Lysosomal storage diseases. Mucolipidosis

The epidemiology, clinical, biochemical and molecular genetic characteristics of mucolipidoses — autosomal recessive lysosomal storage diseases that combine the clinical manifestations of mucopolysaccharidoses and sphingolipidoses — are presented. In accordance with the modern classification, types I, II and III mucolipidoses are classified as glycoproteinoses, and type IV mucolipidoses are classified as gangliosidoses. Mucolipidoses type I, or sialidosis, is caused by the presence of inactivating mutations in the α-neuraminidase gene NEU1, and a related disease is galactosialidosis, accompanied by secondary deficiency of α-neuraminidase and β-galactosidase in the CTSA gene of the protective protein cathepsin A. Both diseases are characterized by early progressive delay in psychomotor development, muscle myoclonus, severe ophthalmopathy and early death of patients. The pathogenesis of diseases is associated with excessive accumulation of sialocontaining glycoproteins and oligosaccharides in lysosomes. Hereditary deficiency of N-acetylglucosaminyl-1-phosphotransferase, necessary for the addition of mannose-6-phosphate to the oligosaccharides of lysosomal enzymes, underlies the development of two allelic diseases caused by mutations in the GNPTAB gene mucolipidoses type II, or “I-cell” disease and mucolipidoses type III, alpha/beta or pseudopolydystrophy of Hurler. Mutations in the GNPTG gene, which encodes the gamma subunit of this enzyme, are responsible for the development of the milder type III mucolipidoses (gamma). All these diseases are characterized by impaired phosphorylation and transport of lysosomal enzymes, which is accompanied by severe growth retardation, skeletal abnormalities and early death of patients. Pathogenesis of mucolipidoses type IV, or sialolipidosis, associated with the simultaneous accumulation of phospholipids, sphingolipids, mucopolysaccharides and gangliosides, which occurs as a result of mutations in the MCOLN1 gene, encoding mucolipin 1, which forms a channel localized on the membranes of lysosomes and endosomes, involved in the regulation of lipid and protein transport. The article presents a description of clinical cases of mucolipidosis types II and IIIA. Preclinical trials have shown promise for enzyme replacement therapy, chaperone therapy, and gene therapy for the treatment of sialidosis and galactosialidosis. However, pathogenetic methods of therapy for mucolipidoses have not been described in clinical practice to date.