The cellular pathology of lysosomal diseases.

With a constitutive recycling function and the capacity to digest exogenous material as well as endogenous organelles in the process of autophagy, lysosomes are at the heart of the living cell. Dynamic interactions with other cellular components ensure that the lysosomal compartment is a central point of convergence in countless diverse diseases. Inborn lysosomal (storage) diseases represent about 70 genetically distinct conditions, with a combined birth frequency of about 1 in 7500. Many are associated with macromolecular storage, causing physical disruption of the organelle and cognate structures; in neurons, ectopic dendritogenesis and axonal swelling due to distension with membraneous tubules and autophagic vacuoles are observed. Disordered autophagy is almost universal in lysosomal diseases but biochemical injury due to toxic metabolites such as lysosphingolipid molecules, abnormal calcium homeostasis and endoplasmic reticulum stress responses and immune-inflammatory processes occur. However, in no case have the mechanistic links between individual clinico-pathological manifestations and the underlying molecular defect been precisely defined. With access to the external fluid-phase and intracellular trafficking pathways, the lysosome and its diseases are a focus of pioneering investment in biotechnology; this has generated innovative orphan drugs and, in the case of Gaucher's disease, effective treatment for the haematological and visceral manifestations. Given that two-thirds of lysosomal diseases have potentially devastating consequences in the nervous system, future therapeutic research will require an integrative understanding of the unitary steps in their neuro pathogenesis. Informative genetic variants illustrated by patients with primary defects in this organelle offer unique insights into the central role of lysosomes in human health and disease. We provide a conspectus of inborn lysosomal diseases and their pathobiology; the cryptic evolution of events leading to irreversible changes may be dissociated from the cellular storage phenotype, as revealed by the outcome of therapeutic gene transfer undertaken at different stages of disease.