Clinical Information

The mucopolysaccharidoses are a group of disorders caused by a deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin-6- sulfate, 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. Depending on the extent of the enzyme deficiency and type of accumulating storage material, MPS patients may present with a variety of clinical findings that can include coarse facial features, cardiac abnormalities, organomegaly, intellectual disabilities, short stature, and skeletal abnormalities.

MPS I is an autosomal recessive disorder caused by reduced or absent activity of the enzyme alpha-L-iduronidase due to variants in the IDUA gene. This enzyme deficiency results in a wide range of clinical phenotypes that are further categorized as 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, and death usually occurs 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. 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. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT).

MPS II (Hunter syndrome) is an X-linked lysosomal storage disorder 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 later in life with a milder clinical presentation. In general, symptoms may include coarse facial features, 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. Due to the X-linked inheritance pattern, 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 any 1 of 4 enzymes involved in 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 is 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 an autosomal recessive lysosomal storage disorder caused by the 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. Rapidly progressing forms have an early onset of symptoms, significantly elevated GAG especially dermatan sulfate, and can lead to death before the second or third decade of life. A more slowly progressing form has a later onset, milder skeletal manifestations, smaller elevations of GAG, and typically a longer lifespan. Estimates of the incidence of MPS VI range from 1 in 250,000 to 1 in 300,000. Treatment options include hematopoietic stem cell transplantation and ERT.

MPS VII (Sly syndrome) is caused by a deficiency of the enzyme beta-glucuronidase and is extremely rare. 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. Treatment options include hematopoietic stem cell transplantation and ERT.

Elevations of dermatan sulfate and/or heparan sulfate are seen MPS types I, II, III, VI, and VII.

Elevations of keratan sulfate are seen in MPS types IVA and IVB.