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Lysosomal Storage Diseases Overview




Lysosomal storage diseases [LSDs] are a group of more than 40 disorders that result from mutations in genes encoding lysosomal enzymes or interacting proteins. These genetic mutations then lead to consequent enzyme dysmetabolism from inactivation or decreased function. The altered enzymatic activity leads to a progressive accumulation of undegraded substances in the lysosomes of the cell. This storage is thought to compromise cell function and lead to eventual cell death. The clinical features in patients can be attributed to this storage, the rate and extent of the deposition and the resultant cellular dysfunction. Clinical symptoms affect many organs and are very variable.

The clinical spectrum of these disorders is broad including variations in age of onset, severity of symptoms, organ system involved with especially variable central nervous system effects. Many of the lysosomal disorders have phenotypes that have been recognized as infantile, juvenile and adult. In general, phenotypic expression depends on organ-specific threshold and residual enzymatic expression. The threshold can differ in different tissues as it is affected by substrate flux, cell turnover and metabolic demands. Although residual enzyme activity may vary there is little genotype-phenotype correlation that has been recognized. Many of the lysosomal disorders have characteristic or hallmark features but atypical presentations are common and diagnosis must be established with specific biochemical assay or by DNA mutational analysis.

Biochemical diagnosis can be performed on a variety of tissues including blood plasma, wbc], urine and/or skin fibroblasts. For only a rare few disorders is there no available clinical lab testing. Prenatal diagnosis of most lysosomal disorders can be done by enzymatic, molecular testing or EM of amniocytes/chorionic villus samples. Newborn screening panels are being expanded to include many of the lysosomal disorders as highly sensitive technologies, able to analyze small amounts of sample, have been developed. Genetic counseling is essential to assist patients and their families with an understanding of the genetic mode of inheritance, genetic risk analysis, disease education and supportive counseling.

Medical management of these disorders often requires the coordination of many medical specialties. Although there is active research into potential therapies aimed at ameliorization of the primary defect in these disorders, treatment is often symptomatic. In a growing number of the lysosomal disorders, however, recent and continuing advances in bone marrow transplant, enzyme replacement therapy, substrate inhibition and small molecule therapies have begun to alter the treatment and natural history of these disorders. Intense research interest and efforts have been directed at gene therapy and/or stem cell therapies.

Lysosomal storage disorders are classified according to the type of substrate that is stored in the lysosome and the lysosomal function that is affected. Classification can be made into a number of major groups.