Newborn screening and diagnosis of mucopolysaccharidoses

Mol Genet Metab. Sep-Oct 2013;110(1-2):42-53. doi: 10.1016/j.ymgme.2013.06.007. Epub 2013 Jun 21.


Mucopolysaccharidoses (MPS) are caused by deficiency of lysosomal enzyme activities needed to degrade glycosaminoglycans (GAGs), which are long unbranched polysaccharides consisting of repeating disaccharides. GAGs include: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in combination depending on the specific enzyme deficiency. There are 11 known enzyme deficiencies, resulting in seven distinct forms of MPS with a collective incidence of higher than 1 in 25,000 live births. Accumulation of undegraded metabolites in lysosomes gives rise to distinct clinical syndromes. Generally, the clinical conditions progress if untreated, leading to developmental delay, systemic skeletal deformities, and early death. MPS disorders are potentially treatable with enzyme replacement therapy or hematopoietic stem cell transplantation. For maximum benefit of available therapies, early detection and intervention are critical. We recently developed a novel high-throughput multiplex method to assay DS, HS, and KS simultaneously in blood samples by using high performance liquid chromatography/tandem mass spectrometry for MPS. The overall performance metrics of HS and DS values on MPS I, II, and VII patients vs. healthy controls at newborns were as follows using a given set of cut-off values: sensitivity, 100%; specificity, 98.5-99.4%; positive predictive value, 54.5-75%; false positive rate, 0.62-1.54%; and false negative rate, 0%. These findings show that the combined measurements of these three GAGs are sensitive and specific for detecting all types of MPS with acceptable false negative/positive rates. In addition, this method will also be used for monitoring therapeutic efficacy. We review the history of GAG assay and application to diagnosis for MPS.

Keywords: CF; CNS; CPC; CS; DBS; DMB; DS; ERT; ESI-MS/MS; GAG; GALNS; GUS; Glycosaminoglycans; HPLC; HS; HSCT; KS; LC–MS/MS; MPS; Monitoring; Mucopolysaccharidoses; N-acetylgalactosamine-6-sulfate sulfatase; NBS; Newborn screening; SRT; Tandem mass spectrometry; central nervous system; cetylpyridinium chloride; chondroitin sulfate; cystic fibrosis; dermatan sulfate; dimethylmethylene blue; dried blood spot; electrospray ionization tandem mass spectrometry; enzyme replacement therapy; glycosaminoglycans; hematopoietic stem cell transplantation; heparan sulfate; high performance liquid chromatography; high performance liquid chromatography tandem mass spectrometry; keratan sulfate; mucopolysaccharidoses; newborn screening; substrate reduction therapy; β-glucuronidase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Chondroitin Sulfates / blood
  • Chromatography, High Pressure Liquid
  • Dermatan Sulfate / blood
  • Genetic Testing*
  • Glycosaminoglycans / blood*
  • Glycosaminoglycans / genetics
  • Heparitin Sulfate / blood
  • Humans
  • Hyaluronic Acid / blood
  • Keratan Sulfate / blood
  • Mucopolysaccharidoses / blood*
  • Mucopolysaccharidoses / diagnosis*
  • Mucopolysaccharidoses / genetics
  • Mucopolysaccharidoses / pathology
  • Tandem Mass Spectrometry


  • Glycosaminoglycans
  • Dermatan Sulfate
  • Hyaluronic Acid
  • Chondroitin Sulfates
  • Heparitin Sulfate
  • Keratan Sulfate