What is lysosomal storage disease? In the early 1960’s, it was described that lysosomal diseases are caused by the deficiency of one lysosomal protein resulting in the accumulation of the single major substrate normally degraded by that specific enzyme. The result is a build-up of this non-degraded primary substrate upstream of where that blockage is occurring, and then the endosomal/lysosomal system becomes overwhelmed with the accumulation of that substrate, the cell becomes dysfunctional and eventually dies.