Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

Tessa M A Peters; Udo F H Engelke; Siebolt de Boer; Joris T G Reintjes; Jean-Baptiste Roullet; Sanne Broekman; Erik de Vrieze; Erwin van Wijk; Mirjam M C Wamelink; Rafael Artuch; Ivo Barić; Jona Merx; Thomas J Boltje; Jonathan Martens; Michèl A A P Willemsen; Marcel M Verbeek; Ron A Wevers; K Michael Gibson; Karlien L M Coene

doi:10.1002/jimd.12657

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

J Inherit Metab Dis. 2023 Jul 16. doi: 10.1002/jimd.12657. Online ahead of print.

Authors

Tessa M A Peters^{1

2}, Udo F H Engelke², Siebolt de Boer², Joris T G Reintjes², Jean-Baptiste Roullet³, Sanne Broekman⁴, Erik de Vrieze⁴, Erwin van Wijk⁴, Mirjam M C Wamelink⁵, Rafael Artuch⁶, Ivo Barić⁷, Jona Merx⁸, Thomas J Boltje⁸, Jonathan Martens⁹, Michèl A A P Willemsen¹⁰, Marcel M Verbeek^{1

2}, Ron A Wevers², K Michael Gibson³, Karlien L M Coene^{2

11}

Affiliations

¹ Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
² Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington, USA.
⁴ Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ Department of Clinical Chemistry, Metabolic Unit, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC Location Vrije Universiteit, Amsterdam, The Netherlands.
⁶ Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, CIBERER and MetabERN Hospital Sant Joan de Déu, Barcelona, Spain.
⁷ Department of Pediatrics, School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia.
⁸ Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Nijmegen, The Netherlands.
⁹ Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Nijmegen, The Netherlands.
¹⁰ Department of Pediatric Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Laboratory of Clinical Chemistry and Haematology, Máxima Medical Center, Veldhoven, The Netherlands.

PMID: 37455357
DOI: 10.1002/jimd.12657

Abstract

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.

Keywords: 4,5-dihydroxyheptanoic acid; 4,5-dihydroxyhexanoic acid; GABA metabolism; biomarker; cerebrospinal fluid; neurotransmission; next generation metabolic screening; pathophysiology; untargeted metabolomics; zebrafish SSADH model.

Publication types

Review

Abstract

Publication types

Grants and funding