Multi-omics in classical galactosemia: Evidence for the involvement of multiple metabolic pathways.

Autor: Hermans ME; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands., van Weeghel M; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., Vaz FM; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; United for Metabolic Diseases, The Netherlands., Ferdinandusse S; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands., Hollak CEM; Department of Internal Medicine, Division of Endocrinology and Metabolism, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., Huidekoper HH; Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center, Rotterdam, The Netherlands., Janssen MCH; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands., van Kuilenburg ABP; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands., Pras-Raves ML; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.; Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Epidemiology and Data Science, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., Wamelink MMC; Department of Clinical Chemistry, Metabolic Unit, Gastroenterology Endocrinology Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Wanders RJA; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.; Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands., Welsink-Karssies MM; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands., Bosch AM; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Emma Children's Hospital, Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology Metabolism, Inborn Errors of Metabolism, Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2022 Nov; Vol. 45 (6), pp. 1094-1105. Date of Electronic Publication: 2022 Aug 25.
DOI: 10.1002/jimd.12548
Abstrakt: Classical galactosemia (CG) is one of the more frequent inborn errors of metabolism affecting approximately 1:40.000 people. Despite a life-saving galactose-restricted diet, patients develop highly variable long-term complications including intellectual disability and movement disorders. The pathophysiology of these complications is still poorly understood and development of new therapies is hampered by a lack of valid prognostic biomarkers. Multi-omics approaches may discover new biomarkers and improve prediction of patient outcome. In the current study, (semi-)targeted mass-spectrometry based metabolomics and lipidomics were performed in erythrocytes of 40 patients with both classical and variant phenotypes and 39 controls. Lipidomics did not show any significant changes or deficiencies. The metabolomics analysis revealed that CG does not only compromise the Leloir pathway, but also involves other metabolic pathways including glycolysis, the pentose phosphate pathway, and nucleotide metabolism in the erythrocyte. Moreover, the energy status of the cell appears to be compromised, with significantly decreased levels of ATP and ADP. This possibly is the consequence of two different mechanisms: impaired formation of ATP from ADP possibly due to reduced flux though the glycolytic pathway and trapping of phosphate in galactose-1-phosphate (Gal-1P) which accumulates in CG. Our findings are in line with the current notion that the accumulation of Gal-1P plays a key role in the pathophysiology of CG not only by depletion of intracellular phosphate levels but also by decreasing metabolite abundance downstream in the glycolytic pathway and affecting other pathways. New therapeutic options for CG could be directed towards the restoration of intracellular phosphate homeostasis.
(© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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