Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

Abstract

Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

Keywords: Autophagy; Crystal structure; GABA (4-aminobutyric acid); GABAergic neurotransmission; GHB (4-hydroxybutyric acid); GWAS; Genome wide association study; Knockout mouse model; Mitophagy; Multifactorial traits; Neurological disease; Oxidative damage; Pathogenic mutations; Pathophysiology; Polymorphisms; SNP (single nucleotide polymorphism); Succinic semialdehyde dehydrogenase deficiency (SSADHD).

Fig. 1. Geographic distribution of SSADHD patients (n=176)

Afghanistan, Argentina, Taiwan, Canada, France, Lebanon, Bulgaria, Life (New Caledonia) (n=2 patients each). Malaysia, UAE (United Arab Emirates), Tunisia, Syria, Luxembourg, Inuit (Iceland), Uruguay, Yemen, Sweden, Denmark, Sicily, Albania, Algeria, Belgium (n=1 patient each; data taken from 36 publications).

Fig. 2. GABA metabolism and SSADHD

GABA normally interconverts to succinic semialdehyde via GABA-transaminase (GABA-T) activity, and subsequently forms succinic acid via succinic semialdehyde dehydrogenase (SSADH), the defect in SSADH deficiency (SSADHD; cross-hatched box). Gamma-hydroxybutyrate (GHB; whose formation is catalyzed by aldo-keto reductase 7a2, AKR7a2), D-2-hydroxyglutaric acid (D-2-HG; the formation of which is catalyzed by nicotinamide-independent D-2-hydroxyglutaric transhydrogenase (TH)), SSA and 4,5-dihydroxyhexanoic acid (DHHA; possibly derived from SSA condensation with an “activated” two carbon species, but unproven) are increased in patient body fluids. Monoamine oxidase (MAO) and β-alanine aminotransferase (βAAT) can also metabolize GABA.

Fig. 3. Interrelationships of GABA and creatine metabolism

Numbered enzymes include: 1, SSADH; 2, arginine-glycine amidinotransferase (AGAT); and 3, guanidinoacetate methyltransferase. The dashed line represents the probable conversion of accumulated GABA to guanidinobutyrate via the action of AGAT, as previously reported (Watanabe et al 1994). Abbreviations: SSA, succinate semialdehyde; GHB, gamma-hydroxybutyrate; GABA, gamma-aminobutyrate; Gly, glycine; Arg, arginine; Orn, ornithine. The structure of guanidinobutyrate is also shown.

Fig. 4. Pathophysiological alterations in heritable SSADH deficiency

Arrows indicate the direction and magnitude of metabolic disturbance. Abbreviations: 4-HNE, 4-hydroxyl-2-nonenal; GSH, glutathione; GluR, glutamate receptors; GABA_AR/GABA_BR, GABA_A and GABA_B receptors; HC, homocarnosine (the dipeptide of GABA:L-histidine); GBA, guanidinobutyrate; Gln, glutamine. See Fig. 2 for other metabolic interconversions associated with GABA. 4-HNE is a major by-product of lipid peroxidation, and is metabolized by SSADH in brain. The dashed boxes indicate recent findings from the knockout mouse model which are not yet published, but are consistent with earlier reports in SSADHD (Pearl et al 2009; Reis et al 2012; Wu et al 2006; Buzzi et al 2006).