Post-mortem tissue analyses in a patient with succinic semialdehyde dehydrogenase deficiency (SSADHD). I. Metabolomic outcomes
Open accessAbstract
Metabolomic characterization of post-mortem tissues (frontal and parietal cortices, pons, cerebellum, hippocampus, cerebral cortex, liver and kidney) derived from a 37 y.o. male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) was performed in conjunction with four parallel series of control tissues. Amino acids, acylcarnitines, guanidino- species (guanidinoacetic acid, creatine, creatinine) and GABA-related intermediates were quantified using UPLC and mass spectrometric methods that included isotopically labeled internal standards. Amino acid analyses revealed significant elevation of aspartic acid and depletion of glutamine in patient tissues. Evidence for disruption of short-chain fatty acid metabolism, manifest as altered C4OH, C5, C5:1, C5DC (dicarboxylic) and C12OH carnitines, was observed. Creatine and guanidinoacetic acids were decreased and elevated, respectively. GABA-associated metabolites (total GABA, γ-hydroxybutyric acid, succinic semialdehyde, 4-guanidinobutyrate, 4,5-dihydroxyhexanoic acid and homocarnosine) were significantly increased in patient tissues, including liver and kidney. The data support disruption of fat, creatine and amino acid metabolism as a component of the pathophysiology of SSADHD, and underscore the observation that metabolites measured in patient physiological fluids provide an unreliable reflection of brain metabolism.
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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 Kirby, Walters, Brown, et al., 2020
The Results (Amino acid analyses using the MassTrak system; page not provided) report significantly elevated aspartic acid in the patient's brain tissue. The paper does not report elevated aspartate in cerebrospinal fluid, so it supports only the brain-tissue part of the claim. (LLM, conf=0.88)
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Cites
Combined Newborn Screening for Succinylacetone, Amino Acids, and Acylcarnitines in Dried Blood Spots
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Research works printed but not linked: 31
- Akaboshi S, Hogema BM, Novelletto A, Malaspina P, Salomons GS, Maropoulos GD, Jakobs C, Grompe M, Gibson KM (2003) Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Hum Mutat 22: 442– 450 14635103
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- Brown M, Ashcraft P, Arning E, Bottiglieri T, Roullet JB, Gibson KM (2019) Gamma-Hydroxybutyrate content in dried bloodspots facilitates newborn detection of succinic semialdehyde dehydrogenase deficiency Mol Genet Metab 128: 109– 112 31345667 PMC6961708
- Brown MN, Turgeon C, Rinaldo P, Pop A, Salomons G, Roullet J-B, Gibson KM (in press-aa) Longitudinal metabolomics in dried bloodspots yields profiles informing newborn screening for succinic semialdehyde dehydrogenase deficiency (SSADHD). J Inherit Metab Dis Rep PMC7203655 32395407
- Brown M, Turgeon C, Rinaldo P, Roullet JB, Gibson KM (2019) Temporal metabolomics in dried bloodspots suggests multipathway disruptions in aldh5a1−/− mice, a model of succinic semialdehyde dehydrogenase deficiency Mol Genet Metab 128: 397– 408 31699650
- Buzzi A, Wu Y, Frantseva MV, Perez Velazquez JL, Cortez MA, Liu CC, Shen LQ, Gibson KM, Snead OC 3rd (2006) Succinic semialdehyde dehydrogenase deficiency: GABAB receptor-mediated function. Brain Res 1090: 15– 22 16647690
- Chace DH, DiPerna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW (2001) Electrospray tandem mass spectrometry for analysis of acylcarnitines in dried postmortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 47: 1166– 1182 11427446
- Chowdhury GM, Gupta M, Gibson KM, Patel AB, Behar KL (2007) Altered cerebral glucose and acetate metabolism in succinic semialdehyde dehydrogenase-deficient mice: evidence for glial dysfunction and reduced glutamate/glutamine cycling. J Neurochem 103: 2077– 2091 17854388
- Gibson KM, Lee CF, Kamali V, Johnston K, Beaudet AL, Craigen WJ, Powell BR, Schwartz R, Tsai MY, Tuchman M (1990a) 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency as detected by radiochemical assay in cell extracts by thin-layer chromatography, and identification of three new cases. Clin Chem 36: 297– 303 2302772
- Gibson KM, Aramaki S, Sweetman L, Nyhan WL, DeVivo DC, Hodson AK, Jakobs C (1990b) Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom 19: 89– 93 2407302
- Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C (1993) Stable-isotope dilution analysis of D- and L-2-hydroxyglutaric acid: application to the detection and prenatal diagnosis of D- and L-2-hydroxyglutaric acidemias. Pediatr Res 34: 277– 280 8134166
- Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J (2000) 2-Methylbutyryl-coenzyme a dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism. Pediatr Res 47: 830– 833 10832746
- Gibson KM, Schor DS, Gupta M, Guerand WS, Senephansiri H, Burlingame TG, Bartels H, Hogema BM, Bottiglieri T, Froestl W, Snead OC, Grompe M, Jakobs C (2002) Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase. JNeurochem 81: 71– 9 12067239
- Gibson KM, Gupta M, Pearl PL, Tuchman M, Vezina LG, Snead OC 3rd, Smit LM, Jakobs C (2003) Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psychiatry 54: 763– 768 14512218
- Gupta M, Polinsky M, Senephansiri H, Snead OC, Jansen EE, Jakobs C, Gibson KM (2004) Seizure evolution and amino acid imbalances in murine succinate semialdehyde dehydrogenase (SSADH) deficiency. Neurobiol Dis 16: 556– 562 15262267
- Haan EA, Brown GK, Mitchell D, Danks DM (1985) Succinic semialdehyde dehydrogenase deficiency–a further case. J Inherit Metab Dis 8: 99 2433500
- Hogema BM, Gupta M, Senephansiri H, Burlingame TG, Taylor M, Jakobs C, Schutgens RB, Froestl W, Snead OC, Diaz-Arrastia R, Bottiglieri T, Grompe M, Gibson KM (2001) Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 29: 212– 216 11544478
- Jansen EE, Verhoeven NM, Jakobs C, Schulze A, Senephansiri H, Gupta M, Snead OC, Gibson KM (2006a) Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency Biochim Biophys Acta 1762: 494– 498 16504488
- Jansen EE, Gibson KM, Shigematsu Y, Jakobs C, Verhoeven NM (2006b) A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 830: 196– 200 16309980
- Jansen EE, Struys E, Jakobs C, Hager E, Snead OC, Gibson KM (2008) Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development. BMC Dev Biol 8: 112 19040727 PMC2642797
- Jansen EE, Vogel KR, Salomons GS, Pearl PL, Roullet JB, Gibson KM (2016) Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis 39: 795– 800 27686230 PMC5115636
- Kok RM, Howells DW, van den Heuvel CC, Guérand WS, Thompson GN, Jakobs C (1993) Stable isotope dilution analysis of GABA in CSF using simple solvent extraction and electron-capture negativeion mass fragmentography J Inherit Metab Dis 16: 508– 512 7541876
- Malaspina P, Roullet JB, Pearl PL, Ainslie GR, Vogel KR, Gibson KM (2016) Succinic semialdehyde dehydrogenase deficiency (SSADHD): pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem Int 99: 72– 84 27311541 PMC5028283
- Novotny EJ Jr, Fulbright RK, Pearl PL, Gibson KM, Rothman DL (2003) Magnetic resonance spectroscopy of neurotransmitters in human brain. Ann Neurol 54(Suppl 6): S25– S31 12891651
- Sauer SW, Kölker S, Hoffmann GF, Ten Brink HJ, Jakobs C, Gibson KM, Okun JG (2007) Enzymatic and metabolic evidence for a region specific mitochondrial dysfunction in brains of murine succinic semialdehyde dehydrogenase deficiency (Aldh5a1−/− mice). Neurochem Int 50: 653– 659 17303287
- Struys EA, Jansen EE, ten Brink HJ, Verhoeven NM, van der Knaap MS, Jakobs C (1998) An accurate stable isotope dilution gas chromatographic-mass spectrometric approach to the diagnosis of guanidinoacetate methyltransferase deficiency. J Pharm Biomed Anal 18: 659– 665 9919967
- Struys EA, Jansen EE, Gibson KM, Jakobs C (2005) Determination of the GABA analogue succinic semialdehyde in urine and cerebrospinal fluid by dinitrophenylhydrazine derivatization and liquid chromatography-tandem mass spectrometry: application to SSADH deficiency. J Inherit Metab Dis 28: 913– 920 16435183
- Vogel KR, Arning E, Wasek BL, Bottiglieri T, Gibson KM (2013) Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood-brain phenylalanine transport in Pah enu2 mice: preliminary findings. Mol Genet Metab 110(Suppl): S71– S78 23999161 PMC4077276
- Walters DC, Jansen EEW, Ainslie GR, Salomons GS, Brown MN, Schmidt MA, Roullet JB, Gibson KM (2019) Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use-limiting visual field defects. Pharmacol Res Perspect 7: e00456 30631446 PMC6321982
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
- Kirby, T., Walters, D. C., Brown, M., Jansen, E., Salomons, G. S., Turgeon, C., Rinaldo, P., Arning, E., Ashcraft, P., Bottiglieri, T., Roullet, J.-B., & Gibson, K. M.
- Affiliations
- Washington State University Spokane (US)
- Amsterdam University Medical Centers (NL)
- Mayo Clinic (US)
- Baylor Scott & White Research Institute (US)
- Corresponding author
- Gibson, K. Michael
- ORCID
- Venue
- Metabolic Brain Disease
- Published
- 2020-03-14
- Volume
- 35
- Issue
- 4
- Pages
- 601-614
- ISSN
- 0885-7490 (ISSN-L)
- 1573-7365
- PMC
- PMC7180121
- OpenAlex
- W3011327711
- Cited by
- 24
- References
- 1
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 2
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-04-18)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Metabolic Brain Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Funders
- National Institute of Child Health and Development (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, postmortem brain, brain metabolomics, amino acids, aspartic acid, glutamine, acylcarnitines, short-chain fatty acid metabolism, creatine, guanidinoacetic acid, succinic semialdehyde, homocarnosine, gamma-hydroxybutyric acid, brain metabolism
- MeSH terms
- Adult, Amino Acid Metabolism, Inborn Errors, Amino Acids, Brain, Carnitine, Developmental Disabilities, Creatine, Creatinine, gamma-Aminobutyric Acid, Glycine, Humans, Male, Succinate-Semialdehyde Dehydrogenase, Metabolomics
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