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Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB

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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.

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Acknowledgements

We would like to thank Dr. Kevin Flanigan, Dr. Kim McBride, Ms. Krista Kunkler for sharing the serum samples collected from MPS III patients. This study was supported by donations from families and friends of patients with Sanfilippo syndromes through LivLife Foundation, Regan’s Hope Foundation, and Ben’s Dream – Sanfilippo Research Foundation. HF, AM, RP and DM were also supported by a translational research grant from NIH/NINDS (U01NS069626). DM and HF were also supported by a grant from NIH/NCI (R01CA172713), and are co-inventors of Abeona Therapeutics’ ABO-101 and ABO-102 and hold stocks of the company. RM and SS are employees of Metabolon, Inc. and, as such, have affiliations with or financial involvement with Metabolon, Inc. The authors have no other relevant conflict of interest.

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  1. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    Haiyan Fu, Aaron S. Meadows, Ricardo J. Pineda & Douglas M. McCarty

  2. Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

    Haiyan Fu & Douglas M. McCarty

  3. Metabolon, Inc., Durham, NC, USA

    Robert P. Mohney & Steve Stirdivant

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  1. Haiyan Fu
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Fu, H., Meadows, A.S., Pineda, R.J. et al. Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB. Metab Brain Dis 32, 1403–1415 (2017). https://doi.org/10.1007/s11011-017-0009-1

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