The presence and severity of epilepsy coincide with reduced GABA and cortical excitatory markers in SSADH deficiency

Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of ɣ-aminobutyrate (GABA) catabolism. Despite the resultant hyperGABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. Methods: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/NAA quantification, and plasma GABA-related metabolite measurements. Results: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p=0.001) and lower levels of GABA (p=0.002), γ-hydroxybutyrate (GHB) (p=0.004), and γ-guanidinobutyrate (GBA) (p=0.003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (rMT) (p=0.04). The cut-off values with the highest discriminative ability to predict seizures were age >9.2 years (p=0.001), GABA<2.57μM/L (p=0.002), GHB<143.6 (p=0.004), and GBA<0.075 (p=0.007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age, lower plasma GABA, GHB, and GBA (area under the ROC of 0.798, p=0.008). Significance: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyperGABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.