Mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes needed for the stepwise breakdown of glycosaminoglycans (also known as mucopolysaccharides). During the last decades the enzyme deficiencies underlying each disease – as well as the molecular defects causing them – have been recognized and extensively analyzed.
As a result, seven different mucopolysaccharidosis are known (some with their own subtypes) which are named after the physicians who first described those syndromes or discovered the underlying deficiency. Although there are nine types of mucopolysaccharidoses, it must be noted that MPS 5 and MPS 8 are no longer used as designations for any disease.
Based on the severity of symptoms, mucopolysaccharidosis type I (MPS 1) can be divided into three major clinical entities – Hurler and Scheie syndromes represent phenotypes at the two different ends of the clinical spectrum, while Hurler-Scheie syndrome represents a phenotype of intermediate clinical severity. All of them are caused by the deficiency of alpha-L-iduronidase and distinction between them is based only on clinical criteria, including the rate of progression of symptoms.
Hurler syndrome (MPS 1-H) represents the most severe form of mucopolysaccharidosis. It is a progressive disorder with multiple tissue and organ involvement that results in early childhood death. The diagnosis is commonly established between 4 and 18 months of age, as infant can appear normal at birth (or presenting with inguinal or umbilical hernias only). The cardiac failure sometimes precedes the recognition of a storage disorder. Dysostosis multiplex represents typical radiologic sign, while the diaphyses of the long bones are enlarged. Mental development starts to regress around the age of two.
Scheie syndrome (MPS 1-S) is, on the other hand, the mildest form of mucopolysacchardosis. Symptoms usually appear after the age of five, while diagnosis is most commonly made after the age of ten. Individuals affected with this type of the disease exhibit normal intelligence, stature and life expectancy. Symptoms include stiff painful joints, carpal tunnel syndrome, glaucoma (with potential clouding of the cornea) and aortic valvular disease.
Hurler-Scheie syndrome (MPS 1H/S) is used to describe a clinical phenotype that is intermediate, i.e. presentation of the disease does not fit clearly in either the milder or more severe category. It is characterized by progressive somatic involvement (including dysostosis multiplex) with vague or no intellectual dysfunction. Symptoms usually become apparent between three and eight years of age and include coarse facial features, corneal clouding, joint stiffness, short stature and hepatosplenomegaly. Survival to adulthood is common.
Hunter syndrome (MPS 2) is the only mucopolysaccharidosis with X-linked inheritance; therefore it occurs almost exclusively in boys with an incidence of 1.3 per 100 thousand live male births. The affected girls are heterozygotes in whom certain additional genetic events have prevented the expression of the normal allele. This rare disease is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), which leads to the accumulation of heparan sulfate and dermatan sulfate within lysosomes.
Hunter syndrome is comprised of two recognized clinical entities (mild and severe), although they represent two ends of a wide spectrum of clinical severity. Hence mutation analysis is often helpful in distinguishing between the two. Early identification of MPS 2 is somewhat challenging as certain initial features (such as otitis media, chronic runny nose and hernias) are commonly seen in the general population. As a result, even though the signs and symptoms of Hunter syndrome typically appear early in childhood, the diagnosis may lag behind by several years.
Sanfilippo syndrome (MPS 3) has four subtypes (from A to D) which are distinguished by deficiencies of four different enzymes involved in heparan sulfate degradation. The condition is characterized by severe central nervous system disease, leading to progressive neurocognitive deterioration. Onset of clinical features usually occurs between two and six years of age, while death is usually expected during the second or third decade of life. Sanfilippo syndrome is thought to be the most common forms of mucopolysaccharidosis, and subtype A is the most severe form.
Morquio syndrome (MPS 4) arises as a result of defective degradation of keratan sulfate due to a deficiency of N-acetyl-galactosamine-6-sulfatase and beta-galactosidase. The predominant clinical features are those related to the skeleton and their effects on the central nervous system, although in most cases normal intelligence is present. Children with severe form of disease usually do not live beyond their twenties or thirties.
Maroteaux-Lamy syndrome (MPS 6) is characterized by a deficiency of the enzyme arylsulfatase B, resulting in an accumulation of dermatan sulfate. Clinical features and disease severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities and facial dysmorphism. The skeletal changes are similar to radiographic findings of Hurler syndrome and intelligence is normal.
Sly syndrome (MPS 7) is characterized by a deficiency of beta-glucuronidase, resulting in the accumulation of dermatan sulfate, chondroitin sulfate and heparan sulfate. The severe neonatal form is the most common type of this syndrome, characterized by hydrops fetalis (abnormal accumulation of fluid in various tissues of the body) and dysmorphic features. Most patients presenting beyond the neonatal period have increased urinary glycosaminoglycans and dysostosis multiplex.
Hyaluronidase deficiency (MPS 9) represents an exceptionally rare form of mucopolysaccharidosis characterized by a deficiency of hyaluronidase enzyme needed for the breakdown of hyaluronan (i.e. hyaluronic acid). This syndrome was initially described in 1996 with manifestations such as short stature, frequent ear infections, cleft palate, soft-tissue masses and acetabular erosions. The inheritance of hyaluronidase deficiency is autosomal recessive.