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

Abstract

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.

Keywords: Acylcarnitines; Amino acids; Dried bloodspots; GABA shunt; Guanidino-metabolites; Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD); aldh5a1(−/−) mice; β-oxidation.