Abstract
Purpose: The urinary glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc4), is a biomarker of glycogen accumulation and tissue damage and is elevated in patients with Pompe disease. We report baseline urinary Glc4 concentrations for patients with classic infantile-onset or late-onset Pompe disease, and those with a pseudodeficiency of acid alpha-glucosidase (GAA), identified through newborn screening (NBS) in Taiwan.
Methods: Infants identified through NBS with (1) classic infantile-onset Pompe disease (NBS-IOPD) (n = 7) defined as patients with evidence for hypertrophic cardiomyopathy by EKG, X-ray, and echocardiogram, (2) a late-onset phenotype (NBS-LOPD) (n = 13) defined as patients without evidence for cardiomyopathy, (3) a GAA pseudodeficiency (n = 58), and (4) one patient with LOPD diagnosed in infancy due to family history were consented to the study. Four infants diagnosed after the onset of clinical symptoms (CLIN-IOPD) were included for comparison. Glc4 concentrations in dried urine samples on filter paper were determined using tandem mass spectrometry.
Results: Baseline Glc4 concentrations were at or above the 90th centile of the age-matched reference range for the NBS-IOPD cohort. The median Glc4 level for this group was lower than that of the CLIN-IOPD group, although not at the level of significance (p = 0.07), but was significantly higher than that of the NBS-LOPD group (p < 0.05). Baseline Glc4 was not elevated for the NBS-LOPD and GAA pseudodeficiency cohorts and remained low for late-onset patients that did not require treatment before the age of three years.
Conclusion: Baseline urinary Glc4 is elevated in neonates with infantile-onset Pompe disease identified through NBS.
Competing interests: None declared
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References
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Acknowledgments
The authors would like to thank the patients and their families for their participation in this study. The authors would also like to acknowledge Genzyme, A Sanofi Company for previous grant support for the development and evaluation of Glc4 as a biomarker in Pompe disease at DUMC and for support of the Taiwan pilot newborn screening program for Pompe disease.
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Communicated by: Verena Peters
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334361_1_En_366_MOESM2_ESM.docx
Figure Supplemental Digital Content 2. Comparison of urinary Glc4 and Ck values at initial evaluation (baseline) following an abnormal newborn screen (see Table, Supplemental Digital Content 1 for ages) for patients who were confirmed with infantile-onset Pompe disease (NBS-IOPD) shown as red squares or with a late-onset phenotype (NBS-LOPD). For the NBS-LOPD group, those who were treated before the age of 3 years are shown as blue triangles (NBS-LOPD-Early Treated) and those who were not treated before the age of 3 years are shown as open diamonds (NBS-LOPD-Group 2). Dashed lines represent the upper limit of the reference ranges. The arrow shows patient NBS9, born at 29 weeks gestation
334361_1_En_366_MOESM3_ESM.docx
Figure Supplemental Digital Content 3. (a) Urinary Glc4 concentrations with age for the four late onset patients identified through newborn screening who were treated at or before the age of 3 years (NBS-LOPD-Early Treated). The dotted lines represent the upper limit of the age-matched reference ranges. The solid black vertical lines represent the age at which treatment was initiated. The details on motor development and serum CK have been reported (Chien et al. 2011). Patients NBSL-1 and NBS-L6 had normal CK levels prior to treatment with ERT, whereas patients NBS-L3 and NBS-L9 had elevated CK. (b) Urinary Glc4 concentrations with age for 7 of 9 NBS-LOPD-Group 2 patients and patient L14 who were not treated at or before the age of 3 years. Monitoring data was not available for NBS-L5 and NBS-L8
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Synopsis
The glucose tetrasaccharide biomarker, Glc4, determined in dried urine spots, was elevated in neonates with infantile-onset Pompe disease identified through newborn screening, compared with infants with a late-onset phenotype or a pseudodeficiency of acid alpha-glucosidase.
Details of Funding
This study was funded in part by Genzyme, a Sanofi Company
Compliance with Ethics Guidelines
Conflict of Interest
Yin-Hsui Chien reports receiving research grant support, honoraria, and travel support from Genzyme, a Sanofi Company and BioMarin Pharmaceutical Inc.
Wuh-Liang Hwu reports receiving research grant support, honoraria, and travel support from Genzyme, a Sanofi Company and BioMarin Pharmaceutical Inc.
Ni-Chung Lee reports receiving travel support from Genzyme, a Sanofi Company.
Shu-Chuan Chiang reports receiving travel support from Genzyme, a Sanofi Company.
Sarah P. Young reports receiving research grant support from Genzyme, a Sanofi Company and Amicus Therapeutics.
David S. Millington reports receiving research grant support from Genzyme, a Sanofi Company and BioMarin Pharmaceutical Inc. David S. Millington was a member of the science advisory board of and received stock options from Advanced Liquid Logics, LLC.
Priya S. Kishnani reports receiving research grant support and honoraria from Genzyme, a Sanofi Company and Amicus Therapeutics, and consulting fees from Genzyme, a Sanofi Company. P.S. Kishnani is a member of the Pompe Disease and the Gaucher Disease Registry Advisory Boards for Genzyme, a Sanofi Company.
Haoyue Zhang reports receiving research grant support from Genzyme, a Sanofi Company and BioMarin Pharmaceutical Inc.
Jennifer L. Goldstein reports receiving research grant support from Genzyme, a Sanofi Company.
P. Brian Smith, Adviye A. Tolun, and Amie E. Vaisnins declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Institutional Review Boards of National Taiwan University Hospital and Duke University Health System) and with the Helsinki Declaration of 1075, as revised in 2000 (5). Informed consent was obtained from parents of all patients.
Author Contributions
Yin-Hsiu Chien and Wuh-Liang Hwu planned the study, coordinated the collection of dried urine samples and the compliance with National Taiwan University Hospital Institutional Review Board, and participated in the data analysis and preparation and final approval of the manuscript.
Sarah P. Young supervised the analysis of Glc4, performed data analysis and interpretation, and participated in the preparation of the manuscript and final approval of the manuscript.
Jennifer Goldstein ensured compliance with Duke Health System Institutional Review Board and participated in the preparation and final approval of the manuscript.
P. Brian Smith performed statistical analysis of the data and participated in the preparation and final approval of the manuscript
Ni-Chung Lee contributed to patient care and data collection, revision, and final approval of the manuscript.
Shu-Chuan Chiang contributed to sample management, revision, and final approval of the manuscript.
Adviye A. Tolun, Haoyue Zhang, and Amie E. Vaisnins conducted Glc4 analysis and data processing and assisted with the data analysis and final approval of the manuscript.
David S. Millington and Priya S. Kishnani participated in data interpretation and the preparation and final approval of the manuscript.
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Chien, YH. et al. (2014). Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 19. JIMD Reports, vol 19. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_366
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DOI: https://doi.org/10.1007/8904_2014_366
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