Disease-specific non–reducing end carbohydrate biomarkers for mucopolysaccharidoses

Lawrence, Roger; Brown, Jillian R.; Al-Mafraji, Kanar; Lamanna, William C.; Beitel, James R.; Boons, Geert‐Jan; Esko, Jeffrey D.; Crawford, Brett E.

doi:10.1038/nchembio.766

Cited by 132 publications

(150 citation statements)

References 42 publications

(56 reference statements)

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“…In 2012, Lawrence et al showed that another new method with enzyme digestion can detect DS and HS by analysis of non-reducing ends of urinary GAGs by LC-MS/MS. Currently, this method does not provide a measure of non-reducing ends for KS [51]. Overall, establishment of methods to measure disaccharides makes it feasible to interpret individual GAG values, leading to feasible and accurate diagnosis, prognosis, and monitoring therapies for MPS.…”

Section: History Of Gag Assay By Tandem Mass Spectrometry (Ms/ms)mentioning

confidence: 99%

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Tomatsu

Shimada

Mason

et al. 2015

Molecular Genetics and Metabolism

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Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have been developed to measure specific GAGs in various human samples to investigate diagnosis, prognosis, pathogenesis, GAG interaction with other molecules, and monitoring therapeutic efficacy. We OPEN ACCESSMetabolites 2014, 4 656 established ELISA, liquid chromatography tandem mass spectrometry (LC-MS/MS), and an automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) to identify epitopes (ELISA) or disaccharides (MS/MS) derived from different GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate). These methods have a high sensitivity and specificity in GAG analysis, applicable to the analysis of blood, urine, tissues, and cells. ELISA is feasible, sensitive, and reproducible with the standard equipment. HT-MS/MS yields higher throughput than conventional LC-MS/MS-based methods while the HT-MS/MS system does not have a chromatographic step and cannot distinguish GAGs with identical molecular weights, leading to a limitation of measurements for some specific GAGs. Here we review the advantages and disadvantages of these methods for measuring GAG levels in biological specimens. We also describe an unexpected secondary elevation of keratan sulfate in patients with MPS that is an indirect consequence of disruption of catabolism of other GAGs.

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Section: History Of Gag Assay By Tandem Mass Spectrometry (Ms/ms)mentioning

confidence: 99%

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Tomatsu

Shimada

Mason

et al. 2015

Molecular Genetics and Metabolism

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“…Urinary GAGs and specific lysosomal enzymes have been the only biomarkers for MPS, although recent studies identified serum heparin cofactor II-thrombin (HCII-T) as a biomarker for MPS I, II, and III; 34 dipeptidyl peptidase IV (DPP-IV) for MPS I, II, III, IVA, and VI; 35 and recently the potential of disease-specific non-reducing end carbohydrate biomarkers for MPS. 36 However, there are currently no specific biomarkers for MPS corresponding to neurological disease severity or therapeutic responsiveness. The critical challenge for finding CNS-specific biomarkers stems from limited access to the CNS tissues of patients, especially at early disease stages.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in a-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-monthold MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.

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“…Thus, GRIL-LC/MS provides a way to determine not only the disaccharide composition of GAG chains, but also the total amount of GAG in a sample. Analysis of GAGs from MPS patients demonstrated the utility of GRIL-LC/MS for determining total storage and uncovered one or more additional peaks of [ 12 C 6 ]anilinetagged material that varied in elution position and mass dependent upon the MPS disorder [18]. Mass spectral analysis revealed that the additional peaks were derived from the nonreducing end of GAG chains.…”

Section: Sensi-pro Assaymentioning

confidence: 99%

“…In this review, we summarize various approaches to glycan-based biomarker development for MPS with a discussion of a new approach that has identified unique glycan NRE biomarkers [18]. We refer the reader to other recent reviews that cover other types of biomarkers based on enzyme mass, enzyme activity and pathological consequences of disease [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Glycan-based biomarkers for the mucopolysaccharidoses

Brown

Lawrence

Langford-Smith

et al. 2011

Molecular Genetics and Metabolism

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The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/ dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.

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Disease-specific non–reducing end carbohydrate biomarkers for mucopolysaccharidoses

Cited by 132 publications

References 42 publications

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Glycan-based biomarkers for the mucopolysaccharidoses

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