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Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models.
J Inherit Metab Dis. 2020 05; 43(3):392-408.JI

Abstract

Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.

Authors+Show Affiliations

Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands. Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands. Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.Department of Pediatrics, Maastricht University Medical Center+, Maastricht, The Netherlands. Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands. GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Pub Type(s)

Journal Article
Systematic Review

Language

eng

PubMed ID

31808946

Citation

Haskovic, Minela, et al. "Pathophysiology and Targets for Treatment in Hereditary Galactosemia: a Systematic Review of Animal and Cellular Models." Journal of Inherited Metabolic Disease, vol. 43, no. 3, 2020, pp. 392-408.
Haskovic M, Coelho AI, Bierau J, et al. Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models. J Inherit Metab Dis. 2020;43(3):392-408.
Haskovic, M., Coelho, A. I., Bierau, J., Vanoevelen, J. M., Steinbusch, L. K. M., Zimmermann, L. J. I., Villamor-Martinez, E., Berry, G. T., & Rubio-Gozalbo, M. E. (2020). Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models. Journal of Inherited Metabolic Disease, 43(3), 392-408. https://doi.org/10.1002/jimd.12202
Haskovic M, et al. Pathophysiology and Targets for Treatment in Hereditary Galactosemia: a Systematic Review of Animal and Cellular Models. J Inherit Metab Dis. 2020;43(3):392-408. PubMed PMID: 31808946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models. AU - Haskovic,Minela, AU - Coelho,Ana I, AU - Bierau,Jörgen, AU - Vanoevelen,Jo M, AU - Steinbusch,Laura K M, AU - Zimmermann,Luc J I, AU - Villamor-Martinez,Eduardo, AU - Berry,Gerard T, AU - Rubio-Gozalbo,M Estela, Y1 - 2020/01/14/ PY - 2019/08/16/received PY - 2019/11/25/revised PY - 2019/12/03/accepted PY - 2019/12/7/pubmed PY - 2021/8/24/medline PY - 2019/12/7/entrez KW - animal models KW - cellular models KW - hereditary galactosemia KW - pathophysiology KW - treatment targets SP - 392 EP - 408 JF - Journal of inherited metabolic disease JO - J Inherit Metab Dis VL - 43 IS - 3 N2 - Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets. SN - 1573-2665 UR - https://www.unboundmedicine.com/medline/citation/31808946/Pathophysiology_and_targets_for_treatment_in_hereditary_galactosemia:_A_systematic_review_of_animal_and_cellular_models_ L2 - https://doi.org/10.1002/jimd.12202 DB - PRIME DP - Unbound Medicine ER -