latzer¹, Mariarita Bertoldi², Nenad Blau³, Melissa L DiBacco⁴, Sarah H Elsea⁵, Àngels García-Cazorla⁶, K Michael Gibson⁷, Andrea L Gropman⁸, Ellen Hanson⁹, Carolyn Hoffman¹⁰, Kathrin Jeltsch¹¹, Natalia Juliá-Palacios¹², Ina Knerr¹³, Henry H C Lee¹⁴, Patrizia Malaspina¹⁵, Alice McConnell¹⁶, Thomas Opladen¹⁷, Mari Oppebøen¹⁸, Alexander Rotenberg¹⁹, Mark Walterfang²⁰, Lee Wang-Tso²¹, Ron A Wevers²², Jean-Baptiste Roullet²³, Phillip L Pearl²⁴

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; School of Medicine, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel Aviv, Israel. Electronic address: itay.tokatlylatzer@childrens.harvard.edu.
² Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Italy. Electronic address: mita.bertoldi@univr.it.
³ Division of Metabolism, University Children's Hospital, Zürich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Switzerland. Electronic address: Nenad.Blau@kispi.uzh.ch.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Melissa.DiBacco@childrens.harvard.edu.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address: Sarah.Elsea@bcm.edu.
⁶ Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: agarcia@sjdhospitalbarcelona.org.
⁷ Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: mike.gibson@wsu.edu.
⁸ Division of Neurogenetics and Neurodevelopmental Disabilities, Children's National Hospital, Washington, D.C, USA. Electronic address: agropman@childrensnational.org.
⁹ Human Neurobehavioral Core, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, MA 02115, USA. Electronic address: Ellen.Hanson@childrens.harvard.edu.
¹⁰ SSADH Association, Delafield, WI 53018, USA.
¹¹ Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany. Electronic address: Kathrin.Jeltsch@med.uni-heidelberg.de.
¹² Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: nataliaalexandra.julia@sjd.es.
¹³ National Centre for Inherited Metabolic Disorders, Children's Health Ireland, Temple Street, Dublin, Ireland. Electronic address: ina.knerr@cuh.ie.
¹⁴ Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: hingcheong.lee@childrens.harvard.edu.
¹⁵ Department of Biology, Tor Vergata University, Via della Ricerca Scientifica s.n.c., Rome 00133, Italy. Electronic address: patrizia.malaspina@uniroma2.it.
¹⁶ SSADH Association, Delafield, WI 53018, USA. Electronic address: alice@speragen.com.
¹⁷ Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany. Electronic address: Thomas.Opladen@med.uni-heidelberg.de.
¹⁸ Oslo University Hospital, Oslo, Norway. Electronic address: maropp@ous-hf.no.
¹⁹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: alexander.rotenberg@childrens.harvard.edu.
²⁰ Neuropsychiatry, Royal Melbourne Hospital, Melbourne, Australia; Department of Psychiatry, University of Melbourne, Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; Department of Health and Medical Sciences, Edith Cowan University, Perth, Australia. Electronic address: Mark.Walterfang@mh.org.au.
²¹ Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
²² Translational Metabolic Laboratory, Department Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands. Electronic address: Ron.Wevers@radboudumc.nl.
²³ Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: j.roullet@wsu.edu.
²⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Phillip.Pearl@childrens.harvard.edu.

PMID: 38452608
PMCID: PMC11073920 (available on 2025-05-01)
DOI: 10.1016/j.ymgme.2024.108363

Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Keywords: GABA; Inherited metabolic disorders; Management; Neurotransmitters; Recommendations; SSADH.

Publication types

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

MeSH terms

Amino Acid Metabolism, Inborn Errors* / diagnosis
Amino Acid Metabolism, Inborn Errors* / genetics
Amino Acid Metabolism, Inborn Errors* / therapy
Consensus
Developmental Disabilities*
Humans
Practice Guidelines as Topic
Succinate-Semialdehyde Dehydrogenase* / deficiency*
Succinate-Semialdehyde Dehydrogenase* / genetics
gamma-Aminobutyric Acid / metabolism

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency

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