keratan-sulfate and Mucopolysaccharidosis-III

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA.

Topics: Bone and Bones; Cartilage; Chondroitin Sulfates; Disease Management; Early Diagnosis; Enzyme Replacement Therapy; Genetic Therapy; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Humans; Keratan Sulfate; Lysosomes; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Nanomedicine; Osteochondrodysplasias; Quality of Life

To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls. Untreated MPS IVA had higher levels of KS in blood and urine than age-matched controls. The ratio of blood di-sulfated KS/total KS in untreated MPS IVA was constant and higher than that in controls for children up to 10 years of age. The ratio of urine di-sulfated KS/total KS in untreated MPS IVA was also higher than that in age-matched controls, but the ratio in untreated MPS IVB was lower than controls. ERT reduced blood DS and HS in MPS II, and urine KS in MPS IVA patients, although GAGs levels remained higher than the observed in age-matched controls. ERT did not change blood KS levels in MPS IVA. MPS VI under ERT still had an elevation of urine DS level compared to age-matched controls. There was a positive correlation between blood and urine KS in untreated MPS IVA patients but not in MPS IVA patients treated with ERT. Blood and urine KS levels were secondarily elevated in MPS II and VI, respectively. Overall, measurement of GAG levels in blood and urine is useful for diagnosis of MPS, while urine KS is not a useful biomarker for monitoring therapeutic efficacy in MPS IVA.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Keratan Sulfate; Male; Mucopolysaccharidoses; Mucopolysaccharidosis II; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Tandem Mass Spectrometry; Young Adult

The physiological relevance of the ability of beta-N-acetylhexosaminidase A to liberate N-acetylglucosamine 6-sulfate from polymeric keratan sulfate was investigated. Upon intravenous injection into rats of [35S]sulfate-labeled proteokeratan sulfate up to 25% of the radioactivity excreted with the urine were identified as N-acetyl-glucosamine 6-sulfate. Within 24 h, however, excretion of inorganic sulfate rose at the expense of the sulfated monosaccharide. Upon incubation in vitro of liver lysosomes from rats treated with proteokeratan sulfate, inorganic sulfate and minor amounts of sulfated monosaccharide were found in the incubation fluid. Cultured rat peritoneal macrophages ingested proteokeratan sulfate with a clearance rate of 6-9 micrograms X h-1 X mg cell protein-1 and degraded it rapidly. Inorganic sulfate but not N-acetylglucosamine 6-sulfate was delivered to the culture medium. During a chase period the amount of intracellular N-acetylglucosamine 6-sulfate fell, and a corresponding amount of sulfate could be found extracellularly. Significant amount of N-acetylglucosamine 6-sulfate were only found in the culture medium when the cells were challenged with zymosan. These results suggest that N-acetylglucosamine 6-sulfate is a physiological intermediate during the degradation of keratan sulfate, but is usually hydrolyzed intralysosomally by N-acetylglucosamine-6-sulfate sulfatase. Genetic deficiency of the sulfatase in humans therefore results in excessive excretion of the sulfated amino sugar but not of keratan sulfate.

Topics: Acetylglucosamine; Animals; Chondroitin Sulfate Proteoglycans; Endocytosis; Glucosamine; Glycosaminoglycans; Humans; In Vitro Techniques; Keratan Sulfate; Lumican; Lysosomes; Macrophages; Male; Mucopolysaccharidosis III; Proteoglycans; Rats; Rats, Inbred Strains; Sulfatases

N-Acetylglucosamine 6-sulfate (GlcNAc6S) has been isolated from human urine and shown to be present at levels of approximately 0.02 and 14 mg/mmole creatinine in urine from normal individuals and a mucopolysaccharidosis type IIID (MPS IIID) patient respectively. We propose that the greater than 500-fold elevation of GlcNAc6S in urine from the MPS IIID patient indicates that this sulfated monosaccharide is also a substrate for the sulfatase deficient in MPS IIID patients. We further propose that part, if not all, of the GlcNAc6S found in urine may be produced from the cleavage by beta-N-acetylhexosaminidase A of non-reducing end beta-linked GlcNAc6S residues of keratan sulfate and/or sulfated glycoproteins.

Topics: Acetylglucosamine; Chromatography; Galactosamine; Glucosamine; Heparitin Sulfate; Humans; Keratan Sulfate; Mucopolysaccharidoses; Mucopolysaccharidosis III; Mucopolysaccharidosis VI

[1-3H]Galactitol-6-sulfate, N- [1-3H]acetylgalactosaminitol-6-sulfate, N-[1-3H]acetylglucosaminitol-6-sulfate, N-acetylglucosamine-6-sulfate, and 6-sulfated tetrasaccharides from chondroitin-6-sulfate have been used for the measurement of 6-sulfatase activity of extracts of normal skin fibroblasts and of fibroblasts cultured from patients with genetic mucopolysaccharidoses. With these substrates, extracts of fibroblasts derived from Morquio patients lack or have greatly reduced activities for galactitol-6-sulfate, N-acetylgalactosaminitol-6-sulfate, and 6-sulfated tetrasaccharides but have normal activity for N-acetylglucosamine-6-sulfate and its alditol; those derived from a patient with a newly discovered mucopolysaccharidosis have greatly reduced activity for N-acetylglucosamine-6-sulfate and its alditol but normal activity for galactitol-6-sulfate, N-acetylgalactosaminitol-6-sulfate, and the 6-sulfated tetrasaccharides. These findings demonstrate the existence of two different hexosamine-6-sulfate sulfatases, specific for the glucose or galactose configuration of their substrates. Their respective deficiencies, causing inability to degrade keratan sulfate and heparan sulfate in one case and keratan sulfate and chondroitin-6-sulfate in the other, are responsible for different clinical phenotypes.

Topics: Acetylgalactosamine; Acetylglucosamine; Cells, Cultured; Child, Preschool; Chondroitin Sulfates; Chondroitinsulfatases; Fibroblasts; Galactitol; Heparitin Sulfate; Humans; Hydrogen-Ion Concentration; Keratan Sulfate; Male; Mucopolysaccharidoses; Mucopolysaccharidosis III; Mucopolysaccharidosis IV; Skin; Substrate Specificity; Sulfatases