Researchers Classify 108 Lysosomal Disorders in Updated Diagnostic Framework

Traditional classifications have focused on enzyme deficiencies and intracellular “storage,” overlooking the broader functions of lysosomes. Researchers have now developed a comprehensive framework that expands the range of recognized lysosomal disorders and could support more precise diagnosis.

University of Sheffield researchers, working with national and international collaborators, developed the classification around the mechanisms underlying inherited lysosomal disorders. Moving beyond enzyme-centered definitions, the framework incorporates lysosomal roles in cellular signaling, nutrient sensing, membrane trafficking, autophagy, and communication between organelles. Disorders were assessed against predefined criteria and grouped according to disruptions in these functions.

The analysis identified 108 disorders, up from the previously recognized 70, including conditions not caused by enzyme deficiencies. These disorders involve defects in 102 genes grouped into 11 categories, reflecting the biological diversity of lysosomal dysfunction. This diversity also extended to clinical presentation: roughly 80% of patients experienced neurological problems and 68% had ocular complications, while gastrointestinal, skeletal, and hematologic manifestations were also common.

The study was published in the Journal of Inherited Metabolic Disease (JIMD) on August 25, 2026. It was led at the University of Sheffield and Salford Royal Hospital, with additional expertise from the University of Oxford, University College London, the University of Manchester, University Children’s Hospital Zürich (Switzerland), Leiden University (Netherlands), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the U.S. National Institutes of Health.

Grouping disorders by shared mechanisms may help define patient subsets for therapies targeting common pathways, inform newborn screening strategies, and facilitate study designs for ultra-rare conditions where conventional trials are challenging.

“Lysosomal disorders are individually rare, but their effects can be debilitating and, in some cases, life-limiting. Our understanding of the lysosome has changed enormously. We now know that it is not simply the cell's waste-disposal system, and lysosomal disease cannot always be understood solely in terms of an enzyme deficiency and the accumulation of material within cells,” said Eamon McCarron, lead author of the study, honorary senior lecturer at the University of Sheffield’s School of Medicine and Population Health and consultant and clinical lead in adult inherited metabolic disorders at the Sheffield Adult Metabolic Service.

“By bringing together 108 inherited disorders within a framework based on modern lysosomal biology, we hope to provide a clearer way of understanding how these diseases relate to one another. This could support more precise diagnosis and genetic interpretation and, in the longer term, help researchers identify shared disease mechanisms that could become targets for new treatments. It may also help inform the future development of newborn screening strategies and clinical trials,” said McCarron.

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