Clinical Information

The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin-6-sulfate, which are collectively called glycosaminoglycans (GAG). Undegraded or partially degraded GAG are stored in lysosomes and excreted in the urine. Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in mucopolysaccharidosis (MPS) disorders. There are 11 known enzyme deficiencies that result in the accumulation of GAG. In addition, abnormal GAG storage is observed in multiple sulfatase deficiency and in I-cell disease. Finally, abnormal excretion of GAG in urine is observed occasionally in other disorders including active bone diseases, connective tissue disease, hypothyroidism, urinary dysfunction, and oligosaccharidoses.

Mucopolysaccharidoses are autosomal recessive disorders except for MPS II, which follows an X-linked inheritance pattern. Affected individuals typically experience a period of normal growth and development followed by progressive disease involvement encompassing multiple systems. The severity and features vary and may include facial coarsening, organomegaly, skeletal changes, cardiac abnormalities, and developmental delays. Moreover, disease presentation varies from as early as late infancy to adulthood.

A diagnostic workup for individuals with suspected MPS should begin with this test, which includes the quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of the specific sulfates or GAG. Interpretation is based upon pattern recognition of the specific sulfates detected by MS/MS and the quantitative analysis of their amounts of excretion. However, an abnormal mucopolysaccharide analysis is not sufficient to conclusively establish a specific diagnosis. It is strongly recommended to seek confirmation by an independent method, typically in vitro enzyme assay (available in either blood or cultured fibroblasts from a skin biopsy) or molecular analysis.

After a specific diagnosis has been established, this test can be appropriate for monitoring the effectiveness of treatment, such as a bone marrow transplant or enzyme replacement therapy (ERT). This test allows for monitoring of the excretion of specific sulfates, as these may change in patients with an MPS disorder undergoing treatment.

Table: Enzyme Defects and Excretion Products of Mucopolysaccharidoses

KEY: C6S, chondroitin 6-sulfate; DS, dermatan sulfate; HS, heparan sulfate; KS, keratan sulfate

MPS I is caused by a reduced or absent activity of the alpha-L-iduronidase enzyme. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. This enzyme deficiency results in a wide range of clinical phenotypes that are further categorized into 3 main types: MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), which are not typically distinguishable via biochemical methods. Clinically, they are also referred to as MPS I and attenuated MPS I. MPS IH is the most severe and has an early onset consisting of skeletal deformities, coarse facial features, hepatosplenomegaly, macrocephaly, cardiomyopathy, hearing loss, macroglossia, and respiratory tract infections. Developmental delay is noticed as early as 12 months of age, with death occurring usually before 10 years of age when left untreated. MPS IH/S has an intermediate clinical presentation characterized by progressive skeletal symptoms called dysostosis multiplex. Individuals typically have little or no intellectual dysfunction. Corneal clouding, joint stiffness, deafness, and valvular heart disease can develop by early to mid-adolescence. Survival into adulthood is common. Cause of death usually results from cardiac complications or upper airway obstruction. Comparatively, MPS IS presents with the mildest phenotype. The onset occurs after 5 years of age. It is characterized by normal intelligence and stature; however, affected individuals do experience joint involvement, visual impairment, and obstructive airway disease.

MPS II (Hunter syndrome) is caused by a reduced or absent activity of the enzyme iduronate 2-sulfatase. The clinical features and severity of symptoms of MPS II are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. The clinical presentation of MPS II is similar to that of MPS I with the notable difference of the lack of corneal clouding in MPS II. The inheritance pattern is X-linked and as such MPS II is observed almost exclusively in male patients with an estimated incidence of 1 in 170,000 male births. Female patients who are symptomatic carriers are very rare but have been reported. Treatment options include hematopoietic stem cell transplantation and ERT.

MPS III (Sanfilippo syndrome) is caused by a reduced or absent activity of 1 of 4 enzymes (see Table above), resulting in a defect of heparan sulfate degradation. Patients with MPS III uniformly excrete heparan sulfate resulting in similar clinical phenotypes, and are further classified as type A, B, C, or D based upon the specific enzyme deficiency. MPS III is characterized by severe central nervous system (CNS) degeneration but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPS. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the third decade of life (20s). The occurrence of MPS III varies by subtype with types A and B being the most common and types C and D being very rare. The collective incidence is approximately 1 in 58,000 live births. Treatment options are limited to symptomatic management.

MPS IVA (Morquio A syndrome) is caused by a reduced or absent N-acetylgalactosamine-6-sulfate sulfatase. Clinical features and severity of symptoms of MPS IVA are widely variable but may include skeletal dysplasia, short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal. Estimates of the incidence of MPS IVA syndrome range from 1 in 200,000 to 1 in 300,000 live births. Treatment with ERT is available.

MPS IVB (Morquio B syndrome) is caused by a reduced or absent beta-galactosidase activity, which gives rise to the physical manifestations of the disease. Clinical features and severity of symptoms of MPS IVB are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, but no neurological involvement. The incidence of MPS IVB is estimated to be about 1 in 250,000 live births. Treatment options are limited to symptomatic management.

MPS VI (Maroteaux-Lamy syndrome) is caused by a deficiency of the enzyme arylsulfatase B. Clinical features and severity of symptoms are widely variable but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, claw-hand deformities, carpal tunnel syndrome, hepatosplenomegaly, corneal clouding, and cardiac defects. Intelligence is usually normal. Estimates of the incidence of MPS VI range from 1 in 200,000 to 1 in 300,000 live births. Treatment options include hematopoietic stem cell transplantation and ERT.

MPS VII (Sly syndrome) is caused by a deficiency of the enzyme beta-glucuronidase. The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function. Likewise, the age of onset is variable ranging from prenatal to adulthood. MPS VII is extremely rare, affecting approximately 1 in 1,500,000 individuals. Treatment options include hematopoietic stem cell transplantation and ERT.

MPS IX is a very rare disorder caused by a deficiency of the enzyme hyaluronidase. Patients present with short stature, flat nasal bridge, and joint findings. Urine GAG are normal in MPS IX.