The genetic lysosomal diseases: Tay-Sachs disease as the prototype

Abstract

The lysosome is an intracellular organelle essential for degradation of cellular constituents for normal metabolic turnover. It contains the enzymatic machineries that are required for sequential breakdown of macromolecules. When any one of the series of lysosomal enzymes are genetically defective, the normal metabolic turnover is halted at that step and consequently the partially degraded material accumulates abnormally in the tissue causing dysfunction. Lysosomal disease is a group of disorders in which lysosomal enzymes and related proteins essential for degradation of tissue constituents, lipids, glycoproteins, or mucopolysaccharides are genetically defective. Major manifestations of the majority of lysosomal diseases involve dysfunction of the nervous system, including mental retardation. Many of the lysosomal diseases were first defined clinically and pathologically starting more than a century ago. The phases of biochemical identification of the abnormal “storage” materials and of elucidation of the underlying enzymatic defects followed. During the past decade, most of the genes responsible for these disorders have been cloned and characterized, opening the way for their understanding on the gene level. Many disease‐causing mutations have been identified in most lysosomal diseases. Nevertheless, the pathogenetic mechanisms that cause severe brain damage are not well understood. Previous attempts at treating patients have been largely disappointing, but successful enzyme replacement and bone marrow transplantation in some diseases have been reported. Gene therapy approaches have been pursued in earnest in recent years. However, given the unique complexity of the brain, pragmatically meaningful gene therapy for these devastating neurologic diseases appears to be many years away. © 1996 Wiley‐Liss, Inc.