Lysosomal storage diseases are the result of genetic deficiency in certain enzymes found in tissue cell cytoplasmic lysosomes. These enzymes help metabolize certain glycoproteins, glycolipids, and mucopolysaccharides. The substance normally altered by the deficient enzyme accumulates in the cell lysosome area, and a storage disease results. The nonmetabolized substance either is stored in the tissue cell cytoplasm or is taken up by phagocytes. Most of these conditions can be diagnosed by rather sophisticated assays for the enzyme that is deficient. In some instances the assay can be carried out on plasma or serum; in other cases, on peripheral blood white blood cells (WBCs); and for some enzymes, it is necessary to use patient fibroblasts obtained by skin biopsy and grown in tissue culture. In some cases the diagnosis can be made from fetal cells obtained by amniocentesis and grown in tissue culture. In most cases the assays are available only at university medical centers or specialized clinics. A few are available at certain large reference laboratories. It is recommended that a university medical center specializing in such problems or the Neurological Diseases branch of the National Institutes of Health be contacted for details on how to proceed with any patient suspected of having a lipid storage disease. It is highly preferable that the patient be sent directly to the center for biopsy or required specimen collection to avoid unnecessary and costly delays and to prevent damage to the specimen in transport.

The lysosomal storage diseases can be divided into two major categories: the sphingolipidoses and the mucopolysaccharidoses. A short summary of these conditions is presented. Several are described below in more detail. Many of these disorders can be diagnosed in the first trimester of pregnancy by chorionic villus biopsy.

Sphingolipidoses (disordered lipid metabolism) The best known of this group are glycolipid storage diseases, including ganglioside storage (Tay-Sachs disease and metachromatic leukodystrophy) and ceramide storage diseases (Gaucher’s disease and Niemann-Pick disease).

Tay-Sachs disease. This condition is due to accumulation of the ganglioside GM2 in various tissues but most notably in the brain. The defective enzyme responsible is known as “hexaminidase.” There are two forms (similar to isoenzymes) of hexaminidase, commonly abbreviated as hex-A and hex-B. The ethnic groups most often affected by classic Tay-Sachs disease are Ashkenazic (Central or Eastern European) Jews and, to a lesser extent, other Jews and inhabitants of the Middle East country of Yemen. There are several other very similar disorders involving hexaminidase deficiency that are generally considered variants of Tay-Sachs disease and are not commoner in Jews. In the classic and commonest form of Tay-Sachs disease, the infant appears normal at birth and for the first 5-6 months but then fails to develop any further mentally, loses some motor ability, and develops a “cherry-red spot” on the macula of the eye. The disease proceeds to dementia, flaccid muscles followed by spastic muscles, blindness, and death by age 3 years. There are less common variants that proceed more swiftly or in a somewhat more prolonged fashion.

Diagnosis. The classic form of Tay-Sachs disease is due to deficiency in hex-A enzyme. The hex-A enzyme can be assayed in serum; peripheral blood WBCs and patient fibroblasts can also be used. The diagnosis can be established in the fetus by amniocentesis. The hex-A assay can be used to detect carriers of the Tay-Sachs gene. The disease is transmitted as an autosomal recessive trait, so that if one parent is tested and has normal hex-A levels, the infant will not be homozygous. Therefore, the infant will not be clinically affected, even if the other parent has the gene. DNA probe diagnosis is available in addition to hex-A enzyme measurement. Screening for Tay-Sachs disease can be performed on the fetus in utero by chorionic villus biopsy in the first trimester.

Gaucher’s disease. Gaucher’s disease is a disorder in which the glycolipid cerebroside compound kerasin is phagocytized by the reticuloendothelial system. There seem to be two subgroups of this disorder: a fatal disease of relatively short duration in infancy accompanied by mental retardation, and a more slowly progressive disease found in older children and young adults and not accompanied by mental retardation. Splenomegaly is the most characteristic finding, but the liver and occasionally the lymph nodes also may become enlarged. The most characteristic x-ray findings are aseptic necrosis of the femoral heads and widening of the femoral marrow cavities; although typical, these findings may be absent. Anemia is frequent, and there may be leukopenia and thrombocytopenia due to hypersplenism. The serum acid phosphatase level usually is elevated if the chemical method used is not reasonably specific for prostatic acid phosphatase. (There are several widely used chemical methods, and although none is completely specific for prostatic acid phosphatase, some are considerably more so than others.)

Before the late 1970s, diagnosis was made by bone marrow aspiration. Wright-stained bone marrow smears frequently would contain characteristic Gaucher’s cells, which are large mononuclear phagocytes whose cytoplasm is filled with a peculiar linear or fibrillar material. Splenic aspiration or liver biopsy was also done in problematic cases. The diagnosis is now made by assay of peripheral blood leukocytes for beta-glucosidase, the enzyme whose deficiency is the cause of the disease. Skin biopsy with tissue culture of skin fibroblasts followed by beta-glucosidase assay is also possible.

Niemann-Pick disease. Niemann-Pick disease is similar clinically and pathologically to the fatal early childhood form of Gaucher’s disease, except that the abnormal lipid involved is the phospholipid sphingomyelin. As in Gaucher’s disease, diagnosis used to be made by bone marrow aspiration, although the phagocytic cells are not as characteristic as those of Gaucher’s disease. Splenic biopsy with tissue lipid analysis was also done. The diagnosis is now made by skin biopsy with tissue culture of the fibroblasts and assay of the fibroblasts for sphingomyelinase, the enzyme whose deficiency is the cause of the disease.