Temporal metabolomics in dried bloodspots suggests multipathway disruptions in aldh5a1−/− mice, a model of succinic semialdehyde dehydrogenase deficiency

Madalyn Brown, Coleman Turgeon, Piero Rinaldo, Jean Baptiste Roullet, K. Michael Gibson

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations


Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD; OMIM 271980) is a rare disorder featuring accumulation of neuroactive 4-aminobutyric acid (GABA; γ-aminobutyric acid, derived from glutamic acid) and 4-hydroxybutyric acid (γ-hydroxybutyric acid; GHB, a short-chain fatty acid analogue of GABA). Elevated GABA is predicted to disrupt the GABA shunt linking GABA transamination to the Krebs cycle and maintaining the balance of excitatory:inhibitory neurotransmitters. Similarly, GHB (or a metabolite) is predicted to impact β-oxidation flux. We explored these possibilities employing temporal metabolomics of dried bloodspots (DBS), quantifying amino acids, acylcarnitines, and guanidino- metabolites, derived from aldh5a1+/+, aldh5a1+/− and aldh5a1−/− mice (aldehyde dehydrogenase 5a1 = SSADH) at day of life (DOL) 20 and 42 days. At DOL 20, aldh5a1−/− mice had elevated C6 dicarboxylic (adipic acid) and C14 carnitines and threonine, combined with a significantly elevated ratio of threonine/[aspartic acid + alanine], in comparison to aldh5a1+/+ mice. Conversely, at DOL 42 aldh5a1−/− mice manifested decreased short chain carnitines (C0-C6), valine and glutamine, in comparison to aldh5a1+/+ mice. Guanidino species, including creatinine, creatine and guanidinoacetic acid, evolved from normal levels (DOL 20) to significantly decreased values at DOL 42 in aldh5a1−/− as compared to aldh5a1+/+ mice. Our results provide a novel temporal snapshot of the evolving metabolic profile of aldh5a1−/− mice while highlighting new pathomechanisms in SSADHD.

Original languageEnglish (US)
Pages (from-to)397-408
Number of pages12
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Dec 2019


  • Acylcarnitines
  • Amino acids
  • Dried bloodspots
  • GABA shunt
  • Guanidino-metabolites
  • Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD)
  • aldh5a1 mice
  • β-oxidation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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