A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an 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.

Circadian distribution of generalized tonic–clonic seizures associated with murine succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

“…The study of adult mutant mice was possible only after maintaining them exclusively on the KD from weaning day (P20) onward [9,10]. Aldh5a1 −/− pups that continue to suckle beyond P20 survive longer than their weaned mutant littermates (unpublished), suggesting that the high-fat dam's milk exerts a beneficial effect in this disorder.…”

“…For wild-type (WT) mice, food and water were freely available throughout the study. Mutant mice were obtained from litters maintained exclusively on the KD [9,10] from weaning day onward. The rationale for using KD-treated animals is that absent this dietary treatment, no mutant animals survived to adulthood.…”

“…Absence-like seizure activity with 7-Hz spike-and-wave discharges first appear in Aldh5a1 −/− mice by the second postnatal week and then rapidly evolve into generalized convulsive seizures and lethal status epilepticus by 3 weeks of age [6][7][8]. However, with the introduction at weaning of the ketogenic diet (KD), a high-fat, adequate-protein, low-carbohydrate diet commonly used in the treatment of drug-resistant forms of epilepsy [9], it is possible for Aldh5a1 −/− mice to survive well into adulthood [10], albeit with significant motor and metabolic dysfunction, allowing for further study relevant to their corresponding clinical population. An understanding of how biological timing mechanisms influence seizure expression (i.e., what time of day seizures are more likely to occur) is of great clinical import.…”

1. Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: A multimodal evoked potentials study

“…In hippocampal in vitro seizures models, KD feeding limited epileptic activity in several portions of the hippocampus by promoting ATP-sensitive K+ channel activity that is implicated in plasma membrane excitability and in regulation of aerobic metabolism [29][30][31]. Both augmentation of fast GABAergic (GABA A ) neurotransmission and decreased probability of excitatory neurotransmitter release from presynaptic neurons have been implicated in the anticonvulsivant actions of the KD [32,33]. In fact, elevated concentrations of KBs have been reported to increase and maintain synaptosomal GABA contents at a higher value [34] and increase the intracellular concentration [35] and cause presynaptic input reduction of glutamate [31].…”

Ketogenic diets in patients with inherited metabolic disorders

“…It was shown that in Aldh5a1(-/-) mice KD restores hippocampal ATP levels (Nylen et al 2009) and significantly improves clinical phenotype (Nylen et al 2008). However, there are no reports of KD treatment of patients with SSADH deficiency.…”