Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective
Open accessAbstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma‐aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma‐hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next‐generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4‐guanidinobutanoic acid, and 2‐hydroxyglutaric acid, and prominent elevations of GHB and 4,5‐dihydroxyhexanoic acid (4,5‐DHHA) in SSADHD samples. Remarkably, the intensities of 4,5‐DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5‐DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5‐DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5‐dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.
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Elevated aspartate levels have been confirmed in cerebrospinal fluid and brain tissue of SSADH deficient patients.
“elevated aspartate levels have been confirmed in both cerebrospinal fluid and brain tissue of SSADH deficient patients (Kirby, Walters, Brown, et al., 2020;Peters et al., 2023)”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Peters et al., 2023
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Andersen, J. V., Marian, O. C., Qvist, F. L., Westi, E. W., Aldana, B. I., Schousboe, A., Don, A. S., Skotte, N. H., & Wellendorph, P. (2024) · Glia · doi:10.1002/glia.24585 · Cited by 13 · see citing works
- Authors
- Peters, T. M. A., Engelke, U. F. H., de Boer, S., Reintjes, J. T. G., Roullet, J., Broekman, S., de Vrieze, E., van Wijk, E., Wamelink, M. M. C., Artuch, R., Barić, I., Merx, J., Boltje, T. J., Martens, J., Willemsen, M. A. A. P., Verbeek, M. M., Wevers, R. A., Gibson, K. M., & Coene, K. L. M.
- Affiliations
- Radboud University Nijmegen (NL)
- Radboud University Medical Center (NL)
- Department of Laboratory Medicine, Translational Metabolic Laboratory (TML) Radboud University Medical Center Nijmegen The Netherlands
- Washington State University Spokane (US)
- Department of Otorhinolaryngology Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center Nijmegen The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (NL)
- Hospital Sant Joan de Déu Barcelona (ES)
- University Hospital Centre Zagreb (HR)
- Corresponding author
- Wevers, Ron A.
- ORCID
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2023-07-29
- Volume
- 47
- Issue
- 3
- Pages
- 417-430
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W4384493217
- Cited by
- 7
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Stichting Stofwisselkracht (10.13039/100016065)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01‐HD91142)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- succinic semialdehyde dehydrogenase deficiency, GABA pathway, gamma-hydroxybutyric acid, cerebrospinal fluid metabolites, epileptogenesis, neurometabolic disorders, untargeted metabolomics
- MeSH terms
- Adolescent, Amino Acid Metabolism, Inborn Errors, Animals, Child, Child, Preschool, Disease Models, Animal, Epilepsy, Female, gamma-Aminobutyric Acid, Humans, Hydroxybutyrates, Infant, Language Development Disorders, Male, Succinate-Semialdehyde Dehydrogenase, Mice, Metabolomics
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