Mucopolysaccharidosis, type IV

Mucopolysaccharidosis, type IV (synonyms: galactose-6-sulfatase deficiency, beta-galactosidase deficiency, Morkio syndrome, mucopolysaccharidosis IVA, mucopolysaccharidosis IVB).

[1]

Epidemiology

The disease is found all over the world, the average frequency of the disease in the population is 1 per 40 000 live births.

[2], [3], [4], [5]

Causes of the mucopolysaccharidosis type IV

Mucopolysaccharidosis IV is an autosomal recessive progressive genetically heterogeneous disease that occurs as a result of mutations in genes encoding galactose-6-sulphatase (N-acetylgalactosamine-6-sulfatase) that participates in the metabolism of keratan sulfate and chondroitin sulfate or in the beta-galactosidase gene (this form is an allelic variant of Gml-gangliosidosis) leading to the manifestation of mucopolysaccharidosis IVA and mucopolysaccharidosis IVB, respectively. The gene N-acetyl-galactosamine-6-sulphatase - GALNS - is located on the long arm of the chromosome 16 - 16q24.3. Among the 148 known mutations, missense mutations account for 78.4%, nonsense mutations - 5%, small deletions - 9.2% major deletions and inserts - 4%. 26.4% of the mutations were found in dinucleotides. The beta-galactosidase gene - GBS - is located on the short arm of the chromosome 3 - 3p21.

[6], [7]

Symptoms of the mucopolysaccharidosis type IV

With both subtypes of Morkio syndrome, growth retardation, corneal opacity, skeletal disorders (kyphoscoliosis, keeled thoracic deformation, subluxation of the hip joints), aortic valve insufficiency and preserved intelligence are observed.

Usually mucopolysaccharidosis IVA is more severe than mucopolysaccharidosis IVB. Valgus deformity of the joints, kyphosis, growth retardation with shortening of the trunk and neck and walking disorders are the first symptoms characteristic of Morkio syndrome. Other common disorders in this disease are mild corneal opacity, glaucoma, small teeth with an enamel structure disorder, multiple caries, hepatomegaly, acquired heart defects with predominant aortic valve involvement. Odontoid hypoplasia in combination with weakness of the ligamentous apparatus can lead to atlantoaxial subluxation and myelopathy of the cervical spine.

Forms

There are two subtypes of mucopolysaccharidosis, type IV: mucopolysaccharidosis IVA and mucopolysaccharidosis IVB, which differ in their primary biochemical defect.

[8], [9], [10], [11], [12], [13], [14]

Diagnostics of the mucopolysaccharidosis type IV

To confirm the diagnosis of mucopolysaccharidosis IV, a determination is made of the level of urinary glycosaminoglycan excretion and measurement of the activity of lysosomal N-acetyl-galactosamine-6-sulfatase and beta-galactosidase. In the case of mucopolysaccharidosis IV, as a rule, the total excretion of glycosaminoglycans in urine increases and hyperexceration of keratan sulfate is observed. However, cases without hyperexcretion of keratan sulfate are known. Enzyme activity is measured in leukocytes or a culture of skin fibroblasts using an artificial fluorogenic substrate.

Prenatal diagnosis is possible by measuring the activity of enzymes in the chorionic villus sampling at the 9-11th week of pregnancy and / or by determining the spectrum of glycosaminoglycans in the amniotic fluid at the 20-22nd week of pregnancy. For families with a known genotype, it is possible to carry out DNA diagnostics in the early stages of pregnancy.

[15], [16], [17]

Differential diagnosis

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

Treatment of the mucopolysaccharidosis type IV

Effective methods are not developed. Symptomatic therapy is performed. The drug for enzyme replacement therapy is being developed and is undergoing the II stage of clinical trials.