Mucopolysaccharidoses represent a family of heritable disorders caused by a deficiency of lysosomal enzymes required to degrade glycosaminoglycans (also known as mucopolysaccharides, which is their older designation). These disorders are chronic and progressive, usually displaying a wide spectrum of clinical manifestations within one enzyme deficiency.

In patients affected with the disease, malfunction or deficiency of certain lysosomal enzymes result in an abnormal accumulation of certain complex carbohydrates (i.e.glycosaminoglycans) in the various tissues throughout the body. Therefore, mucopolysaccharidoses are one example of lysosomal storage diseases – a group of approximately 50 diseases characterized by an accumulation of waste products in the lysosomes.

Several different types and subtypes of mucoploysaccharidosis are known, depending on which enzyme groups are affected. The prevalence of mucopolysaccharidoses is estimated to be one in 25 thousand births. Nevertheless, milder forms of the disease tend to go unrecognized, thus making these disorders under-diagnosed or even misdiagnosed.

charidoses represent a family of heritable disorders caused by a deficiency of lysosomal enzymes required to degrade glycosaminoglycans (also known as mucopolysaccharides, which is their older designation). These disorders are chronic and progressive, usually displaying a wide spectrum of clinical manifestations within one enzyme deficiency.

In patients affected with the disease, malfunction or deficiency of certain lysosomal enzymes result in an abnormal accumulation of certain complex carbohydrates (i.e.glycosaminoglycans) in the various tissues throughout the body. Therefore, mucopolysaccharidoses are one example of lysosomal storage diseases – a group of approximately 50 diseases characterized by an accumulation of waste products in the lysosomes.

Several different types and subtypes of mucoploysaccharidosis are known, depending on which enzyme groups are affected. The prevalence of mucopolysaccharidoses is estimated to be one in 25 thousand births. Nevertheless, milder forms of the disease tend to go unrecognized, thus making these disorders under-diagnosed or even misdiagnosed.

Pathophysiology of muclopolysaccharidosis

Each type of mucopolysaccharidosis is caused by a deficiency in the activity of a single, specific lysosomal enzyme required for the degradation of glycosaminoglycans. A combination of different enzymes can also be affected. Depending on the enzyme deficiency, the catabolism of dermatan sulfate, heparan sulfate, chondroitin sulfate, keratan sulfate or hyaluronan is blocked.

Lysosomal accumulation of glycosaminoglycan molecules that cannot be degraded results in cell, tissue and organ dysfunction. This leads to a myriad of pathological conditions, with mental retardation, dysostosis, short stature, cornea abnormalities, hepatosplenomegaly and cardiac involvement being the most common ones.

Patients with severe form of the disease exhibit signs and symptoms occurring early in childhood and simultaneously affecting several diverse organ systems, with frequent cognitive impairment in those mucopolysaccharidoses for which it is a characteristic trait. Conversely, individuals with attenuated disease have lesser number and later occurrence of symptoms - usually without cognitive impairment.

With the exception of Hunter syndrome, mucopolysaccharidoses are inherited in an autosomal recessive pattern, affecting both males and females equally. Hunter syndrome (also known as mucopolysaccharidosis or MPS 2) represents an X-linked recessive disorder that generally affects only males as mother passes along the defective gene to a son, although rare female patients have also been described.

Diagnosis

Early and accurate diagnosis of mucopolysaccharidoses is pivotal in optimizing treatment outcomes, and open communication between laboratories and physicians is crucial in order to facilitate the interpretation of specific diagnostic results. Together with adequate evaluation of medical history and signs of the disease, specific diagnostic tests are key in diagnosing this condition.

The diagnosis of mucopolysaccharidosis should be considered for individuals with suggestive joint symptoms without signs of inflammation, particularly when other clinical signs are present (such as frequent respiratory infections or gastrointestinal complaints, heart murmur, short stature, corneal clouding and history of hernia repair).

A clinically suspected mucopolysaccharidosis constitutes grounds for determining a concentration of urinary glycosaminoglycans. A positive result of this test is very suggestive of this disease, albeit false-negative results due to insufficient sensitivity of various assays or overly diluted samples are very common. Therefore a negative urinary analysis is not sufficient to rule out mucopolysaccharidosis.

Enzyme activity testing that are based on cultured fibroblasts (acquired by skin biopsy), but sometimes also leukocytes or plasma cells, are definitive for specific mucopolysaccharidosis, thus are considered the gold standard for diagnosis. It must be noted that molecular testing has limited utility in initial screening due to the pronounced genetic heterogeneity of different types of disease, so its primary use is to confirm the diagnosis or to evaluate family members.

No established biomarkers for any of the disease types are available at the moment. Even though levels of glycosaminoglycans in urine usually drop with treatment, they do not represent an ideal biomarker. There is an ongoing research on several other biomarkers, such as heparin cofactor II–thrombin complex and dipeptidyl-peptidase IV. High clinical suspicion and positive results from multiple samples with multiple tests are a way to ensure an accurate diagnosis.