Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Epidemiological, clinical, biochemical and molecular-genetic characteristics of lysosomal leukodystrophies are presented, which include metachromatic leukodystrophy, globoid cell leukodystrophy, or Krabbe disease, combined saposin and multiple sulfatase deficiency. The pathogenesis of metachromatic and globoid cell leukodystrophy is based on hereditary deficiency of two lysosomal enzymes — arylsulfatase A and galactocerebrosidase, accompanied by excessive accumulation of galactosphingosulfatides and galactosylceramide, respectively. The consequence of this is demyelination of the central and peripheral nervous system and damage to the white matter of the brain. Experimental models show effectiveness of pathogenetic approaches, such as hematopoietic stem cell transplantation and gene therapy, only if treatment is started before the development of severe neurological anomalies. In this regard, neonatal screening methods for these two forms of leukodystrophy are being developed, which have been particularly successful in the early diagnosis of Krabbe disease. For each of the two leukodystrophies (metachromatic and globoid cell), rare genetic variants have been described due to the absence of activator proteins for arylsulfatase A and galactocerebrosidase (saposins B and C), respectively, due to specific mutations in the gene of the precursor of saposins, prosaposin (PSPA). Mutations in the PSPA gene resulting in the absence of all four saposins (A, D, C and D) are the cause of combined saposin deficiency, characterized by the development of severe neurological disorders soon after birth and death before the age of 1 year. The pathogenesis of multiple sulfatase deficiency is based on the accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates, caused by inactivating mutations in the SUMF1 gene of the sulfatase-modifying factor 1 involved in the biosynthesis of all sulfatases. The disease is characterized by a combined manifestation of metachromatic leukodystrophy and mucopolysaccharidosis in combination with severe neurological disorders, mental retardation, sensorineural hearing loss and ichthyosis. Clinical guidelines for the diagnosis, management and therapy of combined saposin and multiple sulfatase deficiency have not yet been developed. The article presents a description of a clinical case of Krabbe disease in a child observed in the medical genetic center of St. Petersburg.