A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype.

Abstract Succinic semialdehyde dehydrogenase (SSADH) deficiency is a heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse ( Aldh5a1 −/− ). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [ 35 S]TBPS binding in both Aldh5a1 −/− mice and control ( Aldh5a1 +/+ ) mice. We found that the KD prolonged the lifespan of mutant mice by > 300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1 −/− mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [ 35 S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [ 35 S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1 −/− mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.