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

We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (gamma-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of gamma-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH-/- (e.g. Aldh5a1-/-) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1-/- mice accumulate GHB and gamma-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1-/- mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.