Acta Neuropathologica

, Volume 66, Issue 4, pp 325–336 | Cite as

Niemann-Pick disease type C

Study on the nature of the cerebral storage process
  • M. Elleder
  • A. Jirásek
  • F. Šmíd
  • J. Ledvinová
  • G. T. N. Besley
Original Works


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.

Key words

Niemann-Pick disease type C Neuronal storage Sphingomyelin Neutral glycosphingo-lipids Sphingomyelinase 


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  1. Anzil AP, Blinzinger K, Mehraein P, Dozic (1973) Niemann-Pick disease type C: case report with ultrastructural findings. Neuropädiatrie 4:207–225Google Scholar
  2. Besley GTN (1977) Sphingomyelinase defect in Niemann-Pick disease, type C, fibroblasts. FEBS Lett 80:71–74Google Scholar
  3. Besley GTN, Moss SE (1983a) Studies on sphingomyelinase and beta-glucosidase activities in Neimann-Pick disease variants. Biochim Biophys Acta 752:54–64Google Scholar
  4. 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) 29:259–267Google Scholar
  5. Brunngraber EG, Berra B, Zambotti V (1973) Altered levels of tissue glycoproteins, gangliosides, glycosaminoglycans and lipids in Niemann-Pick's disease. Clin Chim Acta 48:173–181Google Scholar
  6. Cowen D, Olmstead EV (1963) Infantile neuroxonal dystrophy. J Neuropathol Exp Neurol 22:175–236Google Scholar
  7. Crocker AC (1961) The cerebral defect in Tay-Sachs and Niemann-Pick disease. J Neurochem 7:69–80Google Scholar
  8. Crocker AC, Farber S (1958) Niemann-Pick's disease: a review of eighteen patients. Medicine (Baltimore) 37:1–96Google Scholar
  9. Dawson G (1972) Glycosphingolipid levels in an unusual neurovisceral storage disease characterized by lactosglyceramide galactosyl hydrolase deficiency: lactosylceramidosis. J Lipid Res 13:207–219Google Scholar
  10. Dawson G, Stein AO (1970) Lactosyl ceramidosis: catabolic enzyme defect of glycosphingolipid metabolism. Science 170:556–558Google Scholar
  11. de Leon GA, Kaback MM, Elfenbein IB, Percy AK, Brady RC (1969) Juvenile dystonic lipidosis. Johns Hopkins Med J 125:62–77Google Scholar
  12. Didion H (1949) Vergleichend histopathologische Untersuchungen an einem Zwillingspaar mit Niemann-Pickscher Krankheit (NPK). Frankf Z Pathol 60:194–227Google Scholar
  13. Elleder M (1977) Lipid histochemistry — a critical survey. Acta Histochem [Suppl] XIX:239–265Google Scholar
  14. Elleder M (1982) Lipid histochemistry. Methodological study and evaluation of its significance in diagnosis of disorders of lipid metabolism. ThesisGoogle Scholar
  15. Elleder M (1983) Lipid histochemistry of Niemann-Pick disease. Histochem J 15:319–322Google Scholar
  16. Elleder M, Jirásek A (1981) Neuropathology of various types of Niemann-Pick disease. Acta Neuropathol [Suppl] (Berlin) VII:201–203Google Scholar
  17. Elleder M, Jirásek A (1983a) New enzyme findings in infantile neuroaxonal dystrophy. Acta Neuropathol (Berlin) 60:153–155Google Scholar
  18. Elleder M, Jirásek A (1983b) Niemann-Pick disease. Report on a symposium held in Prague 1982. Acta Univ Carol [Med] (Praha) 29:259–267Google Scholar
  19. Elleder M, Lojda Z (1968) Remarks on the “OTAN” reaction. Histochemie 14:47–64Google Scholar
  20. Elleder M, Lojda Z (1971) Studies in lipid histochemistry. VI. Problems of extraction with acetone in lipid histochemistry. Histochemie 28:68–87Google Scholar
  21. Elleder M, Lojda Z (1972) Studies in lipid histochemistry. VIII. Some problems of the bromination particularly in relation to lipid histochemistry. Histochemie 32:285–299Google Scholar
  22. Elleder M, Lojda Z (1973a) Studies in lipid histochemistry. XI. New, rapid, simple and selective method for the demonstration of phospholipids. Histochemie 36:149–166Google Scholar
  23. Elleder M, Lojda Z (1973b) Studies in lipid histochemie. XII. Histochemical detection of sphingomyelin. Histochemie 37:371–373Google Scholar
  24. Elleder M, Šmíd F (1977) Lysosomal non-lipid component of Gaucher's cells. Virchows Arch [Cell Pathol] 26:133–138Google Scholar
  25. Elleder M, Hrodek J, Čihula J (1983) Niemann-Pick disease: lipid storage in bone marrow macrophages. Histochemical J 15:1065–1077Google Scholar
  26. 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] 402:307–317Google Scholar
  27. Elleder M, Šmíd F, Hyniová H, Čihula J, Zeman J, Macek M (1984b) Liver findings in Niemann-Pick disease type C. Histochem J 16:1147–1170Google Scholar
  28. Elfenbein IB (1968) Dystonic juvenile idiocy without amaurosis. A new syndrome. Light- and electron-microscopic study of cerebrum. Johns Hopkins Med J 123:205–211Google Scholar
  29. Emeis JJ, Gent van CM, Sabben van CM (1977) An enzymatic method for the histochemical localization of free and esterified cholesterol separately. Histochem J 9:197–204Google Scholar
  30. Emery JM, Green WR, Huff DS, Sloan HR (1972) Niemann-Pick disease (type C). Histopathology and ultrastructure. Am J Ophthalmol 74:1144–1154Google Scholar
  31. 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 783:807Google Scholar
  32. Glew RH, Peters SP (1979) Practical enzymology of the sphingolipidoses. Liss, New YorkGoogle Scholar
  33. Greenbaum M, Hoffman LM, Schneck L (1976) Ceramid hexosides in Niemann-Pick disease brain. J Neurol 213: 251–255Google Scholar
  34. 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 9:59–73Google Scholar
  35. 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 525–546Google Scholar
  36. Harzer K, Peiffer J (1981) Morbus Niemann-Pick Typ C (subakute neuroviscerale Lipidose). Zur Frage der veränderten Sphingomyelinase-Aktivität im Gehirn. Arch Psychiatr Nervenkr 230:71–79Google Scholar
  37. 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) 43:97–104Google Scholar
  38. Horoupian DS, Yang S (1978) Paired helical filaments in neurovisceral lipidosis (juvenile dystonic lipidosis). Ann Neurol 4:404–411Google Scholar
  39. Jellinger K, Jirásek A (1971) Neuroxonal dystrophy in man: character and natural history. Acta Neuropathol (Berlin) [Suppl] V:3–16Google Scholar
  40. 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 117:379–394Google Scholar
  41. 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 355:551–556Google Scholar
  42. Kean EL (1966) Separation of gluco- and galactocerebrosides by means of borate-thin-layer chromatography. J Lipid Res 7:449–452Google Scholar
  43. 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 754:82–92Google Scholar
  44. Lake BD (1981) Metabolic disorderes: general considerations. In: Berry CL (ed) Pediatric pathology. Springer, Berlin Heidelberg New York, pp 617–639Google Scholar
  45. 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) 29:259–267Google Scholar
  46. Lojda Z, Gossrau R, Schiebler T (1979) Enzyme histochemistry — a laboratory manual. Springer, Berlin Heidelberg New YorkGoogle Scholar
  47. Lowden JA, La Ramée MA, Wentworth P (1967) The subacute form of Niemann-Pick disease. Arch Neurol 17:230–237Google Scholar
  48. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  49. 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 27:45–51Google Scholar
  50. 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 108:1101–1106Google Scholar
  51. Müller H, Harzer K (1980) Partial purification of acid sphingomyelinase from normal and pathological (M. Niemann-Pick type C) human brain. J Neurochem 34:446–448Google Scholar
  52. 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) 20:507–513Google Scholar
  53. 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 96:97–120Google Scholar
  54. Norman RM, Forrester RM, Tingey AH (1967) The juvenile form of Niemann-Pick disease. Arch Dis Childh 42:91–96Google Scholar
  55. 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 78:409–421Google Scholar
  56. Norton WT, Korey SR, Brotz M (1962) Histochemical demonstration of unsaturated lipids by a bromine-silver method. J Histochem Cytochem 10:83–88Google Scholar
  57. Oppenheimer DR, Norman RM, Tingey AH, Aherne WA (1967) Histological and chemical findings in juvenile Niemann-Pick disease. J Neurol Sci 5:575–580Google Scholar
  58. Pearse AGE (1968) Histochemistry. Theoretical and applied. Churchill, LondonGoogle Scholar
  59. 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) 34:65–76Google Scholar
  60. 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 20:227–238Google Scholar
  61. Rao BG, Spence MW (1973) Niemann-Pick disease type D: lipid analyses and studies on sphingomyelinases. Ann Neurol 1:385–392Google Scholar
  62. Robert J, Rebel G (1975) Quantitation of neutral glycolipids by thin-layer chromatography on precoated plates. J Chromatogr 110:393–397Google Scholar
  63. 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 5:494–496Google Scholar
  64. Saito T, Hakomori S-I (1971) Quantitative isolation of total glyco sphingo lipids from animal cells. J Lipid Res 12:257–259Google Scholar
  65. 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 40:802–813Google Scholar
  66. 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 43–71Google Scholar
  67. 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 12:629–638Google Scholar
  68. Suzuki K, Suzuki K, Chen Gc (1967) Isolation and chemical characterization of metachromatic granules from a brain with metachromatic leukodystrophy. J Neuropathol Exp Neurol 26:537–550Google Scholar
  69. Ueno K, Audo S, Yu RK (1978) Gangliosides of human, cat, and rabbit spinal cords and cord myelin. J Lipid Res 19:863–871Google Scholar
  70. van Hoof F (1973) Mucopolysaccharidoses, chapt 8. In: Hers HG, van Hoof F (eds) Lysosomes and storage diseases. Academic Press, New York, pp 218–261Google Scholar
  71. Vanier M-T (1983) Biochemical studies in Niemann-Pick diesease. I. Major sphingolipids of liver and spleen. Biochem Biophys Acta 750:178–184Google Scholar
  72. 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 130:155–161Google Scholar
  73. Wenger DA, Sattler M, Clark C, Tanaka H, Suzuki K, Dawson G (1975) Lactosylceramidosis: normal activity for two lactosyl ceramide-beta-galactosidases. Science 188:1310–1312Google Scholar
  74. Yagishita S, Kimura S (1975) Infantile neuroaxonal dystrophy (Seitelberger's disease). A light- and ultrastructural study. Acta Neuropathol (Berlin) 31:191–200Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • M. Elleder
    • 1
  • A. Jirásek
    • 1
  • F. Šmíd
  • J. Ledvinová
    • 2
  • G. T. N. Besley
    • 3
  1. 1.Hlava's Institute of Pathological AnatomyCharles University Medical FacultyPragueCzechoslovakia
  2. 2.Laboratory for ProteosynthesisCharles University Medical FacultyPragueCzechoslovakia
  3. 3.Dept. of Genetic PathologyHospital for Sick ChildrenEdinburgh

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