Reduced evoked cortical beta and gamma activity and neuronal synchronization in succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism

Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited metabolic disorder of gamma-aminobutyric acid catabolism manifested by intellectual disability, expressive aphasia, movement disorders, psychiatric ailments and epilepsy. Subjects with succinic semialdehyde dehydrogenase deficiency are characterized by elevated gamma-aminobutyric acid and related metabolites, such as gamma-guanidinobutyric acid, and an age-dependent downregulation of cerebral gamma-aminobutyric acid receptors. These findings indicate impaired gamma-aminobutyric acid and gamma-aminobutyric acid sub-type A (GABA(A)) receptor signalling as major factors underlying the pathophysiology of this neurometabolic disorder. We studied the cortical oscillation patterns and their relationship with gamma-aminobutyric acid metabolism in 18 children affected by this condition and 10 healthy controls. Using high-density EEG, we recorded somatosensory cortical responses and resting-state activity. Using electrical source imaging, we estimated the relative power changes (compared with baseline) in both stimulus-evoked and stimulus-induced responses for physiologically relevant frequency bands and resting-state power. Stimulus-evoked oscillations are phase locked to the stimulus, whereas induced oscillations are not. Power changes for both evoked and induced responses as well as resting-state power were correlated with plasma gamma-aminobutyric acid and gamma-guanidinobutyric acid concentrations and with cortical gamma-aminobutyric acid measured by proton magnetic resonance spectroscopy. Plasma gamma-aminobutyric acid, gamma-guanidinobutyric acid and cortical gamma-aminobutyric acid were higher in patients than in controls (P < 0.001 for both). Beta and gamma relative power were suppressed for evoked responses in patients versus controls (P < 0.01). No group differences were observed for induced activity (P > 0.05). The mean gamma frequency of evoked responses was lower in patients versus controls (P = 0.002). Resting-state activity was suppressed in patients for theta (P = 0.011) and gamma (P < 0.001) bands. Evoked power changes were inversely correlated with plasma gamma-aminobutyric acid and with gamma-guanidinobutyric acid for beta (P < 0.001) and gamma (P < 0.001) bands. Similar relationships were observed between the evoked power changes and cortical gamma-aminobutyric acid for all tested areas in the beta band (P < 0.001) and for the posterior cingulate gyrus in the gamma band (P < 0.001). We also observed a negative correlation between resting-state activity and plasma gamma-aminobutyric acid and gamma-guanidinobutyric acid for theta (P < 0.001; P = 0.003), alpha (P = 0.003; P = 0.02) and gamma (P = 0.02; P = 0.01) bands. Our findings indicate that increased gamma-aminobutyric acid concentration is associated with reduced sensory-evoked beta and gamma activity and impaired neuronal synchronization in patients with succinic semialdehyde dehydrogenase deficiency. This further elucidates the pathophysiology of this neurometabolic disorder and serves as a potential biomarker for therapeutic trials.

Automated summary

Succinic semialdehyde dehydrogenase deficiency is a rare metabolic disorder that affects the metabolism of gamma-aminobutyric acid. In this study, researchers found abnormal gamma-aminobutyric acid metabolism and brain activity in children with this condition through EEG and proton magnetic resonance spectroscopy. These findings provide insights into the pathophysiology of this disorder and may serve as potential biomarkers for therapeutic trials.