Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, ‘storage’) or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic.
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F.M.P. is a Royal Society Wolfson Merit award holder and a Wellcome Trust Investigator in Science. A.d.A. is supported by NIH grants DK095169 and GM104981, the Assisi Foundation of Memphis, Ultragenyx Pharmaceutical and the American Lebanese Syrian Associated Charities (ALSAC) and holds the Jewellers for Children Endowed Chair in Genetics and Gene Therapy. A.d.A. thanks B. Stelter (St. Jude Biomedical Communication) for help with the graphic design of Fig. 3 and I. Annunziata for her assistance with literature screening and building the End Note library for the Mechanisms/pathophysiology section. B.L.D. is supported by the Children’s Hospital of Philadelphia Research Institute and the NIH (NS76631, NS090390 and NS94355) and holds the Arthur V. Meigs Chair in Pediatrics. C.J.T. is supported by the Division of Intramural Research of the National Human Genome Research Institute of the NIH, US Department of Health and Human Services. C.J.T. thanks M. Huizing for design of Fig. 4 and organization of the section on disorders of LROs.
Nature Reviews Disease Primers thanks M. Beck, J. Cooper, R. Giugliani, C. Hollak, G. Pastores and other anonymous referee(s) for their contribution to the peer review of this work.