Molecular Genetics of Tay-Sachs and Related Disorders: A Personal Account

Abstract

The history of human genetic lysosomal disorders began in 1881 with the description of what is now known as Tay-Sachs disease. In the early 1960s, when I entered the field while I was a neurology resident, the first phase of studies of lysosomal disorders was being replaced with the second analytical biochemistry phase. Saul Korey, the first Chairman of the Department of Neurology, Albert Einstein College of Medicine, initiated the first integrated approach with a team consisting of clinical neurologists, neuropathologists, electron microscopists, cell biologists, organic chemists, and enzymologists. Despite his tragic death in 1963 in his mid-forties, the field flourished along the line of his vision through the third enzymology phase to the fourth and current molecular biology phase. The concept of Tay-Sachs disease as the only ganglioside storage disease has expanded to two forms of gangliosidoses, GM1- and GM2-gangliosidoses, and the latter into three distinct genetic disorders. Tay-Sachs disease, Sandhoff disease and the GM2 activator protein deficiency. More recently, all three genes coding for the three proteins each responsible for distinct genetic forms of GM2-gangliosidosis--beta-hexosaminidase alpha and beta subunits and the GM2 activator protein--have been cloned and many disease-causing mutations have been identified. We have reached the halfway point in our quest for eventual understanding of the pathogenesis and effective treatment of these disorders, starting from the clinical phenotype through biochemistry to the gene. With this new knowledge on the gene level, we should be tracing the route back to enzymology, biology and pathogenetic mechanism of these disorders in the years to come.(ABSTRACT TRUNCATED AT 250 WORDS)