title: 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 [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.
authors.affiliation: Program in Neuroscience and Mental Health, Hospital for Sick Children, and Department of Pharmacology, University of Toronto, Ontario, Canada. kirk.nylen@utoronto.ca
authors.forename: Kirk
authors.initials: K
authors.lastname: Nylen
authors.forename: Jose Luis Perez
authors.initials: JL
authors.lastname: Velazquez
authors.forename: Sergei S
authors.initials: SS
authors.lastname: Likhodii
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cortez
authors.forename: Lily
authors.initials: L
authors.lastname: Shen
authors.forename: Yevgen
authors.initials: Y
authors.lastname: Leshchenko
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: W M
authors.initials: WM
authors.lastname: Burnham
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000178:diet therapy* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001259:Ataxia / Q000209:etiology / Q000235:genetics; D001345:Autoradiography; D001835:Body Weight / Q000502:physiology; D001921:Brain / Q000166:cytology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D050528:Diet, Carbohydrate-Restricted / Q000379:methods*; D004569:Electroencephalography / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005223:Fats / Q000008:administration & dosage*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010641:Phenotype; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005223:Fats; C037476:tert-butylbicyclophosphorothionate; D050644:Succinate-Semialdehyde Dehydrogenase