Mucopolysaccharidosis, type II: causes, symptoms, diagnosis, treatment

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

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

ICD-10 code

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

Epidemiology

Mucopolysaccharidosis II is a panethnic disease with an average incidence in the world of up to 1 in 75,000 liveborn newborns. The incidence of the disease in the population ranges from 1 in 165,000 (Australia) to 1 in 34,000 (Israel) in live newborn boys.

Causes and pathogenesis of mucopolysaccharidosis II

The development of mucopolysaccharidosis II is due to mutations in the structural gene of lysosomal iduronate-2-sulfatase-IDS, located on the long arm of the X chromosome at the locus Xq28. More than 300 different mutations in the IDS gene have now been described. 53.4% of the mutations are dotted (missense and nonsense) mutations, 26.1% are small deletions and insertions, 11.2% are major deletions and rearrangements of the IDS gene, 9.3% are mutations of splice sites. Most of the mutations found are unique. For Russian patients, DNA analysis of the IDS gene showed that major deletions and rearrangements of the IDS gene account for only 5.4% of the number of mutations found.

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

Symptoms of mucopolysaccharidosis II

The clinical phenotype is extremely heterogeneous and rather conditionally subdivided into a heavy and light form, representing in fact a continuum of clinical phenotypes that differ in severity. In patients with severe mucopolysaccharidosis II, clinical symptoms similar to those of Hurler's syndrome are observed, but there is no opacification of the cornea in the Gunther syndrome and the progression of the disease is slower. Usually the severe form of the Gunther syndrome manifests itself at the age of 1 to 3 years. In such patients, by the second year of life, there are changes in facial features such as gargoyleism, growth retardation, signs of multiple bone dysostosis, and decreased intelligence. Often there are "Mongoloid spots" in the lumbosacral region, hirsutism, coarsening and thickening of the skin. In some patients, local changes in the skin are noted in the form of formations resembling an ivory-colored sea shingle, usually located in the interscapular area, the sternum, the neck and symmetrically along the back axillary line. Such skin changes are specific for this type of mucopolysaccharidosis. Most patients have gastroenterological disorders in the form of chronic diarrhea. Among the neurological disorders often observed symptoms of progressive communicating hydrocephalus, spastic paraplegia as a result of compression of the spinal cord and progressive deafness. Just like with the Hurler syndrome. Note hepatosplenomegaly, stiffness of large and small joints, cardiopulmonary disorders. Lethal outcome usually occurs in the second decade of life from progressive neurological disorders.

The lung form is very similar to the Scheye syndrome (MPS IS); for it is characterized by normal intelligence with slowly progressing somatic pathology and slowly progressing multiple bone dysostosis. The disease manifests at the age of 3-8 years or in the case of benign forms in 10-15 years. The main clinical symptoms of this form of the disease are obstructive upper respiratory tract syndrome, acquired heart defects, hearing loss, joint stiffness. Life expectancy varies in a very wide range and depends on the severity of the somatic pathology: it can be normal (described by a patient of 87 years old), 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 the Hunter disease, a determination is made of the level of excretion of glycosaminoglycans in the urine and the measurement of the activity of lysosomal idononate-2-sulfatase. In the case of mucopolysaccharidosis II in the urine, the total excretion of glycosaminoglycans increases and there is hyperexcretion of dermatan sulfate and heparan sulfate. Activity of iduronate-2-sulfatase is measured in leukocytes or culture of skin fibroblasts using an artificial fluorogenic substrate. Given the prevalence of unique mutations in the IDS gene , carrying out the DNA analysis is a very long and complex diagnostic procedure. The determination of molecular defects leading to Hunter's disease is more of a scientific interest, contributing to the understanding of the phenotype-genotypic correlations in diseases and, possibly, the creation of certain selection criteria for subsequent effective treatment. If necessary, for treatment, the definition of carriage, or if prenatal diagnosis is planned in burdened families, it is possible to perform an individual search for family mutations.

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

Prenatal diagnosis is possible by measuring the activity of iduronate-2-sulfatase in a chorionic villus sampling at the 9-11th week of pregnancy and / or determining the spectrum of GAG in the amniotic fluid at the 20-22nd week of pregnancy. For families with a known genotype or informative distribution of polymorphic markers of the X chromosome, it is possible to carry out DNA diagnostics in the early stages of pregnancy.

Functional research

With MRI of the brain in patients with mucopolysaccharidosis II, an increase in signal intensity in the projection of white matter, ventriculomegaly, expansion of perivascular and subarachnoid spaces is observed.

Differential diagnostics

Differential diagnosis is performed both within the mucopolysaccharidosis group and with other lysosomal accumulation diseases: mucolipidosis, galactosialidosis, sialidosis, mannosidosis, fucosidosis, GM1-gangliosidosis.

Treatment of mucopolysaccharidosis II

Symptomatic therapy is performed. The preparation of idursulfase (elapraza) is registered in European countries, the USA for the treatment of mucopolysaccharidosis, type II (Hunter disease). The drug is indicated for the correction of mild and moderate severity of the disease and extra-neural complications in severe form. The drug is administered weekly, intravenously, by drop, at a dose of 2 mg / kg.

[1], [2], [3], [4]