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Niemann-Pick disease type C

Study on the nature of the cerebral storage process

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Summary

A complex neuropathological study of two cases of Niemann-Pick disease (NPD) type C (NPDC) revealed some novel features in the chemical pathology of the neuronal storage. Lipid histochemistry showed the presence of a lipid which met the criteria of a neuronal glycosphingolipid. Sphingomyelin (SM) was not detected in the neurones in any of the regions examined. Lipid chemical analysis of total extracts and of partially purified lysosomal fraction of the brain cortex showed markedly increased levels of neutral ceramide hexosides especially of glucosylceramide and ceramide dihexoside (mostly of its slower band). Phospholipids were not significantly increased. Monosialogangliosides GM2 and GM3 were increased only slightly. The storage process displayed the well known fine structure and was accompanied by a marked secondary increase in some lysosomal enzyme activities. There was neuroaxonal dystrophy (NAD) of considerable intensity and extent. Many spheroids contianed masses of degenerated organelles and neurofilaments in various proportions and displayed variable activities of acid phosphatase, nonspecific esterase and dehydrogenases. There was marked brain atrophy accompanied in one case by severe demyelination. Enzyme studies revealed partial decrease of sphingomyelinase (SMase) and betaglucosidase activities in cultured fibroblasts, as well as lack of cathodic SMase activity on isoelectric focusing. No defects of these enzymes were found in the brain samples. The findings are regarded as significant since they indicate a biochemical defect in which SM is not primarily involved and which may thus be fundamentally different from that in type A of NPD.

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References

  • Anzil AP, Blinzinger K, Mehraein P, Dozic (1973) Niemann-Pick disease type C: case report with ultrastructural findings. Neuropädiatrie 4:207–225

    Google Scholar 

  • Besley GTN (1977) Sphingomyelinase defect in Niemann-Pick disease, type C, fibroblasts. FEBS Lett 80:71–74

    Google Scholar 

  • Besley GTN, Moss SE (1983a) Studies on sphingomyelinase and beta-glucosidase activities in Neimann-Pick disease variants. Biochim Biophys Acta 752:54–64

    Google Scholar 

  • Besley GTN, Moss SE (1983b) Sphingomyelinase studies in Niemann-Pick disease with special reference to isoelectric focusing changes in type C disease. Quoted in Elleder M, Jirásek A: Niemann-Pick disease. Reprot on a symposium held in Prague, September 1982. Acta Univ Carol [Med] (Praha) 29:259–267

    Google Scholar 

  • Brunngraber EG, Berra B, Zambotti V (1973) Altered levels of tissue glycoproteins, gangliosides, glycosaminoglycans and lipids in Niemann-Pick's disease. Clin Chim Acta 48:173–181

    Google Scholar 

  • Cowen D, Olmstead EV (1963) Infantile neuroxonal dystrophy. J Neuropathol Exp Neurol 22:175–236

    Google Scholar 

  • Crocker AC (1961) The cerebral defect in Tay-Sachs and Niemann-Pick disease. J Neurochem 7:69–80

    Google Scholar 

  • Crocker AC, Farber S (1958) Niemann-Pick's disease: a review of eighteen patients. Medicine (Baltimore) 37:1–96

    Google Scholar 

  • Dawson G (1972) Glycosphingolipid levels in an unusual neurovisceral storage disease characterized by lactosglyceramide galactosyl hydrolase deficiency: lactosylceramidosis. J Lipid Res 13:207–219

    Google Scholar 

  • Dawson G, Stein AO (1970) Lactosyl ceramidosis: catabolic enzyme defect of glycosphingolipid metabolism. Science 170:556–558

    Google Scholar 

  • de Leon GA, Kaback MM, Elfenbein IB, Percy AK, Brady RC (1969) Juvenile dystonic lipidosis. Johns Hopkins Med J 125:62–77

    Google Scholar 

  • Didion H (1949) Vergleichend histopathologische Untersuchungen an einem Zwillingspaar mit Niemann-Pickscher Krankheit (NPK). Frankf Z Pathol 60:194–227

    Google Scholar 

  • Elleder M (1977) Lipid histochemistry — a critical survey. Acta Histochem [Suppl] XIX:239–265

    Google Scholar 

  • Elleder M (1982) Lipid histochemistry. Methodological study and evaluation of its significance in diagnosis of disorders of lipid metabolism. Thesis

  • Elleder M (1983) Lipid histochemistry of Niemann-Pick disease. Histochem J 15:319–322

    Google Scholar 

  • Elleder M, Jirásek A (1981) Neuropathology of various types of Niemann-Pick disease. Acta Neuropathol [Suppl] (Berlin) VII:201–203

    Google Scholar 

  • Elleder M, Jirásek A (1983a) New enzyme findings in infantile neuroaxonal dystrophy. Acta Neuropathol (Berlin) 60:153–155

    Google Scholar 

  • Elleder M, Jirásek A (1983b) Niemann-Pick disease. Report on a symposium held in Prague 1982. Acta Univ Carol [Med] (Praha) 29:259–267

    Google Scholar 

  • Elleder M, Lojda Z (1968) Remarks on the “OTAN” reaction. Histochemie 14:47–64

    Google Scholar 

  • Elleder M, Lojda Z (1971) Studies in lipid histochemistry. VI. Problems of extraction with acetone in lipid histochemistry. Histochemie 28:68–87

    Google Scholar 

  • Elleder M, Lojda Z (1972) Studies in lipid histochemistry. VIII. Some problems of the bromination particularly in relation to lipid histochemistry. Histochemie 32:285–299

    Google Scholar 

  • Elleder M, Lojda Z (1973a) Studies in lipid histochemistry. XI. New, rapid, simple and selective method for the demonstration of phospholipids. Histochemie 36:149–166

    Google Scholar 

  • Elleder M, Lojda Z (1973b) Studies in lipid histochemie. XII. Histochemical detection of sphingomyelin. Histochemie 37:371–373

    Google Scholar 

  • Elleder M, Šmíd F (1977) Lysosomal non-lipid component of Gaucher's cells. Virchows Arch [Cell Pathol] 26:133–138

    Google Scholar 

  • Elleder M, Hrodek J, Čihula J (1983) Niemann-Pick disease: lipid storage in bone marrow macrophages. Histochemical J 15:1065–1077

    Google Scholar 

  • Elleder M, Jirásek A, Šmíd F, Ledvinová J, Besley GTN, Stopeková M (1984a) Niemann-Pick disease type C with enhanced glycolipid storage. Report on further case of socalled lactosylceramidosis. Virchows Arch [Pathol Anat] 402:307–317

    Google Scholar 

  • Elleder M, Šmíd F, Hyniová H, Čihula J, Zeman J, Macek M (1984b) Liver findings in Niemann-Pick disease type C. Histochem J 16:1147–1170

    Google Scholar 

  • Elfenbein IB (1968) Dystonic juvenile idiocy without amaurosis. A new syndrome. Light- and electron-microscopic study of cerebrum. Johns Hopkins Med J 123:205–211

    Google Scholar 

  • Emeis JJ, Gent van CM, Sabben van CM (1977) An enzymatic method for the histochemical localization of free and esterified cholesterol separately. Histochem J 9:197–204

    Google Scholar 

  • Emery JM, Green WR, Huff DS, Sloan HR (1972) Niemann-Pick disease (type C). Histopathology and ultrastructure. Am J Ophthalmol 74:1144–1154

    Google Scholar 

  • Fredrickson DS, Sloan HR (1972) Sphingomyelin lipidosis: Niemann-Pick disease. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 783:807

    Google Scholar 

  • Glew RH, Peters SP (1979) Practical enzymology of the sphingolipidoses. Liss, New York

    Google Scholar 

  • Greenbaum M, Hoffman LM, Schneck L (1976) Ceramid hexosides in Niemann-Pick disease brain. J Neurol 213: 251–255

    Google Scholar 

  • Hagberg B, Haltis M, Sourander P, Svennerholm L, Vanier M-T, Ljunggren CG (1978) Neurovisceral storage disorder simulating Niemann-Pick disease. A new form of oligosaccharidosis. Neuropädiatrie 9:59–73

    Google Scholar 

  • Harzer K, Benz HU (1976) Sphingomyelinoses (Niemann-Pick'sche Erkrankung). In: Schettler G, Greten H, Schlierf C, Seidel D (Hrsg) Handbuch der Inneren Medizin, Bd VIII/4: Fettstoffwechsel. Springer, Berlin Heidelberg New York, pp 525–546

    Google Scholar 

  • Harzer K, Peiffer J (1981) Morbus Niemann-Pick Typ C (subakute neuroviscerale Lipidose). Zur Frage der veränderten Sphingomyelinase-Aktivität im Gehirn. Arch Psychiatr Nervenkr 230:71–79

    Google Scholar 

  • Harzer K, Schlote W, Peiffer J, Benz HU, Anzill AP (1978) Neurovisceral lipidosis compatible with Niemann-Pick disease type C: Morphological and biochemical studies of a late infantile case and enzyme and lipid assays in a prenatal case of the same family. Acta Neuropathol (Berlin) 43:97–104

    Google Scholar 

  • Horoupian DS, Yang S (1978) Paired helical filaments in neurovisceral lipidosis (juvenile dystonic lipidosis). Ann Neurol 4:404–411

    Google Scholar 

  • Jellinger K, Jirásek A (1971) Neuroxonal dystrophy in man: character and natural history. Acta Neuropathol (Berlin) [Suppl] V:3–16

    Google Scholar 

  • Kamoshita S, Aron AM, Suzuki K, Suzuki K (1969) Infantile Niemann-Pick disease. A chemical study with isolation and characterization of membranous cytoplasmic bodies and myelin. Am J Dis Child 117:379–394

    Google Scholar 

  • Kannan K, Hong-Boen Tjiong, Debuch H, Wiedemann H-R (1974) Unusual glycolipids in brain cortex of a visceral lipidosis (Niemann-Pick disease?). Hoppe-Seyler's Z Physiol Chem 355:551–556

    Google Scholar 

  • Kean EL (1966) Separation of gluco- and galactocerebrosides by means of borate-thin-layer chromatography. J Lipid Res 7:449–452

    Google Scholar 

  • Kudoh T, Velkoff MA, Wenger DA (1983) Uptake and metabolism of radioactively labeled sphingomyelin in cultured skin fibroblasts from controls and patients with Niemann-Picks disease and other lysosomal sorage diseases. Biochim Biophys Acta 754:82–92

    Google Scholar 

  • Lake BD (1981) Metabolic disorderes: general considerations. In: Berry CL (ed) Pediatric pathology. Springer, Berlin Heidelberg New York, pp 617–639

    Google Scholar 

  • Lake BD (1983) The diagnosis of ophthalmoplegic lipidosis —experience with 50 patients. Quoted in Elleder M, Jirásek A: Niemann-Pick disease. Report on a symposium held in Prague 1982. Acta Univ Carol [Med] (Praha) 29:259–267

    Google Scholar 

  • Lojda Z, Gossrau R, Schiebler T (1979) Enzyme histochemistry — a laboratory manual. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Lowden JA, La Ramée MA, Wentworth P (1967) The subacute form of Niemann-Pick disease. Arch Neurol 17:230–237

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    Google Scholar 

  • Martin JJ, Philippart M, Hauwaert JV, Callahan JW, Deberdt R (1972) Niemann-Pick disease (Crocker's group A) Late onset and pigmentary degeneration resembling Hallervorden-Spatz syndrome. Arch Neurol 27:45–51

    Google Scholar 

  • Mazière C, Mazière J-C, Mora L, Routier JD, Polonovski J (1982) In situ degradation of sphingomyelin by cultured normal fibroblasts and fibroblasts from patients with Niemann-Pick disease types A and C. Biochem Biophys Res Commun 108:1101–1106

    Google Scholar 

  • Müller H, Harzer K (1980) Partial purification of acid sphingomyelinase from normal and pathological (M. Niemann-Pick type C) human brain. J Neurochem 34:446–448

    Google Scholar 

  • Navarro J, Escourolle R, Berger B, Ferriere G, Bure Y, Raimbault J, Trastour J-C, Polonowski C (1973) Participation nerveuse péripherique de la maladie de Niemann-Pick. A propos d'un cas. Ann Pediat (Paris) 20:507–513

    Google Scholar 

  • Neville BGR, Lake BD, Stephens R, Sanders MD (1973) A neurovisceral storage disease with vertical supranuclear ophthalmoplegia and its relationship to Niemann-Pick disease — a report of nine cases. Brain 96:97–120

    Google Scholar 

  • Norman RM, Forrester RM, Tingey AH (1967) The juvenile form of Niemann-Pick disease. Arch Dis Childh 42:91–96

    Google Scholar 

  • Norman RM, Urich H, Tingey AH, Goodbody RA (1959) Tay-Sachs disease with visceral involvement and its relationship to Niemann-Pick's disease. J Pathol Bacteriol 78:409–421

    Google Scholar 

  • Norton WT, Korey SR, Brotz M (1962) Histochemical demonstration of unsaturated lipids by a bromine-silver method. J Histochem Cytochem 10:83–88

    Google Scholar 

  • Oppenheimer DR, Norman RM, Tingey AH, Aherne WA (1967) Histological and chemical findings in juvenile Niemann-Pick disease. J Neurol Sci 5:575–580

    Google Scholar 

  • Pearse AGE (1968) Histochemistry. Theoretical and applied. Churchill, London

    Google Scholar 

  • Pellissier JF, Hassoun J, Gambarelli D, Bryon PA, Casanova P, Toga M (1976) Maladie de Niemann-Pick type “C” de Crocker. Etude ultrastructure d'un cas. Acta Neuropathol (Berlin) 34:65–76

    Google Scholar 

  • Philippart M, Martin L, Martin JJ, Menkes JH (1969) Niemann-Pick disease. Morphological and biochemical studies in the visceral form with late central nervous system involvement (Crocker's group C). Arch Neurol 20:227–238

    Google Scholar 

  • Rao BG, Spence MW (1973) Niemann-Pick disease type D: lipid analyses and studies on sphingomyelinases. Ann Neurol 1:385–392

    Google Scholar 

  • Robert J, Rebel G (1975) Quantitation of neutral glycolipids by thin-layer chromatography on precoated plates. J Chromatogr 110:393–397

    Google Scholar 

  • Rouser G, Fleischer S, Yamamoto A (1970) Two-dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids 5:494–496

    Google Scholar 

  • Saito T, Hakomori S-I (1971) Quantitative isolation of total glyco sphingo lipids from animal cells. J Lipid Res 12:257–259

    Google Scholar 

  • Scallen TJ, Dietert SE (1969) The quantitative retention of cholesterol in mouse liver prepared for electron microscopy by fixation in digitonine-containing aldehyde solution. J Cell Biol 40:802–813

    Google Scholar 

  • Scitelberger F (1975) General neuropathology of the degenerative diseases of the central nervous system. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 21, part I. North-Holland, Amsterdam, pp 43–71

    Google Scholar 

  • Suzuki K (1965) The pattern of mammalian brain gangliosides. II. Evaluation of the extraction procedure, post mortem changes and the effect of formalin preservation. J Neurochem 12:629–638

    Google Scholar 

  • Suzuki K, Suzuki K, Chen Gc (1967) Isolation and chemical characterization of metachromatic granules from a brain with metachromatic leukodystrophy. J Neuropathol Exp Neurol 26:537–550

    Google Scholar 

  • Ueno K, Audo S, Yu RK (1978) Gangliosides of human, cat, and rabbit spinal cords and cord myelin. J Lipid Res 19:863–871

    Google Scholar 

  • van Hoof F (1973) Mucopolysaccharidoses, chapt 8. In: Hers HG, van Hoof F (eds) Lysosomes and storage diseases. Academic Press, New York, pp 218–261

    Google Scholar 

  • Vanier M-T (1983) Biochemical studies in Niemann-Pick diesease. I. Major sphingolipids of liver and spleen. Biochem Biophys Acta 750:178–184

    Google Scholar 

  • Vanier M-T, Rousson R, Louisot P (1983) Chromatofocusing of skin fibroblast sphingomyelinase: alterations in Niemann-Pick disease type C shared by GM1 — gangliosidosis. Clin Chim Acta 130:155–161

    Google Scholar 

  • Wenger DA, Sattler M, Clark C, Tanaka H, Suzuki K, Dawson G (1975) Lactosylceramidosis: normal activity for two lactosyl ceramide-beta-galactosidases. Science 188:1310–1312

    Google Scholar 

  • Yagishita S, Kimura S (1975) Infantile neuroaxonal dystrophy (Seitelberger's disease). A light- and ultrastructural study. Acta Neuropathol (Berlin) 31:191–200

    Google Scholar 

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Authors and Affiliations

  1. Hlava's Institute of Pathological Anatomy, Charles University Medical Faculty, Prague, Czechoslovakia

    M. Elleder & A. Jirásek

  2. Laboratory for Proteosynthesis, Charles University Medical Faculty, Prague, Czechoslovakia

    J. Ledvinová

  3. Dept. of Genetic Pathology, Hospital for Sick Children, Edinburgh

    G. T. N. Besley

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  1. M. Elleder
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  2. A. Jirásek
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  3. F. Šmíd
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  4. J. Ledvinová
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  5. G. T. N. Besley
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Elleder, M., Jirásek, A., Šmíd, F. et al. Niemann-Pick disease type C. Acta Neuropathol 66, 325–336 (1985). https://doi.org/10.1007/BF00690966

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