Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue.

Abstract

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 (RT2 Profiler PCR Arrays, GABA, glutamate; Qiagen) revealed dysregulation in 14/15 GABAA receptor subunits in cerebellum, parietal, and frontal lobes with the most significant downregulation in ∊, θ, ρ1, and ρ2 subunits (7.7-9.9-fold). GABAB 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.

• Authors: Dana C Walters, Regan Lawrence, Trevor Kirby, Jared T Ahrendsen, Matthew P Anderson, Jean-Baptiste Roullet, Eric J Murphy, K Michael Gibson, SSADH Deficiency Investigators Consortium (SDIC)
• Journal: Journal of child neurology (J Child Neurol) Vol. 36 Issue 13-14 Pg. 1177-1188 (11 2021) ISSN: 1708-8283 [Electronic] United States
• PMID: 33557678 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipids
• Succinate-Semialdehyde Dehydrogenase

Topics

• Adult
• Amino Acid Metabolism, Inborn Errors (genetics, metabolism, pathology)
• Autopsy
• Brain (pathology)
• Developmental Disabilities (genetics, metabolism, pathology)
• Gene Expression (genetics)
• Humans
• Lipids (analysis)
• Male
• Succinate-Semialdehyde Dehydrogenase (deficiency, genetics, metabolism)