2. Academic Validation
  3. Glycosphingolipid synthesis is impaired in SLC35A2-CDG and improves with galactose supplementation

Glycosphingolipid synthesis is impaired in SLC35A2-CDG and improves with galactose supplementation

  • Cell Mol Life Sci. 2025 Jun 27;82(1):257. doi: 10.1007/s00018-025-05759-w.
Andrea Jáñez Pedrayes 1 2 3,  Sam De Craemer 1 2,  Jakub Idkowiak 4,  Dries Verdegem 1 2,  Christian Thiel 5,  Rita Barone 6 7,  Mercedes Serrano 8,  Tomáš Honzík 9,  Eva Morava 10,  Pieter Vermeersch 11 12,  François Foulquier 13,  Willy Morelle 13,  Johannes V Swinnen 4,  Daisy Rymen 14,  David Cassiman 15 16 17,  Bart Ghesquière # 1 2,  Peter Witters # 18 19
Affiliations

Affiliations

  • 1 Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium.
  • 2 Metabolomics Expertise Center, Center for Cancer Biology VIB, Leuven, 3000, Belgium.
  • 3 Department of Development and Regeneration, KU Leuven, Leuven, 3000, Belgium.
  • 4 Laboratory of Lipid Metabolism and Cancer, Department of Oncology, Leuven Cancer Institute (LKI) and Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, 3000, Belgium.
  • 5 Center for Pediatric and Adolescent Medicine, Department Pediatrics I, Heidelberg University, 69120, Heidelberg, Germany.
  • 6 Child Neurology and Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, 95131, Italy.
  • 7 Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, 94018, Italy.
  • 8 Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, 08950, Spain.
  • 9 Department of Paediatrics and Inherited Metabolic Disorders, First Medical Faculty, Charles University and General University Hospital in Prague, Prague 2, CZ-121 08, Czech Republic.
  • 10 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 11 Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, 3000, Belgium.
  • 12 Department of Cardiovascular Sciences, KU Leuven, Leuven, 3000, Belgium.
  • 13 UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, CNRS, University of Lille, Lille, F-59000, France.
  • 14 Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, Leuven, 3000, Belgium.
  • 15 Department of Hepatology, University Hospitals Leuven, Leuven, 3000, Belgium.
  • 16 Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, 3000, Belgium.
  • 17 Metabolic Center, University Hospitals Leuven, Leuven, 3000, Belgium.
  • 18 Department of Development and Regeneration, KU Leuven, Leuven, 3000, Belgium. peter.witters@uzleuven.be.
  • 19 Center for Metabolic Diseases, Department of Paediatrics, University Hospitals Leuven, Leuven, 3000, Belgium. peter.witters@uzleuven.be.
  • # Contributed equally.
PMID: 40576648 DOI: 10.1007/s00018-025-05759-w
Abstract

SLC35A2-CDG is an X-linked congenital disorder of glycosylation (CDG), characterized by defective UDP-galactose transport into the Golgi and endoplasmic reticulum and consequent insufficient galactosylation of glycans. Clinically, this translates into a range of predominantly neurological symptoms. Although the pathomechanism of this disorder is not fully understood, oral galactose supplementation has led to clinical and biochemical improvement in some patients. Here, we show that protein glycosylation (N- and O-linked) was only minimally disturbed in SLC35A2-CDG patient-derived fibroblasts. However, lipid glycosylation was significantly impaired, with accumulation of glucosylceramide and deficiency of digalactosylated glycosphingolipids (GSLs) and complex gangliosides. Galactose supplementation increased UDP-galactose, its transport into the Golgi, and improved deficient GSL synthesis through direct incorporation of the provided galactose. This improved GSL homeostasis in all patient-derived fibroblasts and in another SLC35A2 deficient cell model (CHO-Lec8). Additionally, SLC35A2-CDG serum analysis identified hydroxylated GSLs, particularly GM3, as potential disease biomarkers. Given the essential role of gangliosides in central nervous system function, their deficiency is likely a key factor in the neurological involvement of this disorder. These findings pave the way for new nutritional therapies with GSL supplements and highlight the importance of studying lipid glycosylation to better understand the complex pathophysiology of CDG.

Keywords

CDG; GSL; Gangliosides; Glycosphingolipids; SLC35A2-CDG; Tracer metabolomics.

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