TY - JOUR
T1 - Multi-omics in classical galactosemia
T2 - Evidence for the involvement of multiple metabolic pathways
AU - Hermans, Merel E.
AU - van Weeghel, Michel
AU - Vaz, Frédéric M.
AU - Ferdinandusse, Sacha
AU - Hollak, Carla E. M.
AU - Huidekoper, Hidde H.
AU - Janssen, Mirian C. H.
AU - van Kuilenburg, André B. P.
AU - Pras-Raves, Mia L.
AU - Wamelink, Mirjam M. C.
AU - Wanders, Ronald J. A.
AU - Welsink-Karssies, Mendy M.
AU - Bosch, Annet M.
N1 - Funding Information: This study was supported by a grant of Stichting Zeldzame Ziekten Fonds. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Publisher Copyright: © 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - GALT-deficiency
KW - galactose-1-phosphate
KW - galactosemia
KW - lipidomics
KW - metabolomics
KW - multi-omics
UR - http://www.scopus.com/inward/record.url?scp=85137061557&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/jimd.12548
DO - https://doi.org/10.1002/jimd.12548
M3 - Article
C2 - 36053831
SN - 0141-8955
VL - 45
SP - 1094
EP - 1105
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 6
ER -