Mucopolysaccharidosis type II: causes, symptoms, diagnosis, treatment

Mucopolysaccharidosis type II (synonyms: lysosomal iduronate-2-sulfatase (aL-iduronosulfate sulfatase) deficiency, Hunter syndrome).

Mucopolysaccharidosis type II is an X-linked recessive disorder resulting from decreased activity of lysosomal iduronate-2-sulfatase, which is involved in the metabolism of glycosaminoglycans. MPS II is characterized by progressive psychoneurological disorders, hepatosplenomegaly, cardiopulmonary disorders, and bone deformities. To date, two cases of the disease in girls have been described, associated with inactivation of the second, normal, X chromosome.

ICD-10 code

• E76 Disorders of glycosaminoglycan metabolism.
• E76.1 Mucopolysaccharidosis, type II.

Epidemiology

Mucopolysaccharidosis II is a panethnic disease with an average worldwide incidence of up to 1 in 75,000 live male births. The incidence in the population ranges from 1 in 165,000 (Australia) to 1 in 34,000 (Israel) live male births.

Causes and pathogenesis of mucopolysaccharidosis II

The development of mucopolysaccharidosis II is caused by mutations in the structural gene of lysosomal iduronate-2-sulfatase - IDS, located on the long arm of the X chromosome in the Xq28 locus. Currently, more than 300 different mutations in the IDS gene have been described. 53.4% of mutations are point (missense and nonsense) mutations, 26.1% are small deletions and insertions, 11.2% are large deletions and rearrangements of the IDS gene, 9.3% are mutations of splicing sites. Most of the mutations found are unique. For patients in Russia, DNA analysis of the IDS gene showed that large deletions and rearrangements of the IDS gene account for only 5.4% of the number of mutations found.

The literature describes relatively frequent mutations in the IDS gene, formed in the region of CpG dinucleotides (the so-called "hot spots" of mutagenesis). The frequency of such mutations is 15.2%. According to the totality of data from various laboratories around the world, about 5% of cases of Hunter's disease are caused by mutations that arose de novo. Mutations in the gene of lysosomal iduronate-2-sulfatase lead to disruption of the structure and/or function of the enzyme and accumulation of glycosaminoglycans - dermatan sulfate and heparan sulfate - in lysosomes. The pathogenesis of Hunter's syndrome is similar to the pathogenesis of Hurler syndrome.

Symptoms of mucopolysaccharidosis II

The clinical phenotype is extremely heterogeneous and is rather arbitrarily divided into severe and mild forms, actually representing a continuum of clinical phenotypes differing in severity. Patients with severe mucopolysaccharidosis II have clinical symptoms similar to Hurler syndrome, but corneal opacity is not observed in Hunter syndrome and the disease progresses more slowly. Severe form of Hunter syndrome usually manifests itself between the ages of 1 and 3 years. In such patients, by the second year of life, facial features change according to the type of gargoyle, growth retardation, signs of multiple bone dysostosis, and decreased intelligence appear. "Mongoloid spots" in the lumbosacral region, hirsutism, coarsening and thickening of the skin are often found. Some patients have local skin changes in the form of formations resembling ivory-colored sea pebbles, usually located in the interscapular region, sternum, neck, and symmetrically along the posterior axillary line. Such skin changes are specific to this type of mucopolysaccharidosis. Most patients have gastrointestinal disorders in the form of chronic diarrhea. Among neurological disorders, symptoms of progressive communicating hydrocephalus, spastic paraplegia due to spinal cord compression, and progressive hearing loss are often observed. As with Hurler syndrome, hepatosplenomegaly, stiffness of large and small joints, and cardiopulmonary disorders are noted. Death usually occurs in the second decade of life from progressive neurological disorders.

The mild form is very similar to Scheie syndrome (MPS IS); it is characterized by normal intelligence with slowly progressive somatic pathology and slowly progressive multiple bone dysostosis. The disease manifests itself at the age of 3-8 years or in the case of benign forms at 10-15 years. The main clinical symptoms of this form of the disease are obstructive syndrome of the upper respiratory tract, acquired heart defects, hearing loss, and joint stiffness. Life expectancy varies widely and depends on the severity of the somatic pathology: it can be normal (an 87-year-old patient was described), but can be significantly reduced (second-third decade of life). The most common cause of death is heart failure or airway obstruction.

Diagnosis of mucopolysaccharidosis II

Laboratory research

To confirm Hunter's disease, the level of glycosaminoglycan excretion in urine and the activity of lysosomal iduronate-2-sulfatase are determined. In case of mucopolysaccharidosis II, the total excretion of glycosaminoglycans in urine increases and hyperexcretion of dermatan sulfate and heparan sulfate occurs. The activity of iduronate-2-sulfatase is measured in leukocytes or skin fibroblast culture using an artificial fluorogenic substrate. Given the prevalence of unique mutations in the IDS gene, DNA analysis is a very lengthy and complex diagnostic procedure. Determination of molecular defects leading to Hunter's disease is of more research interest, contributing to the understanding of phenotype-genotypic correlations in diseases and, possibly, the creation of certain selection criteria for subsequent effective treatment. If necessary for treatment, determination of carriage, or if prenatal diagnostics are planned in affected families, an individual search for familial mutations can be performed.

In the case of mucopolysaccharidosis II, indirect DNA diagnostic methods can also be used, based on the study of X-chromosome loci located close to the IDS gene.

Prenatal diagnosis is possible by measuring iduronate-2-sulfatase activity in chorionic villus biopsy at 9-11 weeks of pregnancy and/or determining the GAG spectrum in amniotic fluid at 20-22 weeks of pregnancy. For families with a known genotype or informative distribution of polymorphic markers of the X chromosome, DNA diagnostics can be performed in early pregnancy.

Functional studies

MRI of the brain in patients with mucopolysaccharidosis II reveals increased signal intensity in the projection of white matter, ventriculomegaly, and expansion of perivascular and subarachnoid spaces.

Differential diagnostics

Differential diagnostics are carried out both within the group of mucopolysaccharidoses and with other lysosomal storage diseases: mucolipidoses, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1 gangliosidosis.

Treatment of mucopolysaccharidosis II

Symptomatic therapy is carried out. The drug idursulfase (elaprase) is registered in European countries and the USA for the treatment of mucopolysaccharidosis, type II (Hunter's disease). The drug is indicated for the correction of mild and moderate forms of the disease and extraneural complications in severe forms. The drug is administered weekly, intravenously, by drip, at a dose of 2 mg/kg.

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