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


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 [35S]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 [35S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [35S]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.

DOI: 10.1016/j.expneurol.2007.11.015
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@article{Nylen2008AKD, title={A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype.}, author={Kirk Nylen and Jose Luis Perez Velazquez and Sergei S Likhodii and Miguel A Cortez and Lily Shen and Yevgen Leshchenko and Khosrow Adeli and K Michael Gibson and W M Burnham and O Carter Snead}, journal={Experimental neurology}, year={2008}, volume={210 2}, pages={449-57} }