Sphingolipidoses are inherited
genetic diseases due to mutations in genes encoding
proteins involved in the lysosomal catabolism of
sphingolipids. Despite a low incidence of each individual disease, altogether, the number of patients involved is relatively high and resolutive approaches for treatment are still lacking. The chaperone
therapy is one of the latest pharmacological approaches to these storage diseases. This
therapy allows the mutated
protein to escape its natural removal and to increase its quantity in lysosomes, thus partially restoring the metabolic functions.
Sandhoff disease is an autosomal recessive inherited disorder resulting from β-
hexosaminidase deficiency and characterized by large accumulation of
GM2 ganglioside in brain. No enzymatic replacement
therapy is currently available, and the use of inhibitors of
glycosphingolipid biosynthesis for substrate reduction
therapy, although very promising, is associated with serious side effects. The chaperone
pyrimethamine has been proposed as a very promising
drug in those cases characterized by a residual
enzyme activity. In this review, we report the effect of
pyrimethamine on the recovery of β-
hexosaminidase activity in cultured fibroblasts from Sandhoff patients.