J Inherit Metab Dis. 2026 Sep;49(5):e70245. doi: 10.1002/jimd.70245.
ABSTRACT
Lysosomal disorders (LDs) have traditionally been defined by intra-lysosomal substrate accumulation resulting from deficiencies of lysosomal enzymes or associated proteins. Advances in lysosomal biology have demonstrated that lysosomes function as central regulators of cellular signalling, membrane trafficking, autophagy, nutrient sensing, organelle communication and cellular homeostasis, expanding the spectrum of inherited disorders associated with lysosomal dysfunction beyond classical storage phenotypes. We developed a contemporary pathomechanistic nosology of inherited LDs through expert curation and targeted review of databases and published literature. Disorders were included when pathogenic variants resulted in lysosomal dysfunction as a major disease mechanism through defects affecting lysosomal degradation, membrane function, intracellular trafficking, biogenesis, autophagy-lysosome pathways or lysosome-related organelles. A total of 108 inherited lysosomal disorders caused by defects in 102 genes were identified and organised into 11 major disease categories. Neurologic and eye involvement were the most frequently affected organ-system categories, occurring in 80.6% and 68.5% of disorders, respectively. Digestive (including hepatosplenomegaly), dysmorphic, skeletal and haematological involvement occurred in 48.1%, 45.4%, 40.7% and 38.9% of disorders, respectively. Distinct phenotypic signatures were observed across disease categories despite substantial mechanistic overlap involving impaired autophagy, vesicular trafficking, lysosomal stress and altered organelle homeostasis. This proposed nosology extends disease classification beyond substrate accumulation alone and provides a biologically informed framework for disease classification, genomic interpretation, biomarker development, patient stratification and the development of mechanism-based therapies.
PMID:42642022 | DOI:10.1002/jimd.70245