Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue
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This study has extended previous metabolic measures in postmortem tissues (frontal and parietal lobes, pons, cerebellum, hippocampus, and cerebral cortex) obtained from a 37-year-old male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) who expired from SUDEP (sudden unexplained death in epilepsy). Histopathologic characterization of fixed cortex and hippocampus revealed mild to moderate astrogliosis, especially in white matter. Analysis of total phospholipid mass in all sections of the patient revealed a 61% increase in cortex and 51% decrease in hippocampus as compared to (n = 2-4) approximately age-matched controls. Examination of mass and molar composition of major phospholipid classes showed decreases in phospholipids enriched in myelin, such as phosphatidylserine, sphingomyelin, and ethanolamine plasmalogen. Evaluation of gene expression (RT 2 Profiler PCR Arrays, GABA, glutamate; Qiagen) revealed dysregulation in 14/15 GABA A receptor subunits in cerebellum, parietal, and frontal lobes with the most significant downregulation in ∊, θ, ρ1, and ρ2 subunits (7.7-9.9-fold). GABA B receptor subunits were largely unaffected, as were ionotropic glutamate receptors. The metabotropic glutamate receptor 6 was consistently downregulated (maximum 5.9-fold) as was the neurotransmitter transporter (GABA), member 13 (maximum 7.3-fold). For other genes, consistent dysregulation was seen for interleukin 1β (maximum downregulation 9.9-fold) and synuclein α (maximal upregulation 6.5-fold). Our data provide unique insight into SSADHD brain function, confirming astrogliosis and lipid abnormalities previously observed in the null mouse model while highlighting long-term effects on GABAergic/glutamatergic gene expression in this disorder.
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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 Walters et al., 2021
The Results report reactive astrogliosis in the patient’s cortex and hippocampus, assessed by GFAP immunohistochemistry. This supports the patient-brain finding, but the paper does not report a measured increase in GFAP expression. The mouse finding has separate citations and is not the part attributed to Walters et al. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAstrocytes 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 Walters et al., 2021
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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
- Walters, D. C., Lawrence, R., Kirby, T., Ahrendsen, J. T., Anderson, M. P., Roullet, J.-B., Murphy, E. J., Gibson, K. M., & the SSADH Deficiency Investigators Consortium (SDIC)
- Affiliations
- Washington State University Spokane (US)
- University of North Dakota (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Gibson, K. Michael
- ORCID
- Venue
- Journal of Child Neurology
- Publisher
- SAGE Publications
- Published
- 2021-02-09
- Volume
- 36
- Issue
- 13-14
- Pages
- 1177-1188
- ISSN
- 0883-0738 (ISSN-L)
- 1708-8283
- PMC
- PMC8349921
- OpenAlex
- W3127908757
- Cited by
- 11
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 2
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Child Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Child Health and Human Development (R01HD91142)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- succinic semialdehyde dehydrogenase deficiency, sudden unexpected death in epilepsy, postmortem brain, astrocyte activation, phospholipid composition, GABAA receptor subunits, GABAB receptors, mGluR6, GABA transporter 1, gene expression dysregulation, epilepsy, IL-1β
- MeSH terms
- Adult, Amino Acid Metabolism, Inborn Errors, Autopsy, Brain, Developmental Disabilities, Humans, Lipids, Male, Gene Expression, Succinate-Semialdehyde Dehydrogenase
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