TY - JOUR
T1 - Succinic semialdehyde dehydrogenase deficiency in mice and in humans
T2 - An untargeted metabolomics perspective
AU - Peters, Tessa M. A.
AU - Engelke, Udo F. H.
AU - de Boer, Siebolt
AU - Reintjes, Joris T. G.
AU - Roullet, Jean-Baptiste
AU - Broekman, Sanne
AU - de Vrieze, Erik
AU - van Wijk, Erwin
AU - Wamelink, Mirjam M. C.
AU - Artuch, Rafael
AU - Barić, Ivo
AU - Merx, Jona
AU - Boltje, Thomas J.
AU - Martens, Jonathan
AU - Willemsen, Michèl A. A. P.
AU - Verbeek, Marcel M.
AU - Wevers, Ron A.
AU - Gibson, K. Michael
AU - Coene, Karlien L. M.
N1 - Funding Information: The authors thank Melissa DiBacco for her help with the data from the Natural History Study, Dana C Walters for her help with the sample selection and intercontinental transfer, and the patients and families for participating in parts of this study. This study was funded by Stofwisselkracht under the project name of “Innovative diagnostics in cerebrospinal fluid of patients with neurometabolic disorders” (KLM Coene and MM Verbeek), by the NIH/NICHD (1R01‐HD91142, KM Gibson) and by the SSADH Association ( https://www.ssadh.net/ , KM Gibson). Publisher Copyright: © 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - 4,5-dihydroxyheptanoic acid
KW - 4,5-dihydroxyhexanoic acid
KW - GABA metabolism
KW - biomarker
KW - cerebrospinal fluid
KW - neurotransmission
KW - next generation metabolic screening
KW - pathophysiology
KW - untargeted metabolomics
KW - zebrafish SSADH model
UR - http://www.scopus.com/inward/record.url?scp=85166420322&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12657
DO - https://doi.org/10.1002/jimd.12657
M3 - Review article
C2 - 37455357
SN - 0141-8955
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
ER -