LSDs

Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by defects in lysosomal enzymes, transporters, or other proteins required for lysosome function. The resulting impairment of lysosomal degradation leads to accumulation of complex substrates in cells throughout the body. LSDs are rare; collectively they comprise many distinct conditions and can affect multiple organ systems, most prominently the nervous system, liver, spleen, bones, heart, and eyes. Most LSDs are autosomal recessive, though some are X-linked or due to de novo mutations. Onset and progression vary widely, from severe infantile forms to milder adult-onset diseases.

Common examples include Gaucher disease (glucocerebrosidase deficiency), Fabry disease (alpha-galactosidase A deficiency), Pompe disease (acid alpha-glucosidase deficiency), Niemann-Pick diseases (acid sphingomyelinase deficiency), Hurler syndrome and other mucopolysaccharidoses (defects in glycosaminoglycan degradation), and Tay-Sachs and Sandhoff diseases (beta-hexosaminidases). Clinical features are diverse and may include hepatosplenomegaly, skeletal abnormalities, developmental delay, neurodegeneration, cardiomyopathy, and ocular findings. Disease course depends on the specific LSD and its severity.

Diagnosis relies on clinical suspicion supported by biochemical tests that measure enzyme activity in blood or cultured cells, as well as genetic testing. Newborn screening programs are expanding for selected disorders.

Management focuses on disease-modifying therapies when available. Enzyme replacement therapy provides missing enzyme for many LSDs, improving somatic symptoms but often not CNS involvement. Substrate reduction therapy and pharmacological chaperones are used for selected diseases. Hematopoietic stem cell transplantation may benefit some early-onset forms. Research continues in gene therapy and advanced approaches.