Abstracts

Rationale: SSADH deficiency is an inherited defect of GABA degradation causing heterogeneous neurological deficits and a wide range of seizures. There is no widely effective treatment for SSADH deficiency. A murine analog for SSADH deficiency (Aldh5a1-/-) has been developed (Hogema et al, 2003). All Aldh5a1-/- mice exhibit developmental delay, ataxia and seizures that progress from absence to lethal status epilepticus by P25 (Cortez et al, 2004). These mice allow us to study the pathophysiology and treatment of SSADH deficiency. Here, we assess the effectiveness of a ketogenic diet (KD) in the treatment of Aldh5a1-/- mice.Methods: Aldh5a1-/- mice were treated with either standard mouse chow (CD) or a 4:1 KD. Aldh5a1+/+ mice fed a CD served as controls. Subjects were weighed and assessed for ataxia daily. We used whole cell voltage clamping to record miniature post-synaptic currents (mPSC). We also determined serum levels of glucose, beta-hydroxybutyrate and free fatty acids.Results: The KD prolonged the lives of Aldh5a1-/- mice by >300%. KD fed mutants demonstrated significant improvements in ataxia and weight gain. Electrophysiologically, mIPSCs were significantly reduced in Aldh5a1-/- mice. Interestingly, mIPSCs in KD fed mutants were completely normalized. mEPSCs were not significantly altered. Serum biochemistry revealed that glucose and NEFAs were not significantly altered, however, βOHB levels were significantly elevated in KD fed mice and CD fed mutants.Conclusions: Our data show that the KD has a profound ability to rescue the SSADH deficient phenotype. Post-kainate reductions in mIPSCs have been associated with epileptogenesis (Hirsch et al, 1999). The ability of the KD to restore mIPSC activity may be a key mechanism in this model. Ketosis has been implicated in the KD’s mechanism. It is unknown whether ketones themselves, or a general change in energy metabolism, confer protective effects. These studies are the first to show that the KD affects spontaneous synaptic activity. Further, these data suggest that the KD may be useful in the clinical treatment of SSADH deficiency.