Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the
gamma-aminobutyric acid (
GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of
GABA and
gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel
therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of
aspartic acid,
glutaric acid,
glycolic acid, 4-guanidinobutanoic
acid, and
2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic
acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish
epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high
biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel
biomarker 4,5-dihydroxyheptanoic
acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of
epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology.