What is the significance of elevated urinary heparan sulfate and dermatan sulfate levels?

From the Guidelines

Increased urinary heparan sulfate and dermatan sulfate is a strong indicator of a mucopolysaccharidosis (MPS) disorder, specifically suggesting the presence of MPS II (Hunter syndrome) as evidenced by the accumulation of these glycosaminoglycans due to the deficiency of the lysosomal enzyme iduronate-2-sulfatase 1. The presence of elevated heparan sulfate and dermatan sulfate in urine is a key diagnostic marker for MPS disorders, which are a group of inherited lysosomal storage diseases.

• These disorders result from deficiencies in enzymes needed to break down glycosaminoglycans (GAGs), including heparan sulfate and dermatan sulfate.
• When these substances cannot be properly degraded, they accumulate in cells throughout the body, causing progressive damage to tissues and organs.
• Specific MPS types associated with elevated heparan sulfate include MPS I (Hurler, Hurler-Scheie, Scheie syndromes), MPS II (Hunter syndrome), and MPS III (Sanfilippo syndrome).
• Elevated dermatan sulfate is seen in MPS I, MPS II, MPS VI (Maroteaux-Lamy syndrome), and MPS VII (Sly syndrome). Diagnosis of the specific MPS type requires additional testing, including:
• Enzyme activity assays to determine the level of enzyme deficiency
• Genetic testing to identify the specific enzyme deficiency and confirm the diagnosis Treatment options vary by MPS type but may include:
• Enzyme replacement therapy, such as idursulfase (Elaprase) for MPS II 1
• Hematopoietic stem cell transplantation
• Supportive care to manage symptoms and prevent complications
• Emerging gene therapies, which are being researched as potential treatments for MPS disorders Early diagnosis and intervention are crucial for managing symptoms and potentially slowing disease progression, as evidenced by the importance of evidence-based recommendations for the treatment of rare diseases like MPS II 1.

From the FDA Drug Label

Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes of various cell types. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, GAG progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction. Decreases in urinary GAG levels were observed following treatment with ELAPRASE.

Increased urinary heparan sulfate and dermatan sulfate may indicate a buildup of these glycosaminoglycans (GAG) in the body, which can be a sign of a lysosomal storage disorder such as Hunter syndrome or Mucopolysaccharidosis I.

• The accumulation of GAG can lead to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction.
• Enzyme replacement therapies like idursulfase (ELAPRASE) or laronidase (ALDURAZYME) may help reduce urinary GAG levels by providing exogenous enzyme for uptake into cellular lysosomes and increasing the catabolism of GAG 2, 3.

From the Research

Increased Urinary Heparan Sulfate and Dermatan Sulfate

• Increased urinary heparan sulfate and dermatan sulfate can be indicative of mucopolysaccharidosis type I (MPS I) or mucopolysaccharidosis type II (MPS II), which are autosomal recessive or X-linked lysosomal storage disorders, respectively 4, 5, 6, 7.
• These disorders are caused by deficiencies in specific enzymes, leading to the accumulation of dermatan sulfate and heparan sulfate in lysosomes, resulting in progressive multiorgan dysfunction 4, 5.
• The accumulation of these glycosaminoglycans (GAGs) can lead to various clinical manifestations, including skeletal disease, upper airway disease, cardiac disease, and cognitive impairment 6.
• Enzyme replacement therapy (ERT) has been shown to reduce the levels of dermatan sulfate and heparan sulfate in blood and urine, and can improve clinical outcomes in patients with MPS I and MPS II 4, 8, 6, 7.
• The measurement of urinary GAGs, including dermatan sulfate and heparan sulfate, can be used as a diagnostic tool and to monitor the efficacy of treatment 4, 8, 6.

Biomarkers for Mucopolysaccharidosis

• Dermatan sulfate and heparan sulfate can serve as biomarkers for MPS I and MPS II, reflecting the accumulation of these GAGs in tissues and organs 4, 5.
• The levels of these biomarkers can be measured in blood and urine using various analytical techniques, including liquid chromatography tandem mass spectrometry and HPLC-MS/MS analysis 4, 8.
• The use of these biomarkers can help to monitor the efficacy of treatment and to identify patients who may benefit from specific therapies, such as ERT or hematopoietic stem cell transplantation (HSCT) 4, 8, 6, 7.

Clinical Implications

• Increased urinary heparan sulfate and dermatan sulfate can have significant clinical implications, including the diagnosis and management of MPS I and MPS II 4, 5, 6, 7.
• The measurement of these biomarkers can help to identify patients who may be at risk of developing severe clinical manifestations, such as cognitive impairment or cardiac disease 6.
• The use of ERT and other therapies can help to reduce the levels of dermatan sulfate and heparan sulfate, and can improve clinical outcomes in patients with MPS I and MPS II 4, 8, 6, 7.