Fig. 1.

Metabolic interrelationships in SSADH Deficiency. Shown are the GABA catabolic pathway, GABA shunt, fatty acid metabolism, and the Krebs cycle. Abbreviations: 4-GBA, 4-guanidinobutyric acid; L-Arg, L-arginine; L-His, L-histidine; Gln, L-glutamine; L-Gly, L-glycine; Guac, guanidinoacetic acid; GABA, 4-aminobutyric acid; GHB, γ-hydroxybutyric acid; SSA, succinic semialdehyde; D-2-HG, D-2-hydroxyglutaric acid; α-KG, α-ketoglutaric acid (or 2-oxoglutaric acid); 4,5-DHHA, 4,5 dihydroxyhexanoic acid. Enzyme abbreviations: GAD, glutamic acid decarboxylase; GABA-T, GABA-transaminase (also aminobutyrate aminotransferase); AKR, aldo-keto reductase; SSADH, succinic semialdehyde dehydrogenase (the site of the block in patients with SSADHD, indicated by the cross-hatched box); TH, D-2-hydroxyglutarate transhydrogenase; PDH, pyruvate dehydrogenase complex; LCFA, MCFA and SCFA, representing long-chain, medium-chain and short-chain fatty acids, respectively. The reaction normally catalyzing the conversion of L-glycine and L-arginine to guanidinoacetic acid is catalyzed by arginine:glycine amidinotransferase, the first step of creatine and creatinine formation. When elevated, GABA is postulated to interfere with this reaction, replacing L-glycine with GABA to yield 4-GBA. Potential interference of β-oxidation by SSA or GHB is shown by T-bars. The site of entry of amino acids shown to be dysregulated in the current study (aspartic acid, glutamine, serine, lysine, methionine, valine, isoleucine) into the Kreb cycle is also shown, as well as their relative alterations compared to control tissues (upward arrows, elevated; downward arrows, decreased). Directional arrows (upward) also show elevations for GABA-related intermediates as well as guanidinoacetic acid. A question mark next to the latter indicates a paradoxical finding in view of the elevation of 4-GBA