Journal Article

Lysosomal storage diseases—the horizon expands

Boustany, Rose-Mary Naaman

2013

Overview

The concept of lysosomal storage disorders (LSDs) has existed for over 50 years, but our understanding of the causes and pathobiology of these diseases have come to light only recently, following advances in genetic technology. In this Review, Rose-Mary Boustany summarizes current understanding of known LSDs, highlighting existing treatment approaches for patients with these often devastating disorders, and outlining the barriers to development of novel therapies. Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)—disorders characterized by aberrant, excessive storage of cellular material in lysosomes—developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed. Key Points The spectrum of lysosomal storage disease (LSD) includes defects in degradative and synthetic enzymes, lysosomal membrane defects, the neuronal ceroid lipofuscinoses (NCLs) and disorders of lysosome biogenesis and endosome–lysosome traffic LSDs result in excess cellular storage and cell death in the CNS, PNS, lungs, liver, bone, skeletal and cardiac muscle and the reticuloendothelial system; symptomatology includes neurocognitive decline, seizures, blindness and hepatosplenomegaly NCLs are typified by abnormal inclusions in brain, eye, liver, skin and the reticuloendothelial system, with clinical manifestations such as neurocognitive decline, blindness, seizures and early death Therapies involving enzyme replacement, substrate reduction and chaperone-mediated delivery, as well as haematopoetic and other stem-cell therapies, have had modest successes in the treatment of patients with LSDs LSDs and NCLs share pathological features: abnormal lipid trafficking, dysregulation of apoptosis and autophagy, prolonged inflammation, disturbed endoplasmic reticulum–cytosol calcium balance, cellular stress, and the unfolded protein response The biological underpinnings of LSDs and NCLs partly explain the limited success of 'direct' therapies for these disorders, but also provide novel targets for therapeutic approaches

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/420 / 692/699/317 / 692/699/375/365 / 692/700/565 / Apoptosis / Autophagy / Care and treatment / Cell death / Disease / Enzymes / Homeostasis / Humans / Inflammation / Lysosomal Storage Diseases - etiology / Lysosomal Storage Diseases - metabolism / Lysosomal Storage Diseases - therapy / Medicine / Medicine & Public Health / Metabolism, Inborn errors of / Metabolites / Neurology / Neuronal Ceroid-Lipofuscinoses - etiology / Neuronal Ceroid-Lipofuscinoses - metabolism / Neuronal Ceroid-Lipofuscinoses - therapy / Neuronal ceroid-lipofuscinosis / review-article / Risk factors / Signal transduction