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

Abstract

Human succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism associated with motor impairment and epileptic seizures. Similarly, mice with targeted deletion of the Aldh5a1 gene (Aldh5a1(-/-)) exhibit SSADH deficiency and seizures early in life. These seizures begin as absence seizures the second week of life, but evolve into generalized convulsive seizures that increase in severity and become lethal during the fourth postnatal week. The seizures are alleviated and survival is prolonged when the mutant animals are weaned onto a ketogenic diet (KD). The persistence of spontaneous, recurrent, generalized tonic-clonic seizures in KD-treated adult Aldh5a1(-/-) mice allowed us to quantify their daily (circadian) distribution using a novel behavioral method based on the detection of changes in movement velocity. Adult KD-treated Aldh5a1(-/-) mice exhibited a seizure phenotype characterized by fits of wild running clonus accompanied by jumping and bouncing. These hypermotor seizures were largely spontaneous and occurred daily in a nonrandom pattern. The seizure rhythm showed a peak shortly after dark phase onset (2008 hours) with near-24-hour periodicity. Age-matched wild-type littermates showed no evidence of abnormal motor behavior. These new data suggest that generalized tonic-clonic seizures in Aldh5a1(-/-) mice are more frequent during a specific time of day and will provide useful information to clinicians for the treatment of seizures associated with human SSADH deficiency.

Fig. 1

Twenty-four-hour distributions of motor behavior and generalized tonic–clonic seizures in Aldh5a1^−/− mice. (A) Daily patterns of movement velocity (MV, vertical bars) and jumps above the floor plane (JFP, filled circles) in Aldh5a1^−/− (upper panel) and WT (lower panel) mice. Mutant mice exhibited significantly higher MV and JFP compared with the WT group across nearly all time points, but both groups of mice displayed similar levels of overall behavioral activity (i.e., total movements, inset a). (B) The distribution of spontaneous seizures in Aldh5a1^−/− mice based on standardized MV (zMV). For each mouse, seizures for which the zMV scores were ≥2SD above their respective means were categorized as spontaneous hypermotor seizures.