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.

Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…A rare disorder of GABA catabolism, SSADHD has been reported in approximately 200 patients worldwide (Malaspina et al 2016). The phenotype is non-specific, with developmental delay, hypotonia, absence of formulated speech, and the onset of neuropsychiatric morbidity (obsession-compulsion, attention-deficit, oppositional defiant disorders) in adolescence to adulthood.…”

Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency

“…1) (Goullé et al 2003). The phenotype of SSADHD routinely includes neuropsychiatric morbidity from adolescence to adulthood, including attention deficit-hyperactivity, oppositional defiant and obsessive compulsive disorders (Malaspina et al 2016), representing significant disease morbidity. It is tempting to speculate that the nadir of hair GHB levels we observed (~12-13 years of age) may correlate with altered GABA levels and the onset of neuropsychiatric morbidity in SSADHD (Parviz et al 2014).…”

“…Sample collection kits were sent to all participants following consent. Patient demographics included 10 patients, age range 3-36 years (median age, 13 years; 9 males), representing approximately 5% of published patients (Malaspina et al 2016). Race as well as hair color can influence the concentration of GHB in hair (Goullé et al 2003).…”

“…Succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism, manifests with accumulation of both gamma-aminobutyrate (GABA) and gamma-hydroxybutyrate (GHB) in patient biological fluids (Malaspina et al 2016). While the neurochemistry of GABA is well known (Hillmer et al 2015), the pharmacology of GHB remains unclear.…”

“…GHB, an endogenous intermediate in the central nervous system present at~1% of parent GABA, is neuromodulatory in its effects on dopamine release and uptake (Maitre et al 2016). Additionally, GHB is used therapeutically for the treatment of narcolepsy, and employed illicitly as a drug of abuse and agent in the facilitation of sexual assault (Malaspina et al 2016). Because of its short terminal plasma half-life (~0.5 h) (Brenneisen et al 2004), forensic methods have been developed to quantify GHB in non-physiological fluids, including hair (Jagerdeo et al 2015).…”