Which of the following is a characteristic of lysosomal storage disorders?
Lysosomal storage disorders form a group of about seventy rare inherited metabolic diseases sharing unifying pathophysiology despite diverse enzyme defects. Mutations in genes encoding lysosomal acid hydrolases, accessory activator proteins GM2 activator and saposins, sulfatases requiring formylglycine modification by SUMF1, or lysosomal integral membrane transporters such as cystinosin and sialin impair specific catabolic steps. Because residual enzyme activity falls below threshold, typically less than ten percent of normal, undegraded macromolecular substrates such as sphingolipids, mucopolysaccharides, glycogen, oligosaccharides, ceroid lipofuscin or free amino acids accumulate inside endolysosomal compartments, physically swelling lysosomes to microns, engorging cytoplasm, disrupting trafficking, autophagy, mTOR signaling and calcium homeostasis via TRPML1 inhibition. Neurons, macrophages, hepatocytes and skeletal muscle heavily loaded with storage material display vacuolation, impaired function and apoptosis. Examples include Tay-Sachs with GM2 ganglioside accumulation from hexosaminidase A deficiency, Gaucher with glucosylceramide, Pompe with glycogen, and cystinosis with cystine crystals due to defective cystine exporter. Cells show material overload rather than overexpression of enzymes; often mutant enzymes are unstable, misfolded and degraded by ER-associated degradation. Lysosomal biogenesis via TFEB compensates initially but fails as storage progresses, causing multi-systemic pathology often beginning in infancy.
Ref: Parenti et al., Nature Reviews Drug Discovery 2015: Lysosomal Storage Disorders – Substrate Accumulation.