Lysosomes are subcellular organelles that contain degradative enzymes for complex glycosaminoglycans, also called mucopolysaccharides. Glycosaminoglycans are macromolecules that play a number of roles within cells. Genetic disorders result from abnormal formation of the lysosome itself or from deficiency in specific hydrolytic enzymes, in the mechanisms that protect intralysosomal enzymes from hydrolytic destruction, or in the transport of materials into the lysosome and of metabolites out of the lysosome. These materials are stored in cells and ultimately result in their destruction, especially in the nervous system. The clinical disorders are diverse, reflecting tissue specificity of lysosomal function and the intrinsic turnover rates of the compounds whose cycling is affected (Table 56-1). Some disorders affect many tissues but spare the brain. Some are apparent only during adult life. Storage in solid organs results in organomegaly. In many of these disorders, developmental delay, corneal clouding, and limitation of joint mobility are common features. Storage in tissues of the upper and lower airways may result in respiratory compromise. Non-immune hydrops fetalis occurs in several lysosomal disorders.
Diagnostic testing includes measurement of glycosaminoglycans in urine and specific assays for lysosomal enzyme activity in white blood cells. If the urine test is positive, it helps direct specific enzyme measurement. If it is negative, it does not exclude a lysosomal storage disorder, and other testing modalities are needed if clinical signs are convincing. In disorders in which specific mutations are known, molecular testing refines the diagnosis. Specific diagnosis, carrier testing, and evaluation of at-risk family members require one of these approaches. Making a specific diagnosis is assuming increasing importance because specific treatment for some lysosomal disorders is very effective.
Specific treatment directed at the metabolic abnormality isavailable for some lysosomal disorders. In specific disorders (Gaucher disease) oral medication may be successfulin reducing the accumulation of the metabolite that cannotbe catabolized. For some disorders, bone marrow (stem cell)transplantation can restore lysosomal function. For others, replacement of the missing hydrolytic enzyme by systemic administration of the enzyme allows degradation of stored material. The disorders caused by deficient α-l-iduronidase (Hurler syndrome, Scheie syndrome, and theirvariants) respond to treatment with intravenous humanrecombinant α-l-iduronidase (laronidase). Other disorders for which enzyme therapy is available include MPS VI(Maroteaux-Lamy syndrome), Gaucher disease, Fabry disease, and MPS II (Hunter syndrome). Stem cell transplantation has been helpful or is under investigation in the followingdisorders: MPS type IH (Hurler syndrome), MPS type VI(Maroteaux-Lamy syndrome), MPS type VII (Sly syndrome),Krabbe disease, metachromatic leukodystrophy, alpha-fucosidosis, alpha-mannosidosis, Gaucher disease, and Nie-mann-Pick disease type B. However, treatment for many ofthese conditions is supportive, with careful attention to respiratory status and physical therapy. As a result of the rapidlychanging therapeutic options, geneticists with a special interest in these disorders should be consulted when a diagnosis issuspected. Treatment decisions should be made by the familyin the light of the potential therapeutic benefits and burdensof therapy and typically should be resolved before the onset ofcentral nervous system manifestations, which are typically notimproved by these approaches.