Tay–Sachs Disease

Abstract

Abstract GM2 gangliosidosis is a family of three diseases that include Tay–Sachs disease (described over a century ago), Sandhoff disease and the AB‐variant form, reflecting the need of three gene products to hydrolyse GM2 ganglioside. The recent elucidation of the crystal structures these three proteins have provided a better understanding of the molecular basis of GM2 gangliosidosis. The discovery that most deleterious missense mutations affect the folding or the assembly of the heterodimeric enzyme, and that delays in these processes invoke premature degradation by the endoplasmic reticulum‐quality control system, have suggested a novel therapeutic approach, enzyme enhancement therapy, for some forms of this and other genetic diseases. Progress is also being made on developing a more generally applicable approach, based on gene therapy, for Tay–Sachs and Sandhoff disease. If successful, this will also serve as a model for developing similar therapies for other diseases with neurological involvement. Key Concepts: The history of research into Tay–Sachs disease demonstrates the power of the classical scientific approach to problem solving involving building, over many decades, on the contributions from scientists with diverse interests and expertise. The study or rare diseases often lead to unexpected discoveries of broader‐based metabolic pathways and disease mechanisms. The study of rare diseases can also lead to the development of novel therapeutic approaches that can be adapted to more common diseases.