title: Newborn screening for mucopolysaccharidoses: a pilot study of measurement of glycosaminoglycans by tandem mass spectrometry.
abstract: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis.
  
  
  
  This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median + 7× MAD from general newborns.
  
  
  
  The cutoffs were as follows: HS-0S > 90 ng/mL; HS-NS > 23 ng/mL, DS > 88 ng/mL; mono-sulfated KS > 445 ng/mL; di-sulfated KS > 89 ng/mL and ratio di-KS in total KS > 32 %. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS, and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03 % based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9 % based upon a combination of HS-0S and HS-NS.
  
  
  
  Combination of levels of two or more different GAGs improves separation of MPS patients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.
authors.affiliation: Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA.|Department of Biological Sciences, University of Delaware, Newark, DE, USA.
authors.forename: Francyne
authors.initials: F
authors.lastname: Kubaski
authors.affiliation: Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA.|Department of Biological Sciences, University of Delaware, Newark, DE, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mason
authors.affiliation: Department of Pediatrics, Nagasaki University, Nagasaki, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakatomi
authors.affiliation: Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Shintaku
authors.affiliation: Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Laboratory Genetic Metabolic Diseases Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Naomi N
authors.initials: NN
authors.lastname: van Vlies
authors.affiliation: Willink Biochemical Genetics Unit Regional Genetics Laboratory Genetic Medicine, St Mary's Hospital Manchester, Manchester, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Church
authors.affiliation: Medical Genetics Service, HCPA, Dep. Genetics, UFRGS, and INAGEMP, Porto Alegre, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Department of Pediatrics, Shimane University, Izumo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Shimane University, Izumo, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Medical Education Development Center, Gifu University, Gifu, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Gifu University, Yanagido-1-1, Gifu, 501-1194, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Orii
authors.affiliation: Department of Pediatrics, Gifu University, Yanagido-1-1, Gifu, 501-1194, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
authors.affiliation: Department of Pediatrics, Saint Louis University, St. Louis, MO, USA.|Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Montaño
authors.affiliation: Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, 19899, DE, USA. stomatsu@nemours.org.|Department of Pediatrics, Shimane University, Izumo, Japan. stomatsu@nemours.org.|Department of Pediatrics, Gifu University, Yanagido-1-1, Gifu, 501-1194, Japan. stomatsu@nemours.org.
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
mesh_terms: D000118:Acetylglucosaminidase / Q000097:blood / Q000378:metabolism; D002810:Chondroitinases and Chondroitin Lyases / Q000097:blood / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D003871:Dermatan Sulfate / Q000097:blood / Q000378:metabolism; D004187:Disaccharides / Q000097:blood / Q000378:metabolism; D006025:Glycosaminoglycans / Q000097:blood / Q000378:metabolism*; D006497:Heparan Sulfate / Q000097:blood / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D009083:Mucopolysaccharidoses / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism; D015997:Neonatal Screening / Q000379:methods; D010865:Pilot Projects; D011133:Polysaccharide-Lyases / Q000097:blood / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D000118:Acetylglucosaminidase; D002810:Chondroitinases and Chondroitin Lyases; D003871:Dermatan Sulfate; D004187:Disaccharides; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D011133:Polysaccharide-Lyases; C086950:keratanase II; C446037:chondroitinase B; C021349:heparitinsulfate lyase