Lysosomal storage diseases. Sphingolipidoses — sphingomyelin lipidosis, or Niemann–Pick disease, Wolman disease

Abstract

The epidemiology, clinical biochemical and molecular genetic characteristics of glycosphingolipidoses with impaired metabolism and excessive accumulation in parenchymal organs, bone and brain not only of sphingolipids, but also free cholesterol are presented. First of all, it is sphingomyelin lipidosis, or NiemannPick disease, a clinically polymorphic and genetically heterogeneous group of rare monogenic diseases. Types A and B, which differ in onset and severity, are allelic diseases and are caused by the presence of recessive mutations in the lysosomal acid sphingomyelinase (SMPD1) gene. Type A is a classic acute neuronopathy, which starts in 85% of cases before 6 months, death occurs before the age of 3 years. The cause of the disease is mutations with premature termination of translation or severe impairment of the catalytic activity of the enzyme. In type B, missense mutations are more common. This is a chronic visceral form, in which neurological symptoms are usually absent, and patients survive into adolescence. Juvenile and adult forms of chronic neuronopathy type C are genetically heterogeneous. In 95% of cases they are caused by mutations in the NPC1 gene (type C1) and in 5% in the NPC2 gene (type C2). The products of these genes are transmembrane proteins responsible for the transport of cholesterol and other lipids. Cholesterol ester storage disease, or Wolman disease, is caused by hereditary deficiency of lysosomal acid lipase A. The possibility of early diagnosis of these diseases based on neonatal screening is discussed in order to increase the effectiveness of their prevention and treatment. The importance of experimental models for studying the molecular basis of the pathogenesis of these severe hereditary diseases and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy, and substrate-reducing therapy, is emphasized. A clinical example of NiemannPick disease type C is presented.