Murine succinate semialdehyde dehydrogenase (SSADH) deficiency, a heritable disorder of GABA metabolism with epileptic phenotype

Abstract

Murine models of inborn errors of metabolism represent an established approach for investigating pathophysiological mechanisms associated with the corresponding human disorder. Our laboratory studies human inherited defects of GABA synthesis and degradation. One of these, succinate semialdehyde dehydrogenase (SSADH) deficiency (or gamma-hydroxybutyric aciduria; OMIM 271980; E.C. 1.2.1.24), has recently been modeled via gene targeting in the mouse. SSADH-/- mice succumb to early lethality in status epilepticus at postnatal (PN) days 20 - 26. Numerous metabolic, neurochemical and neurophysiological abnormalities have been documented using in vitro and in vivo approaches, substantially altering our thoughts about the complexity of the corresponding human condition. Moreover, novel preclinical treatment paradigms have been developed through drug trials in gene-ablated animals. The greatest utility of this animal, however, may reside in its transition from early absence seizures to generalized convulsions and eventual status epilepticus. Accurate neurochemical assessment during this transition may provide clues to the same transition process in patients, for which the underlying mechanisms remain undefined.

Metabolism of Levulinate in Perfused Rat Livers and Live Rats

“…Two other public health concerns resulted from the very high accumulation, in livers perfused with 4-hydroxypentanoate, of 4-phosphopentanoylCoA and a number of related acyl-CoAs (5). First, in mice with 4-hydroxybutyrate aciduria resulting from a deficiency in succinic semialdehyde dehydrogenase (37), the concentration of 4-phosphobutyryl-CoA in liver and brain was 40 times greater than in wild type mice (5). The accumulation of 4-phosphobutyryl-CoA may be related to the severe epileptic seizures suffered by these mice, and to the inability to reason in persons intoxicated with 4-hydroxybutyrate.…”

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

“…As noted above, the knockout mouse model is a viable phenocopy of the human disease, at least with respect to GHB and GABA (69,71,78,80,90,145) (Fig. 8).…”

“…Glutamine is a major storage form and intermediate for both GABA and glutamate, and the metabolism of this species is well-regulated through localization of specific synthetic=degradative enzymes in various neural intracellular compartments (193). For example, glutamine synthase is localized specifically to astrocytes, whereas the glutamate forming enzyme, glutaminase (converting glutamine to glutamate), is regionalized to the neuronal terminals (71). In this way, glutamine serves as a shuttle form of glutamate and GABA between different cell types in neural tissue.…”

“…Unfortunately, NCS-382 and CGP-35348 are not FDA-approved medications (although ongoing preclinical animal studies, coupled to toxicology data, may eventually support an orphan drug application). Vigabatrin is the most commonly used intervention in SSADH deficiency, and there has been mixed efficacy with this intervention (62,66,70,71,100). The logic of intervening with vigabatrin, in an already hyperGABAergic disease, also remains questionable.…”

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

“…The pharmacological actions of high GHB concentrations are likely mediated through activation of the GABA(B)R. GHB has no affinity for the GABA(A) receptor (GABA(A)R; Castelli et al 2003;Mathivet et al 1997). In Aldh5a1 j/j mice, increased levels of GABA and GHB alter GABA(B)R and GABA(A)R function, which may play a role in pathogenesis Chan et al 2006;Gibson et al 2005;Wu et al 2004aWu et al , 2006. Acute administration of GABA yields an increase in the phosphorylation level of the cAMP-responsive element-binding protein in murine hippocampus, but this phenomenon is abolished after repetitive GABA exposure, suggesting desensitization of the signalling pathways and GABA-induced neuroadaptive processes (Ren and Mody 2006).…”