Heparan sulfate levels in mucopolysaccharidoses and mucolipidoses

Abstract

Glycosaminoglycans are accumulated in both mucopolysaccharidoses (MPS) and mucolipidoses (ML). MPS I, II, III and VII and ML II and ML III patients cannot properly degrade heparan sulphate (HS). In spite of the importance of HS storage in the metabolic pathway in these diseases, blood and urine HS levels have not been determined systematically using a simple and economical method. Using a new ELISA method using anti-HS antibodies, HS concentrations in blood and urine were determined in MPS and ML II and ML III patients. HS concentrations were determined in 156 plasma samples from MPS I (n = 23), MPS II (n = 26), MPS III (n = 24), MPS IV (n = 62), MPS VI (n = 5), MPS VII (n = 5), ML II (n = 8) and ML III (n = 3), and 205 urine samples from MPS I (n = 33), MPS II (n = 33), MPS III (n = 30), MPS IV (n = 82), MPS VI (n = 7), MPS VII (n = 9), ML II (n = 8) and ML III (n = 3). The ELISA method used monoclonal antibodies against HS. MPS I, II, III and VII and ML II and III patients had significant elevation in plasma HS, compared to the age-matched controls (p < 0.0001). Eighty-three out of 89 (93.3%) of individual values in the above MPS types and ML were above the mean +2SD of the controls. In urine samples, 75% of individual values in patients with those types were above the mean +2SD of the controls. In contrast to the previous understanding of the HS metabolic pathway, plasma HS levels in all five MPS VI and 15% of MPS IV patients were elevated above the mean +2SD of the controls. These findings suggest that HS concentration determined by ELISA, especially in plasma, could be a helpful marker for detection of the most severe MPS I, II, III, VI and VII and ML II, distinguishing them from normal populations.

Chondroitin 6-sulfate as a novel biomarker for mucopolysaccharidosis IVA and VII

“…Additional data from more patients with MPS VII will be required to validate these biomarkers. Blood KS level in control subjects were high during the first 5 years of life and then steadily declined with age before stabilizing in late teenage years, in agreement with prior studies (Tomatsu et al 2005a;Thonar et al 1988). The level of blood KS in patients with MPS IVA was significantly higher than age-matched controls in older children and adults.…”

“…The decreased level of KS in the blood as healthy teenagers move towards adulthood is consistent with the fact that their growth rate begins to decline during this period. In previous studies we showed that blood KS level in severely affected MPS IVA patients less than 10 years old is markedly elevated and that KS level declines to near-normal or normal levels after 15 year of age, following closing of growth plate (Tomatsu et al 2005a(Tomatsu et al , 2010c. In the present study, KS levels are less dramatic and may reflect fewer young patients in this study and/or a cohort of patients with a less severe phenotype.…”

“…The level of blood KS in patients with MPS IVA was significantly higher than age-matched controls in older children and adults. KS in the blood is primarily a result of turnover of cartilage during development (Tomatsu et al 2005a;Thonar et al 1988). Elongation of the long bones during growth occurs through a process of endochondral ossification.…”

“…Elevation of total urinary GAG or KS in the blood and/ or urine of MPS IVA patients has been detected by colorimetric analysis using dimethylmethylene blue (Melrose and Ghosh 1988), ELISA (Tomatsu et al 2004(Tomatsu et al , 2005a, and HPLC methods (Linhardt et al 1989;Whitham et al 1999). We developed a rapid, reproducible, sensitive, and specific assay system in which the disaccharides produced from DS, HS, and KS in the blood, urine, and dried blood spot (DBS) samples are analyzed simultaneously by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Oguma et al 2007a, b;Tomatsu et al 2010aTomatsu et al , b, 2013aHintze et al 2011).…”

Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age

“…The storage materials, heparan sulfate and dermatan sulfate, accumulate within lysosomes and are present in plasma, urine, and cerebral spinal fluid (Neufeld and Muenzer 2001;Tomatsu et al 2005). Although patients with MPS II appear normal at birth, the disease is progressive and signs and symptoms usually become apparent during early childhood (Wraith et al 2008).…”