Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase
Abstract
Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.
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Elevated GFAP expression has been observed in ALDH5A1 KO mice and patient brain tissue.
“Elevated GFAP expression, a marker of astrogliosis, has been observed in both ALDH5A1 KO mice (Brown, Gibson, et al., 2020;Hogema et al., 2001) and patient brain tissue (Walters et al., 2021).”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Hogema et al., 2001
ALDH5A1 KO mice show increased cerebral aspartate levels, whereas previous studies reported unchanged aspartate amounts.
“Previous studies have reported unchanged aspartate amounts in the ALDH5A1 KO brain (Gibson et al., 2002;Gupta et al., 2004;Hogema et al., 2001), whereas we observed increased cerebral aspartate levels.”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Hogema et al., 2001
Astrocytes become reactive in SSADH deficiency.
“Astrocytes become reactive in SSADH deficiency (Brown, Gibson, et al., 2020;Hogema et al., 2001;Walters et al., 2021)”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Hogema et al., 2001
The ALDH5A1 knockout mouse recapitulates several pathological hallmarks of SSADH deficiency including cerebral GABA accumulation and seizures.
“We applied a genetic mouse model of SSADH deficiency, the ALDH5A1 knockout (KO) mouse, recapitulating several pathological hallmarks including cerebral GABA accumulation and seizures (Gupta et al., 2003;Hogema et al., 2001).”
From Deficient brain <scp>GABA</scp> metabolism leads to widespread impairments of astrocyte and oligodendrocyte function (2024) · cites this paper as Hogema et al., 2001
Cited by
Sorted by citations
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
- Hogema, B. M., Gupta, M., Senephansiri, H., Burlingame, T. G., Taylor, M., Jakobs, C., Schutgens, R. B. H., Froestl, W., Snead, O. C., Diaz-Arrastia, R., Bottiglieri, T., Grompe, M., & Gibson, K. M.
- Affiliations
- Oregon Health & Science University (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Novartis (Switzerland) (CH)
- Hospital for Sick Children (CA)
- The University of Texas Southwestern Medical Center (US)
- Baylor University Medical Center (US)
- Corresponding author
- Gibson, K. Michael
- ORCID
- Venue
- Nature Genetics
- Published
- 2001-09-04
- Volume
- 29
- Issue
- 2
- Pages
- 212-216
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1576226022
- Cited by
- 157
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG012300, R03AG016450)
- National Institute of Neurological Disorders and Stroke (R01NS040270, NS 40270)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- ALDH5A1, GABA degradation, gamma-hydroxybutyric acid, seizures, GHB overdose, vigabatrin, taurine, phenobarbital, phenytoin, CGP 35348, GABAB receptor antagonists, gliosis, hippocampus, ataxia, mouse model
- MeSH terms
- Aldehyde Oxidoreductases, Animals, Anticonvulsants, Base Sequence, Brain, Genotype, Glial Fibrillary Acidic Protein, Hydroxybutyrates, Immunohistochemistry, Phenobarbital, Phenytoin, Seizures, DNA Primers, Receptors, GABA-B, Mice, Knockout, Succinate-Semialdehyde Dehydrogenase, Mice
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