ANIMAL MODEL OF HUMAN DISEASE
Niemann-Pick Disease T-pe C Animal Model: Mlouse NiemannPick Disease
Contributed by: M. Adachi, MD, B. W. Volk, MD, and L. Schneck, MD, Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center, Rutland Road and East 49th Street, Brooklyn, New York 1 1203.
Biolgic Features
Niemann-Pick disease occurs spontaneously in mice from a breeding colony of FM mice. The mode of inheritance appears to be autosomal recessive.1 Cinical and Pathoogi Features
The affected animals become noticeably thin at 10 weeks. Thev continue to lose weight, become hunched, and their activity decreases. Death usually occurs wvithin the first 6 months of life. The characteristic histopathologic lesions are seen in the hepatocytes (Figure 1) and the reticuloendothelial cells of the spleen, thvmus, Pever's patches, and mediastinal ly-mph nodes Xwhich contain cytoplasmic -acuoles and are enlarged to various degrees.11 The material is stronglxpositive with acid hematein (Figure 1) and Nile blue stains, w hile it displays moderate reactions w-ith Luxol fast blue, periodic acid-Schiff, and acid phosphatase preparations.2 The Kupffer cells in the liver and macrophages in other viscera exhibit sudanophilic granules which are strongly positive wvith acid phosphatase preparations.2 The central nervous system. on the other hand, showvs neither any visible cytoplasmic inclusions in the neurons nor other alterations in neurons and glial cells with various histochemical preparations. Ultrastructurallv, the liver shows an electron-lucent material in the hepatocvtes which is mixed wvith loosely arranged membranes or moderately electron-dense bodies (Figure 2). A similar material can be observed in the reticuloendothelial cells of the spleen, thymus, and Peyer's patches, w%hile the Kupffer cells and macrophages contain markedly- electron-dense Publication sponsored b! the Registry of Comparatise Patholog! of the Armed Forces Institute of by Public Health Service Grant RR 00:301 from the Division of Research Resources. U S Department of Health. Education and Wselfare. under the auspices of Uni%ersities Associated for Research and Education in Pathologv. Inc 229
Pathology and supported
Figure 1-Portion of liver of 4-month-old mouse showing numerous cytoplasmic inclusions in hepatocytes which display reaction granules (arrows) (Baker acid hematein preparation, x 500). Figure 2-Electron microphotograph of a portion of a hepatocyte obtained from 4month-old FM mouse showing an electron-lucent material mixed with dense bodies or loosely arranged membranous structures (x 28,000).
Vol. 85, No. 1 October 1976
NIEMANN-PICK DISEASE
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bodies. The central nervous system exhibits occasional electron-lucent bodies within the neurons, especially in the Purkinje cells, while the pericytes of the capillaries contain electron-dense inclusions.2
Comparin Wh Human Dise In the FM mice, there is an increase of phospholipids and sphingomyelin in the viscera, but these changes are absent in the central nervous system.2'5'6 Enzyme studies, however, show normal sphingomvelinase activitv in the various organs.5 Whereas the histologic features in these animals are consistent with Type B 4 of human Niemann-Pick disease, the biochemical findings, however, are suggestive of a condition similar to Type C of this disorder 4 which also fails to show a deficiency of sphingomyelinase in the presence of an increase of sphingomvelin and total phospholipids.7 Usefuhiess of he Modde Additional studies of FM mice mav possibly find other pathways of sphingomyelin synthesis which may contribute to a better understanding of the altered lipid metabolism occurring in related lipid storage disease in man.
Animals with this defect are not readily available. The original FM stock was kindlv supplied by Howard R. Sloan, MD, Molecular Disease Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Referenices 1. 2. 3. 4.
5. 6.
7.
Lvon MF, Hulse EV, Rowe CE: Foam-cell reticulosis of mice: An inherited condition resembling Gaucher's and Niemann-Pick disease. J Med Genet 2:99-106, 1965 Adachi M, Tsai C-Y, Hoffman LM, Schneck L, Volk BW: The central nervous system, liver, and spleen of FM mice: Ultrastructural, histochemical and biochemical studies. Arch Pathol 97:232-238, 1974 Luse S: The fine structure of the brain and other organs in Niemann-Pick disease. Inborn Disorders of Sphingolipid NMetabolism. Edited by SMI Aronson, BW V'olk. Oxford, Pergarnon Press, 1967, pp 93-105 Crocker AC: The cerebral defect in Tav-Sachs disease and Niemann-Pick disease. j Neurochem 7:69-80, 1961 Fredrickson DS, Sloan HR, Hansen CT: Lipid abnormalities in foam cell reticulosis of mice, an analogue of human sphingomyelin lipidosis. J Lipid Res 10:288-293, 1969 Hoffmnann LM, Fok W, Schneck L: Quantitative determination of l-solecithin and sphingomvelin in phospholipid mixtures by thin laver chromatography as applied to the thvmus of the fmfm mouse. J Lipid Res 15:283-285, 1974 Schneider PB, Kennedv, EP: Sphingomvelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 8:202-209, 1967
232
ADACHI ET AL
American Journal of Pathology
[End of Article]
Niemann-Pick Disease T-pe C Animal Model: Mlouse NiemannPick Disease
Contributed by: M. Adachi, MD, B. W. Volk, MD, and L. Schneck, MD, Isaac Albert Research Institute of the Kingsbrook Jewish Medical Center, Rutland Road and East 49th Street, Brooklyn, New York 1 1203.
Biolgic Features
Niemann-Pick disease occurs spontaneously in mice from a breeding colony of FM mice. The mode of inheritance appears to be autosomal recessive.1 Cinical and Pathoogi Features
The affected animals become noticeably thin at 10 weeks. Thev continue to lose weight, become hunched, and their activity decreases. Death usually occurs wvithin the first 6 months of life. The characteristic histopathologic lesions are seen in the hepatocytes (Figure 1) and the reticuloendothelial cells of the spleen, thvmus, Pever's patches, and mediastinal ly-mph nodes Xwhich contain cytoplasmic -acuoles and are enlarged to various degrees.11 The material is stronglxpositive with acid hematein (Figure 1) and Nile blue stains, w hile it displays moderate reactions w-ith Luxol fast blue, periodic acid-Schiff, and acid phosphatase preparations.2 The Kupffer cells in the liver and macrophages in other viscera exhibit sudanophilic granules which are strongly positive wvith acid phosphatase preparations.2 The central nervous system. on the other hand, showvs neither any visible cytoplasmic inclusions in the neurons nor other alterations in neurons and glial cells with various histochemical preparations. Ultrastructurallv, the liver shows an electron-lucent material in the hepatocvtes which is mixed wvith loosely arranged membranes or moderately electron-dense bodies (Figure 2). A similar material can be observed in the reticuloendothelial cells of the spleen, thymus, and Peyer's patches, w%hile the Kupffer cells and macrophages contain markedly- electron-dense Publication sponsored b! the Registry of Comparatise Patholog! of the Armed Forces Institute of by Public Health Service Grant RR 00:301 from the Division of Research Resources. U S Department of Health. Education and Wselfare. under the auspices of Uni%ersities Associated for Research and Education in Pathologv. Inc 229
Pathology and supported
Figure 1-Portion of liver of 4-month-old mouse showing numerous cytoplasmic inclusions in hepatocytes which display reaction granules (arrows) (Baker acid hematein preparation, x 500). Figure 2-Electron microphotograph of a portion of a hepatocyte obtained from 4month-old FM mouse showing an electron-lucent material mixed with dense bodies or loosely arranged membranous structures (x 28,000).
Vol. 85, No. 1 October 1976
NIEMANN-PICK DISEASE
231
bodies. The central nervous system exhibits occasional electron-lucent bodies within the neurons, especially in the Purkinje cells, while the pericytes of the capillaries contain electron-dense inclusions.2
Comparin Wh Human Dise In the FM mice, there is an increase of phospholipids and sphingomyelin in the viscera, but these changes are absent in the central nervous system.2'5'6 Enzyme studies, however, show normal sphingomvelinase activitv in the various organs.5 Whereas the histologic features in these animals are consistent with Type B 4 of human Niemann-Pick disease, the biochemical findings, however, are suggestive of a condition similar to Type C of this disorder 4 which also fails to show a deficiency of sphingomyelinase in the presence of an increase of sphingomvelin and total phospholipids.7 Usefuhiess of he Modde Additional studies of FM mice mav possibly find other pathways of sphingomyelin synthesis which may contribute to a better understanding of the altered lipid metabolism occurring in related lipid storage disease in man.
Animals with this defect are not readily available. The original FM stock was kindlv supplied by Howard R. Sloan, MD, Molecular Disease Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda, Md. Referenices 1. 2. 3. 4.
5. 6.
7.
Lvon MF, Hulse EV, Rowe CE: Foam-cell reticulosis of mice: An inherited condition resembling Gaucher's and Niemann-Pick disease. J Med Genet 2:99-106, 1965 Adachi M, Tsai C-Y, Hoffman LM, Schneck L, Volk BW: The central nervous system, liver, and spleen of FM mice: Ultrastructural, histochemical and biochemical studies. Arch Pathol 97:232-238, 1974 Luse S: The fine structure of the brain and other organs in Niemann-Pick disease. Inborn Disorders of Sphingolipid NMetabolism. Edited by SMI Aronson, BW V'olk. Oxford, Pergarnon Press, 1967, pp 93-105 Crocker AC: The cerebral defect in Tav-Sachs disease and Niemann-Pick disease. j Neurochem 7:69-80, 1961 Fredrickson DS, Sloan HR, Hansen CT: Lipid abnormalities in foam cell reticulosis of mice, an analogue of human sphingomyelin lipidosis. J Lipid Res 10:288-293, 1969 Hoffmnann LM, Fok W, Schneck L: Quantitative determination of l-solecithin and sphingomvelin in phospholipid mixtures by thin laver chromatography as applied to the thvmus of the fmfm mouse. J Lipid Res 15:283-285, 1974 Schneider PB, Kennedv, EP: Sphingomvelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 8:202-209, 1967
232
ADACHI ET AL
American Journal of Pathology
[End of Article]
