Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism

Madalyn N. Brown, Dana C. Walters, Michelle A. Schmidt, James Hill, Alice McConnell, Erwin E. W. Jansen, Gajja S. Salomons, Erland Arning, Teodoro Bottiglieri, K. Michael Gibson, Jean-Baptiste Roullet

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3 Citations (Scopus)


Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of γ-aminobutyric acid (GABA) and γ-hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1-/- (SSADHD) mice and their genetic controls (aldh5a1+/+ ) to either a 4% (w/w) glutamine-containing diet or a glutamine-free diet from conception until postnatal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores, and open field testing. Glutamine supplementation did not improve aldh5a1-/- brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1+/+ and 18% for aldh5a1-/- mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1+/+ but not in aldh5a1-/- , but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1-/- mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.
Original languageEnglish
Pages (from-to)1030-1039
Number of pages10
JournalJournal of Inherited Metabolic Disease
Issue number5
Publication statusPublished - 1 Sept 2019


  • GABA
  • GHB
  • dietary supplementation
  • dried bloodspots
  • glutamine
  • knockout mice

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