Disease and subtype specific signatures enable precise diagnosis of the mucopolysaccharidoses

Expanding treatments for the mucopolysaccharidoses-a family of genetic disorders-place unprecedented demands for accurate, timely diagnosis because best outcomes are seen with early initiation of appropriate therapies. Here we sought to improve the diagnostic odyssey by measuring specific glycosaminoglycan fragments with terminal residues complicit with the genetic defect resulting in precise diagnosis rather than the usual first-line, ambiguous total glycosaminoglycan determinations that return poor diagnostic yield.

A derivatizing reagent was added to urine aliquots (0.5 μmol creatinine) before separation of the glycosaminoglycan fragments by liquid chromatography and quantification with electrospray ionization-tandem mass spectrometry using multiple reaction monitoring for 10 targeted fragments plus the internal standard.

All 93 mucopolysaccharidosis patients were correctly identified as 1 of 10 subtypes from a total of 723 de-identified subjects-blinded to diagnosis-based on the presence of specific "signature" glycosaminoglycan fragments. Employing reference intervals calculated from 630 unaffected urines, with 99% confidence intervals, provided a laboratory test with 100% specificity and sensitivity.

This novel urine assay allows diagnosis of 10 mucopolysaccharidosis subtypes in a single test. The precise quantification of unique glycosaminoglycan fragments also enables longitudinal biochemical monitoring following therapeutic interventions.