Genetics of Mucopolysaccharidosis Type II 

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPSs). The MPSs are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Eleven distinct single lysosomal enzyme deficiencies are known to cause 7 recognized phenotypes of MPS. All of the MPSs are inherited in an autosomal recessive fashion, except for Hunter syndrome, which is X-linked.

In the early 1900s, Gertrud Hurler and Charles Hunter first described patients with MPS, whose diseases now bear their names; subsequent MPSs have been assigned numbers and eponyms loosely associated with the chronology and origin of their report. MPS II was first described by Hunter in 1917. This X-linked disorder results from the deficiency of iduronate sulfatase and subsequent accumulation of heparan and dermatan sulfate.

Hunter, an internist in Canada, described a case of 2 brothers with what came to be called Hunter syndrome at the Royal Society of Medicine in London. In 1933, Binswanger and Ullrich coined the term dysostosis multiplex to describe the constellation of skeletal findings specific to patients with MPS and other lysosomal storage disorders. These included a large skull with a J-shaped sella, anterior hypoplasia of the thoracic and lumbar vertebral bodies, hypoplasia of the pelvis with small femoral heads and coxa valga, oar-shaped ribs (narrow at the vertebrae and widening anteriorly), diaphyseal and metaphyseal expansion of long bones with cortical thinning, and tapering of the proximal phalanges. However, this family of diseases was not described as the MPSs until 1952, when Brante isolated the stored mucopolysaccharides in these patients.

In 1957, Dorfman and Lorincz developed clinical assays to detect urinary mucopolysaccharides. The work of Neufeld et al from the late 1960s demonstrated that mucopolysaccharide accumulation in fibroblasts from patients with Hurler and Hunter syndromes could be corrected by co-culturing them with fibroblasts or tissue extracts from patients with a different MPS. This led to the purification and subsequent identification of each defective enzyme.

The MPSs share a chronic progressive course with multisystem involvement, several physical features, laboratory findings, and radiographic abnormalities; these include facial coarsening, hepatomegaly, excretion of urinary GAG fragments, and leukocyte inclusion bodies. Patients with Hunter syndrome are distinguished from patients with other MPSs because of the male dominant pattern due to the X-linked transmission. Females in whom preferential inactivation of the nonmutant paternal allele occurs can have features of Hunter syndrome. Also, corneal clouding is not seen in Hunter syndrome.

GAGs are oligosaccharide components of proteoglycans (macromolecules that provide structural integrity and function to connective tissues). The underlying defect in the MPSs is the inability to degrade GAGs. The chronic progressive course is caused by the accumulation of partially degraded GAGs, with resulting thickening of tissue and compromising of cell and organ function over time. Some of the clinical manifestations of GAG accumulation include coarse facial features, corneal clouding, thickened skin, and organomegaly.

Some of the manifestations of abnormal cell function include mental retardation, growth failure, and skeletal dysplasia. GAGs accumulate in lysosomes and extracellular tissue and are excreted in the urine. The exact mechanism by which GAG accumulation leads to disease features is unknown but may also involve interference in cellular trafficking of molecules, alteration of the extracellular matrix, and interference with cell signaling and cell receptor functions.^[1]

Dermatan sulfate, heparan sulfate, keratan sulfate (KS), and chondroitin sulfate are the main GAGs in tissues. They are composed of sulfated sugar and uronic acid residues (except for KS, which is composed mainly of galactose 6-sulfate alternating with sulfated N -acetylglucosamine residues) and are degraded in a stepwise fashion from the nonreducing end by a series of lysosomal enzymes. Depending on the specific enzyme deficiency, the catabolism of one or more GAGs may be blocked. Clinical features vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.

Heparan sulfate is an essential component of nerve cell membranes, and, therefore, accumulation results in progressive mental deterioration. KS accumulation leads to skeletal deformities. Dermatan sulfate is found mostly in skin but is also found in blood vessels, the heart valves, the lungs, and tendons; thus, accumulation results in myxomatous valvular changes, the characteristic skin deposition, and a progressive restrictive lung disease.

In MPS II, because of the lack of iduronate sulfatase (IDS), dermatan and heparan sulfate accumulate.

The Hunter syndrome is distinct from the other mucopolysaccharidoses in that it is an X-linked disorder. The genetic locus has been mapped to Xq28. The gene defective in this disorder encodes IDS.^{[2, 3]}

Animal models are important tools in understanding the pathogenesis of genetic disorders. For Hunter syndrome, an animal model has been engineered and is currently under evaluation.^[4]

Frequency

United States

Incidence is unknown at present, but estimates may soon be available, following the institution of newborn screening for lysosomal storage disorders. Development of newborn screening strategies is underway.^[5]

International

The estimated incidence of MPS type II widely varies. The estimated incidence is 1 case per 34,000 in Israel, 1 case per 111,000 in British Columbia, and 1 case per 132,000 in the United Kingdom.^{[6, 7, 8]} Recent studies from Germany and the Netherlands report an incidence of 1 case in 140,000-330,000 live births, and 1.3 cases per 100,000 male births.^[9]

Mortality/Morbidity

Two forms of Hunter syndrome are recognized: a severe form, designated as type A, and a milder form, designated as type B. These forms represent two ends of a clinical spectrum of severity. The distinction is clinical because IDS activity is equally depressed in the assay used in both forms of Hunter syndrome. In the more severe form, clinical manifestations become evident in the first few years of life, with the subsequent slow and systematic somatic and neurologic progression that ultimately leads to death by adolescence. The cause of death is frequently cardiorespiratory failure secondary to upper airway obstruction and cardiovascular involvement. Incidence of unexpected sudden death is about 11%.^[10]

Type A MPS II is the more severe form and has clinical features very similar to those observed with Hurler syndrome, except that corneal clouding is not seen and clinical features do not progress as quickly as they do in Hurler syndrome. Development is delayed. These children frequently are deaf and may survive into the second and third decades of life.

Additional disease complications in older patients include carpal tunnel syndrome with entrapment of the medial nerve and a degenerative disease of the hips.

Children with type B MPS II resemble children with Hurler/Scheie (MPS IH/S) or Scheie syndromes (MPS IS). These children usually have normal intelligence but may have airway obstruction secondary to accumulation of mucopolysaccharide in the trachea and bronchi. They survive well into adulthood and may live into the seventh decade of life. Most of these patients develop cardiac valvular disease.

Race

Hunter syndrome is panethnic and rare; however, a higher incidence has been noted in the Jewish population living in Israel.

Sex

Inheritance is X-linked recessive, and affected males do not usually reproduce. The disorder is occasionally diagnosed in females consequent to skewed X inactivation, with the active X carrying the mutant IDS allele.^[11]

Age

The severe form of Hunter syndrome is typically diagnosed in children aged 2-4 years. The mild form of Hunter syndrome may not be diagnosed until the teenage years or well into adulthood.