Sphingolipidoses are a group of inherited metabolic diseases caused by a genetic defect in the catabolism of sphingosine-containing lipids. Glycosphingolipids accumulate in the lysosome due to a mutation in genes that encode their catabolic enzymes or activator proteins. They are fatal disorders and significant for some populations. Sphingolipidoses are relatively common and represent an important health problem in Turkey due to the ‘founder effect’ created by consanguineous marriages. Only a low level of residual enzyme activity is apparently needed to prevent or reverse substrate (glycosphingolipids) storage in these diseases, mostly in juvenile and adult forms. Low molecular weight pharmacological chaperones have newly appeared as enzyme enhancement therapy agents in sphingolipidoses resulting from enzyme protein misfolding or mistracking due to certain missense mutations and some small inframe deletions. Pharmacological chaperones can stabilize the conformation of a mutant protein, allowing it to pass the quality control system of the endoplasmic reticulum. To date, all successful pharmacological chaperones have also been competitive inhibitors of the enzyme proteins. They assist the proper folding of mutant proteins in the endoplasmic reticulum, increase stability, avoid aggregation, and thus increase the activity at their target sites by allowing passage of the mutant protein from the endoplasmic reticulum quality control system. These agents, are attracting considerable interest in the enhancement of quality of life and clinical improvement in the juvenile and adult forms of sphingolipidoses which have residual enzymatic activity. In this review, we describe the actions and usage area of pharmacological chaperones in sphingolipidoses, together with their advantages and disadvantages and recent developments.

Keywords: sfingolipidozlar, enzim inhibitörleri, farmakolojik şaperonlar, protein katlanma bozukluğu, yanlış anlamlı mutasyonlar.