Genetics of Mucopolysaccharidosis Type II

Updated: Jul 28, 2015
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a member of a group of inherited metabolic disorders collectively termed the 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 different and recognized phenotypes of MPS. All of the MPSs are inherited in an autosomal recessive fashion, except for Hunter syndrome, which is inherited as X-linked recessive.

In the early 1900s, Gertrud Hurler and Charles Hunter first described patients with MPSs, whose metabolic disorders now bear their names (MPS I [Hurler syndrome], MPS II [Hunter syndrome]); subsequent MPSs have been assigned numbers and eponyms loosely associated with the chronology and origin of their report. MPS II was first described by Charles Hunter in 1917. This X-linked recessive disorder results from the lysosomal enzyme deficiency of iduronate 2-sulfatase (also labeled as I2S deficiency or iduronate sulfatase deficiency [ISD]). Iduronate sulfatase deficiency leads to the subsequent GAG accumulation of heparan sulfate and chondroitin sulfate B (dermatan sulfate) in the body.

In 1917 at The Royal Society of Medicine Meeting in London, Charles Hunter, a Canadian Professor of Medicine, presented the medical histories of 2 brothers who were later diagnosed with Hunter syndrome. Sixteen years later, physicians Binswanger and Ullrich coined the term dysostosis multiplex to describe the constellation of skeletal findings specific to persons with MPS and other lysosomal storage disorders.

The following are skeletal abnormalities described in dysostosis multiplex:

  • 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 (a hip deformity in which the angle formed between the head and neck of the femur and its shaft is increased, usually above 135°)
  • Oar-shaped ribs (narrow at the vertebrae and widening anteriorly)
  • Diaphyseal and metaphyseal expansion of long bones with cortical thinning
  • Tapering of the proximal phalanges

In 1952, Brante isolated the stored mucopolysaccharides from hepatic and meningeal tissues in patients with MPS; hence, the term mucopolysaccharidoses was used to describe this family of diseases. In 1957, Dorfman and Lorincz developed clinical assays to detect urinary mucopolysaccharides. Neufeld et al, in the late 1960s, demonstrated that mucopolysaccharide accumulation in fibroblasts from patients with Hurler (MPS I) and Hunter (MPS II) syndromes could be corrected by co-culturing them with fibroblasts or tissue extracts from patients with a differently diagnosed MPSs. This led to the purification and subsequent identification of each defective lysosomal enzyme within the mucopolysaccharidoses syndromes. [1]

All MPSs share the following clinical hallmarks:

  • A chronic progressive clinical course with multisystem involvement
  • Several phenotypic features, such as coarse facial appearance, growth failure, and organomegaly
  • Laboratory findings such as excretion of urinary GAG fragments and leukocyte inclusion bodies
  • Radiographic abnormalities, eg, dysostosis multiplex

Patients with Hunter syndrome are distinguished from patients with other MPSs because of the male dominant pattern due to the X-linked recessive genetic transmission. Females in whom preferential inactivation of the non-altered paternal allele occurs can have features of Hunter syndrome. Also, corneal clouding is not observed in Hunter syndrome and is therefore a key absent distinguishing feature within the MPS syndromes.

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Pathophysiology

Glycosaminoglycans (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. Manifestations of abnormal cell function include syndromic intellectual disability, 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 involve interference in cellular trafficking of molecules, alteration of the extracellular matrix, and interference with cell signaling and cell receptor functions. [2]

The primary GAGs in tissues include dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. They are composed of sulfated sugar and uronic acid residues (except keratin sulfate, which is composed of galactose-6-sulfate alternating with sulfated N-acetylglucosamine residues). GAGs 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 in patients vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.

Dermatan sulfate is found mostly in skin but is also found in blood vessels, heart valves, lungs, and tendons; thus, accumulation of this GAG results in a characteristic skin deposition, myxomatous valvular changes (mitral valve prolapse), and progressive restrictive lung disease. Heparan sulfate is an essential component of nerve cell membranes; therefore, accumulation causes progressive neurological deterioration. Keratan sulfate accumulation leads to skeletal deformities. Dermatan and heparan sulfate accumulate in patients with MPS II owing to the lack of lysosomal enzyme, iduronate sulfatase (IDS). [3]

Hunter syndrome is distinct from the other mucopolysaccharidoses in that it is genetically inherited as an X-linked recessive disorder. The genetic locus has been mapped to Xq28. The gene defective in this disorder encodes for IDS. [4, 5] To understand the pathogenesis of genetic disorders, animal models can give important clues. For Hunter syndrome, a MPS II mouse model has been engineered to further understand the disease process. [6, 7]

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Epidemiology

Frequency

United States

Incidence is unknown at present, but estimates may soon be available, following the institution of metabolic newborn screening for lysosomal storage disorders. Development of newborn screening strategies is underway. [8]

International

The estimated incidence of MPS 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. [9, 10, 11] Recent studies from Germany and the Netherlands report an overall incidence of 1 case in 140,000-330,000 live births, and, more specifically, 1 case per 77,000 male births. [12]

Mortality/Morbidity

Two types of Hunter syndrome are recognized; a severe form, designated as type A (MPS IIA), and a milder form, designated as type B (MPS IIB). These forms represent the two ends of a clinical spectrum of severity. The distinction is clinically based because iduronate sulfatase (IDS) activity is equally depressed in the laboratory assay used to diagnose both types of Hunter syndrome.

MPS IIA, the severe type, has clinical features similar to those observed with Hurler syndrome, except that corneal clouding is not seen and multisystem involvement does not progress as quickly as seen in Hurler syndrome. In MPS IIA, clinical manifestations become evident in the first few years of life. Children are developmentally delayed and are often hearing impaired with progression to deafness.

Complications in older patients with MPS IIA include carpal tunnel syndrome with entrapment of the medial nerve and degenerative disease of the hips. Subsequent slow systematic somatic and neurologic progression ultimately leads to death in adolescence; however, some patients may live into their second and third decades of life. The cause of death is frequently cardiopulmonary failure secondary to upper airway obstruction and cardiovascular involvement. Incidence of sudden death is about 11%. [13]

Children with MPS IIB (mild type) resemble children with Hurler/Scheie (MPS IH/S) or Scheie syndromes (MPS IS). These children usually have normal intelligence. They may develop airway obstruction secondary to accumulation of mucopolysaccharide in the trachea and bronchi. Patients survive well into adulthood and may live into their seventh decade of life. Most patients will develop valvular heart 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 mutation in the iduronate sulfatase (IDS) allele. [14]

Age

MPS IIA is typically diagnosed in children aged 2-4 years. MPS IIB may not be diagnosed until adolescence or adulthood.

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