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Figure 1. A schematic illustration of different pathways affected in LSDs. (1) In LSDs, a single gene mutation causes the deficiency of a lysosomal protein or lipid. The defect leads to gradual accumulation of macromolecules, inhibition of other lysosomal components, and enlargement of the lysosome which can be followed by lysosomal rupture and secretion. Furthermore, dysfunction of the lysosome and its altered calcium (Ca²⁺) homeostasis leads to impaired fusion with cellular structures including autophagosomes and endosomes/multivesicular bodies (MVBs). (2) The accumulation of autophagosomes can potentially lead to secretion of the organelle to clear its obstruction. Additionally, autophagy is downregulated by hyperactivation of mTOR in some LSDs (MPS-I, MPS-VI, MPS-VII, and Gaucher Disease). Subsequently, impaired or inhibited autophagy results in mitochondrial dysfunction that can lead to energy imbalance, apoptosis, and inflammation. (3) There is a balance between degradation and EV release, which is highly dependent on the faith of MVBs. (4) Impaired fusion of MVBs with the lysosome can lead to fusion of MVBs with the plasma membrane, which causes increased secretion of EVs (Niemann-Pick type C, Sialidosis, Krabbe and Fabry Disease). Hence, inhibition of autophagy and subsequential increase of EV secretion might be an alternative route for LSD cells to clear obstruction of the accumulating molecules to naturally improve the cellular phenotype. (5) In multiple sphingolipid storage disorders (Gaucher Disease, GM1 and GM2 Gangliosidoses, and Niemann-Pick type A) Endoplasmic reticulum (ER) calcium homeostasis is perturbed, which leads to elevated Ca²⁺ in the cytosol. (6) Dysfunction of the Golgi apparatus has been reported for most lipid storage disorders and MPS IIIB. This includes altered morphology and accumulation of large storage bodies.