title: Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB.
abstract: The monogenic defects in specific lysosomal enzymes in mucopolysaccharidosis (MPS) III lead to lysosomal storage of glycosaminoglycans and complex CNS and somatic pathology, for which the detailed mechanisms remain unclear. In this study, serum samples from patients with MPS IIIA (age 2-9 yr) and MPS IIIB (2-13 yr) and healthy controls (age 2-9 yr) were assayed by global metabolomics profiling of 658 metabolites using mass spectrometry. Significant alterations were detected in 423 metabolites in all MPS III patients, of which 366 (86.5%) decreased and 57 (13.5%) increased. Similar profiles were observed when analyzing data from MPS IIIA and MPS IIIB samples separately, with only limited age variations in 36 metabolites. The observed metabolic disturbances in MPS III patients involve virtually all major pathways of amino acid (101/150), peptide (17/21), carbohydrate (19/23), lipid (221/325), nucleotide (15/25), energy (8/9), vitamins and co-factors (8/21), and xenobiotics (34/84) metabolism. Notably, detected serum metabolite decreases involved all key amino acids, all major neurotransmitter pathways, and broad neuroprotective compounds. The elevated metabolites are predominantly lipid derivatives, and also include cysteine metabolites and a fibrinogen peptide fragment, consistent with the status of oxidative stress and inflammation in MPS III. This study demonstrates that the lysosomal glycosaminoglycans storage triggers profound metabolic disturbances in patients with MPS III disorders, leading to severe functional depression of virtually all metabolic pathways, which emerge early during the disease progression. Serum global metabolomics profiling may provide an important and minimally invasive tool for better understanding the disease mechanisms and identification of potential biomarkers for MPS III.
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA. haiyan.fu@nationwidechildrens.org.|Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA. haiyan.fu@nationwidechildrens.org.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Meadows
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Pineda
authors.affiliation: Metabolon, Inc., Durham, NC, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Metabolon, Inc., Durham, NC, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Stirdivant
authors.affiliation: Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: McCarty
mesh_terms: D000375:Aging / Q000378:metabolism; D000596:Amino Acids / Q000097:blood; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008659:Metabolic Diseases / Q000175:diagnosis / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D055432:Metabolomics / Q000379:methods*; D009084:Mucopolysaccharidosis III / Q000175:diagnosis / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D006025:Glycosaminoglycans; D018377:Neurotransmitter Agents
keywords: Global metabolomics profiling; Lysosomal storage diseases; MPS iii; Mass spectrometry; Metabolic impairments