Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I

Abstract

Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by deficiency of alpha-L-iduronidase leading to accumulation of its catabolic substrates, dermatan sulfate (DS) and heparan sulfate (HS), in lysosomes. This results in progressive multiorgan dysfunction and death in early childhood. The recent success of enzyme replacement therapy (ERT) for MPS I highlights the need for biomarkers that reflect response to such therapy. To determine which biochemical markers are better, we determined serum and urine DS and HS levels by liquid chromatography tandem mass spectrometry in ERT-treated MPS I patients. The group included one Hurler, 11 Hurler/Scheie, and two Scheie patients. Seven patients were treated from week 1, whereas the other seven were treated from week 26. Serum and urine DS (DeltaDi-4S/6S) and HS (DeltaDiHS-0S, DeltaDiHS-NS) were measured at baseline, week 26, and week 72. Serum DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS levels decreased by 72%, 56%, and 56%, respectively, from baseline at week 72. Urinary glycosaminoglycan level decreased by 61.2%, whereas urine DeltaDi-4S/6S, DeltaDiHS-0S, and DeltaDiHS-NS decreased by 66.8%, 71.8%, and 71%, respectively. Regardless of age and clinical severity, all patients showed marked decrease of DS and HS in blood and urine samples. We also evaluated serum DS and HS from dried blood-spot samples of three MPS I newborn patients, showing marked elevation of DS and HS levels compared with those in control newborns. In conclusion, blood and urine levels of DS and HS provide an intrinsic monitoring and screening tool for MPS I patients.

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

“…These findings now make sense in light of the data reported here, suggesting significant secondary dermatan sulfate storage in Sanfilippo cells. Our findings also clarify results from a recently reported diagnostic approach where unexplained elevations of chondroitin/dermatan sulfate disaccharides were detected in Sanfilippo patient serum and urine after enzymatic digests of purified glycosaminoglycans (45). Our findings also suggest that diagnostic approaches that are able to detect dermatan sulfate levels as well as heparan sulfate in Sanfilippo may provide a more accurate index for cellular stress and offer a superior indication of disease progression and prognosis.…”

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

“…After digestion, the samples are loaded into the LC-MS/MS for quantitation, and the results are compared with control samples (Figure 2). The LC-MS/MS method for analysis of disaccharides not only shows sensitivity and specificity for detecting all subtypes of MPS but also can monitor therapeutic efficacy in MPS patients and animal models [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. This method has an advantage of being both GAG-specific and quantitative.…”

Long-term follow up of post-hematopoietic stem cell transplantation for Hurler syndrome: Clinical biochemical and pathological improvements

“…The patient here treated by HSCT can speak, read, and write at an age-appropriate level (8th grade), and is mainstreamed at school. Many children with MPS I develop a short body trunk and a maximum stature of less than 120 cm [26,31]. Additional effectiveness is demonstrated physically; the patient is 162 cm tall and weighs 55.0 kg.…”

“…ΔDiHS-NS of untreated MPS I patients is 10.8 times higher than normal controls. ΔDi-4S (DS) of untreated MPS I patients is 5.64 times higher than normal controls [30,31].…”