. 2025 Mar;144(3):109051.

doi: 10.1016/j.ymgme.2025.109051. Epub 2025 Feb 4.

The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism

Itay Tokatly Latzer¹, Ellen Hanson², Mariarita Bertoldi³, Melissa L DiBacco⁴, Deniz Aygun⁵, Onur Afacan⁶, Àngeles García-Cazorla⁷, Natalia Juliá-Palacios⁸, Thomas Opladen⁹, Oya Kuseyri Hübschmann¹⁰, Kathrin Jeltsch¹¹, Petra Aden¹², Mari Oppebøen¹³, Alexander Rotenberg¹⁴, Melissa Tsuboyama¹⁵, Jean-Baptiste Roullet¹⁶, Phillip L Pearl¹⁷

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; School of Medicine, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv, Israel. Electronic address: itay.tokatlylatzer@childrens.harvard.edu.
² Human Neurobehavioral Core Services, Division of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, MA 02115, USA. Electronic address: Ellen.Hanson@childrens.harvard.edu.
³ Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. Electronic address: mita.bertoldi@univr.it.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Melissa.DiBacco@childrens.harvard.edu.
⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: deniz.aygun@einsteinmed.edu.
⁶ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: onur.afacan@childrens.harvard.edu.
⁷ Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: agarcia@sjdhospitalbarcelona.org.
⁸ Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: nataliaalexandra.julia@sjd.es.
⁹ 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.
¹⁰ Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany. Electronic address: Oya.KuseyriHuebschmann@med.uni-heidelberg.de.
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 Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway. Electronic address: UXPEAD@ous-hf.no.
¹³ Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway. Electronic address: maropp@ous-hf.no.
¹⁴ 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.
¹⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: melissa.tsuboyama@childrens.harvard.edu.
¹⁶ Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: j.roullet@wsu.edu.
¹⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Phillip.Pearl@childrens.harvard.edu.

PMID: 39919676
PMCID: PMC11879317 (available on 2026-03-01)
DOI: 10.1016/j.ymgme.2025.109051

The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism

Itay Tokatly Latzer et al. Mol Genet Metab. 2025 Mar.

. 2025 Mar;144(3):109051.

doi: 10.1016/j.ymgme.2025.109051. Epub 2025 Feb 4.

Authors

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; School of Medicine, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv, Israel. Electronic address: itay.tokatlylatzer@childrens.harvard.edu.
² Human Neurobehavioral Core Services, Division of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, MA 02115, USA. Electronic address: Ellen.Hanson@childrens.harvard.edu.
³ Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. Electronic address: mita.bertoldi@univr.it.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Melissa.DiBacco@childrens.harvard.edu.
⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: deniz.aygun@einsteinmed.edu.
⁶ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: onur.afacan@childrens.harvard.edu.
⁷ Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: agarcia@sjdhospitalbarcelona.org.
⁸ Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: nataliaalexandra.julia@sjd.es.
⁹ 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.
¹⁰ Heidelberg University, Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany. Electronic address: Oya.KuseyriHuebschmann@med.uni-heidelberg.de.
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 Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway. Electronic address: UXPEAD@ous-hf.no.
¹³ Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway. Electronic address: maropp@ous-hf.no.
¹⁴ 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.
¹⁵ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: melissa.tsuboyama@childrens.harvard.edu.
¹⁶ Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: j.roullet@wsu.edu.
¹⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Phillip.Pearl@childrens.harvard.edu.

PMID: 39919676
PMCID: PMC11879317 (available on 2026-03-01)
DOI: 10.1016/j.ymgme.2025.109051

Abstract

Background and objectives: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder resulting in hyper-physiologic concentrations of the neurotransmitter γ-aminobutyrate (GABA). This study aims to provide the most comprehensive description, to date, of the neuropsychological profile of individuals with SSADHD and assess whether neuroimaging, neurophysiologic, and biochemical indices of cortical inhibition correlate with those of standardized behavioral tests.

Methods: Participants enrolled in the SSADHD Natural History Study underwent medical and neurological examinations, magnetic resonance imaging (MRI) and spectroscopy (MRS), biochemical tests of GABA and its related metabolites, transcranial magnetic stimulation (TMS), and gene expression quantification, as well as complete neuropsychological assessment including standardized measures for cognition, adaptive skills, motor function, receptive and expressive language, autism spectrum disorder, and behavior problems.

Results: The neuropsychological profile of the study's 65 enrollees [54 % females, median (interquartile range) age 9.6 (5.4-14.7)] consisted almost universally of intellectual disability, delays in adaptive skills, and deficits in expressive more than receptive language. Autism Spectrum Disorder was noted in ∼50 %, and behavioral problems in ∼70 %, predominated by obsessive-compulsive behaviors and attention problems but also including affective problems, anxiety, and, rarely, aggression and possible psychosis. Correlation analyses showed that increased internalizing, externalizing, and overall psychiatric morbidity significantly correlated with increasing age (R = 0.391, p = 0.033), as well as age-independent indices representing decreased cortical inhibition such as lower MRS-derived GABA (R = -0.530, p = 0.029) and TMS-derived resting motor threshold (R = -0.418, p = 0.053).

Discussion: The natural history study of SSADHD indicates that intellectual disability, delayed adaptive skills, and expressive>receptive language deficits are nearly universal, with behavior problems in the vast majority. Increased psychiatric morbidity in SSADHD with age-independent decreased cortical inhibition may serve as the basis for establishing disorder-specific biomarkers for behavioral and psychiatric outcomes in SSADHD and other non-syndromic psychiatric disorders.

Keywords: Behavior; Developmental; Gamma-aminobutyric acid; Psychiatric; Succinic semialdehyde dehydrogenase.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest A.R. is supported by the National Institutes of Health (1R21NS121858-01A1) and a research grant from the SSADH Association and is a Co-Founder of Galibra Neuroscience, Inc. N.J.P. and A.G.C. are supported by FI21/00073 “Instituto de Salud Carlos III (ISCIII)” and “Fondo Europeo De Desarrollo Regional (FEDER).”

References

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The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism

Affiliations

The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases