Glycosphingolipids

  • Ben J.H.M. Poorthuis
  • Johannes M.F.G. Aerts

Abstract

Sphingolipidoses are a group of rare genetic disorders caused by a = deficiency in the lysosomal degradation or transport of sphingolipids = i.e. sphingomyelin, ceramide, neutral glycosphingo-lipids and = gangliosides. The enzymes involved in the stepwise degradation of = sphingolipids are exo-hydrolases with optimal activity at acidic pH. A = deficiency of one of these enzymes gives rise to a particular = sphingolipid storage disorder. Since most of the enzymes involved in the = degradation of sphingolipids require an activator protein for activity = in vivo, a deficiency of an activator protein gives rise to a storage = disease with clinical features similar to the disease caused by the = enzyme deficiency. Niemann-Pick disease type C is an exception in that = this complex (glycosphingo-) lipid storage disease is not caused by an = enzyme deficiency, but can be considered as a (glycosphingo-)lipid = trafficking defect caused by a deficiency of one of two proteins NPC1 or = NPC2. Early diagnosis of sphingolipidoses is important for genetic = counselling and implementation of therapy. In most cases a definitive = diagnosis can be established by enzyme activity determinations in = leukocytes, fibroblasts or dried blood spots. In some cases histological = examination of cells, determination of the storage product in plasma or = urine, and mutation analysis are also necessary to reach a final = diagnosis. In this chapter methodology to diagnose the sphingolipidoses = is described and the possible pitfalls are discussed.

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References

  1. 1.
    Bach G, Zeigler M, Zlotogora J (2007) Prevention of lysosomal storage diseases in Israel. Mol Genet Metab 90:353–357PubMedCrossRefGoogle Scholar
  2. 2.
    Baum H, Dodgson KS, Spencer B (1959) The assay of arylsulfatases A and B in human urine. Clin Chim Acta 4:453–455PubMedCrossRefGoogle Scholar
  3. 3.
    Beck M (2007) New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 121:1–22PubMedCrossRefGoogle Scholar
  4. 4.
    Ben-Yoseph Y, Gagne R, Parvathy MR, Mitchell DA, Momoi T (1989) Leukocyte and plasma N-laurylsphingosine deacylase (ceramidase) in Farber disease. Clin Genet 36:38–42PubMedCrossRefGoogle Scholar
  5. 5.
    Boot RG, Renkema GH, Verhoek M, Strijland A, Bliek J, de Meulemeester TM, Mannens MM, Aerts JM (1998) The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem 273:25680–25685PubMedCrossRefGoogle Scholar
  6. 6.
    Boot RG, Verhoek M, de Fost M, Hollak CEM, Maas M, Bleijlevens B, van Breemen MJ, van Meurs M, Boven LA, Laman JD, Moran MT, Cox TM, Aerts JMFG (2004) Marked elevation of the chemokine CCL 18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 103:33–39PubMedCrossRefGoogle Scholar
  7. 7.
    Chamoles NA, Blanco M, Gaggioli D (2001) Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta 308:195–196PubMedCrossRefGoogle Scholar
  8. 8.
    Chamoles NA, Blanco M, Gaggioli D, Casentini C (2002) Tay-Sachs and Sandhoff diseases: enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin Chim Acta 318:133–137PubMedCrossRefGoogle Scholar
  9. 9.
    Chamoles NA, Blanco M, Gaggiolo D, Casentini C (2002) Gaucher and Niemann-Pick diseases – enzymatic diagnosis in dried blood spots on filter paper: retrospective diagnoses in newborn-screening cards. Clin Chim Acta 317:191–197PubMedCrossRefGoogle Scholar
  10. 10.
    Chamoles NA, Blanco MB, Iocansky S, Gaggioli D, Specola N, Casentini C (2001) Retrospective diagnosis of GM1 gangliosidosis by use of a newborn-screening card. Clin Chem 47:2068PubMedGoogle Scholar
  11. 11.
    Daniels LB, Glew RH, Diven WF, Lee RE, Radin NS (1981) An improved fluorometric leukocyte beta-glucosidase assay for Gaucher’s disease. Clin Chim Acta 115:369–375PubMedCrossRefGoogle Scholar
  12. 12.
    Deegan PD, Moran MT, McFarlane I, Schofield JP, Boot RG, Aerts JMFG, Cox TM (2005) Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells Mol Dis 35:259–267PubMedCrossRefGoogle Scholar
  13. 13.
    Desnick RJ, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W (1973) Fabry’s disease: enzymatic diagnosis of hemizygotes and heterozygotes. J Lab Clin Med 81:157–171PubMedGoogle Scholar
  14. 14.
    Gieselmann V (1995) Lysosomal storage disorders. Biochim Biophys Acta 1270:103–136PubMedGoogle Scholar
  15. 15.
    Goker-Alpan O.R, Park JK, Stubblefield K, Tayebi N, Sidransky E (2006) Divergent phenotypes in Gaucher disease implicate the role of modifiers J Med Genet 42:37–44CrossRefGoogle Scholar
  16. 16.
    Groener JE, Poorthuis BJ, Kuijper S, Helmond MTJ, Hollak CE, Aerts JM (2007) HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma. Clin Chem 53:742–747PubMedCrossRefGoogle Scholar
  17. 17.
    Guo Y, He W, Boer AM, Wevers RA, de Bruijn AM, Groener JEM, Hollak CEM, Aerts JMFG, Galjaard H, van Diggelen OP (1995) Elevated plasma chitotriosidase activity in various lysosomal storage disorders. J Inherit Metab Dis 18:717–722PubMedCrossRefGoogle Scholar
  18. 18.
    Harzer K, Rolfs A, Bauer P, Zschiesche M, Mengel E, Backes J, Kustermann-Kuhn B, Bruchelt G, van Diggelen OP, Mayrhofer H, Krägeloh-Mann I (2003) Niemann-Pick disease type A and B are clinically but also enzymatically heterogeneous: pitfalls in the laboratory diagnosis of sphingomyelinase deficiency associated with the mutation Q292K. Neuropediatrics 34:301–306PubMedCrossRefGoogle Scholar
  19. 19.
    Ho MW, O’Brien JS (1970) Stimulation of acid beta-galactosidase activity by chloride ions. Clin Chim Acta 30:531–534PubMedCrossRefGoogle Scholar
  20. 20.
    Ho MW, O’Brien JS (1971) Differential effect of chloride ions on beta-galactosidase isoenzymes: a method for separate assay. Clin Chim Acta 32:443–450PubMedCrossRefGoogle Scholar
  21. 21.
    Hollak CEM, Maas M, Aerts JM (2001) Clinically relevant therapeutic endpoints in type I Gaucher disease. J Inherit Metab Dis 24:97–105PubMedCrossRefGoogle Scholar
  22. 22.
    Hollak CEM, van Weely S, van Oers MHJ, Aerts JMFG (1994) Marked elevations of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 93:1288–129PubMedCrossRefGoogle Scholar
  23. 23.
    Inui K, Wenger DA (1984) Usefulness of 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-beta-D-glucopyranoside for the diagnosis of GM2 gangliosidoses in leukocytes. Clin Genet 26:318–321PubMedGoogle Scholar
  24. 24.
    Kaback MM (2001) Screening and prevention in Tay Sachs disease: origins, update and impact. Adv Genet 44:253–265PubMedCrossRefGoogle Scholar
  25. 25.
    Kolter T, Sandhoff K (2005) Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol 21:81–103PubMedCrossRefGoogle Scholar
  26. 26.
    Lee-Vaupel M, Conzelmann E (1987) A simple chromogenic assay for arylsulfatase A. Clin Chim Acta 164:171–180PubMedCrossRefGoogle Scholar
  27. 27.
    Leinekugel P, Michel S, Conzelmann E, Sandhoff K (1992) Quantitative correlation between the residual activity of beta-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum Genet 88:513–523PubMedCrossRefGoogle Scholar
  28. 28.
    Levey S, Jennings ER (1950) The use of control charts in the clinical laboratory. Am J Clin Pathol 20:1059–1066PubMedGoogle Scholar
  29. 29.
    Lowry OH, Rosebrough AL, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  30. 30.
    Lukacs Z, Keil A, Peters V, Kohlschütter A, Hoffmann GF, Cantz M, Kopitz J (2003) Towards quality assurance in the determination of lysosomal enzymes: a two-centre study. J Inherit Metab Dis 26:571–581PubMedCrossRefGoogle Scholar
  31. 31.
    Mayes JS, Scheerer JB, Sifers RN, Donaldson ML (1981) Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry’s disease. Clin Chim Acta 112:247–251PubMedCrossRefGoogle Scholar
  32. 32.
    Meikle PJ, Dallas JG, Dean CJ, Lang DL, Bockmann M, Whittle AM, Fietz MJ, Simonsen H, Fuller M, Brooks DA, Hopwood JJ (2006) Newborn screening for lysosomal storage disorders. Mol Genet Metab 88:307–314PubMedCrossRefGoogle Scholar
  33. 33.
    Meikle PJ, Fietz MJ, Hopwood JJ (2004) Diagnosis of lysosomal storage disorders: current techniques and future directions. Expert Rev Mol Diagn 4:677–691PubMedCrossRefGoogle Scholar
  34. 34.
    Meikle PJ, Hopwood J (2003) Lysosomal storage disorders: emerging therapeutic options require early diagnosis. Eur J Pediatr 162:S34–S37PubMedCrossRefGoogle Scholar
  35. 35.
    Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281:249–254PubMedCrossRefGoogle Scholar
  36. 36.
    Merrill AH Jr, Wang E, Mullins RE, Jamison WCL, Nimkar S, Liotta DC (1988) Quantitation of free sphingosine in liver by high-performance liquid chromatography. Anal Biochem 171:373–381PubMedCrossRefGoogle Scholar
  37. 37.
    Millat G, Baïlo N, Molinero S, Rodriguez C, Chikh K, Vanier MT (2005) Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab 86:220–232PubMedCrossRefGoogle Scholar
  38. 38.
    Mitsuo K, Kobayashi T, Shinnoh N, Goto I (1988) A high-performance liquid chromatographic assay for acid ceramidase activity in cultured fibroblasts from patients with Farber’s disease and from controls. Clin Chim Acta 173:281–288PubMedCrossRefGoogle Scholar
  39. 39.
    Natowicz MR, Prence EM, Chaturvedi P, Newburg DS (1996) Urinary sulfatides and the diagnosis of metachromatic leukodystrophy. Clin Chem 42:232–238PubMedGoogle Scholar
  40. 40.
    O’Brien JS, Okada S, Chen A, Fillerup DL (1970) Tay-Sachs disease. Detection of heterozygotes and homozygotes by serum hexosaminidase assay. N Engl J Med 283:15–20PubMedGoogle Scholar
  41. 41.
    Pavlu-Pereira H, Asfaw B, Poupetova H, Ledvinova J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novaotna Z, Chudoba D, Elleder M (2005) Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study. J Inherit Metab Dis 28:203–227PubMedCrossRefGoogle Scholar
  42. 42.
    Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S, Brady RO (1985) A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci U S A 82:8247–8251PubMedCrossRefGoogle Scholar
  43. 43.
    Peters SP, Glew RH, Lee RE (1977) Gaucher disease In: Glew RH, Peters SP (eds) Practical Enzymology of the Sphingolipidoses. AR Liss, New York, pp 71–100Google Scholar
  44. 44.
    Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, Pinto E, Silva E, Rocha S, Marcao A, Ribeiro I, Lacerda L, Ribeiro G, Amaral O, Sa Miranda MC (2004) Prevalence of lysosomal storage disorders in Portugal. Eur J Hum Genet 12:87–92PubMedCrossRefGoogle Scholar
  45. 45.
    Poorthuis BJHM, Wevers RA, Kleijer WJ, Groener JEM, de Jong JGN, van Weely S, Niezen-Koning KE, van Diggelen OP (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105:151–156PubMedGoogle Scholar
  46. 46.
    Rafi MA, Coppola S, Liu SL, Rao HZ, Wenger DA (2003) Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy. Mol Genet Metab 79:83–90PubMedCrossRefGoogle Scholar
  47. 47.
    Ries M, Schaefer E, Lührs T, Mani L, Kuhn J, Vanier MT, Krummenauer F, Gal A, Beck M, Mengel E (2006) Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C. J Inherit Metab Dis 29:647–652PubMedCrossRefGoogle Scholar
  48. 48.
    Roos D, Loos JA (1970) Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes. I. Stimulation by phytohaemagglutinin. Biochim Biophys Acta 222:565–582PubMedGoogle Scholar
  49. 49.
    Ruijter GJG, Boer M, Weykamp CW, de Vries R, van den Berg I, Janssens-Puister J, Niezen-Koning K, Wevers RA, Poorthuis BJHM, van Diggelen OP (2005) External quality assurance programme for enzymatic analysis of lysosomal storage diseases: a pilot study. J Inherit Metab Dis 28:979–990PubMedCrossRefGoogle Scholar
  50. 50.
    Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (2001) The metabolic molecular bases of inherited disease. Vol III Lysosomal storage disorders McGraw-Hill, New York, Chapters 134, 143, 144–148, 150, 151, and 153Google Scholar
  51. 51.
    Skoog WA, Beck WS (1956) Studies on the fibrinogen, dextran and phytohemagglutinin methods of isolating leukocytes. Blood 11:436–454PubMedGoogle Scholar
  52. 52.
    Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O’Brien JF, Kraft L, Lundquist PA, Patterson MC, Pagano RE, Snow K (2001) Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet 68:1361–1372PubMedCrossRefGoogle Scholar
  53. 53.
    Thomas GH (1994) “Pseudodeficiencies” of lysosomal hydrolases. Am J Hum Genet 54:934–940PubMedGoogle Scholar
  54. 54.
    Van Diggelen OP, Voznyi YV, Keulemans JLM, Schoonderwoerd K, Ledvinova J, Mengel E, Zschiesche M, Santer R, Harzer K (2005) A new fluorimetric assay for the diagnosis of Niemann-Pick A/B, with specificity of natural sphingomyelinase substrate. J Inherit Metab Dis 28:733–741PubMedCrossRefGoogle Scholar
  55. 55.
    Vanier MT (1997) Phenotypic and genetic heterogeneity in Niemann-Pick type C: current knowledge and practical implications. Wien Klin Wochenschr 109:68–73PubMedGoogle Scholar
  56. 56.
    Vanier MT (2002) Prenatal diagnosis of Niemann-Pick types A, B and C. Prenat Diagn 22:630–632PubMedCrossRefGoogle Scholar
  57. 57.
    Vanier M, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64:269–281PubMedCrossRefGoogle Scholar
  58. 58.
    Vanier MT, Rodriguez-Lafrasse C, Rousson R, Gazzah N, Juge M-C, Pentchev PG, Revol A, Louisot P (1991) Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta 1096:328–337PubMedGoogle Scholar
  59. 59.
    Wenger DA (1977) Niemann-Pick disease. In: Glew RH, Peters SP (eds) Practical Enzymology of the Sphingolipidose . AR Liss, New York, pp 39–70Google Scholar
  60. 60.
    Wenger DA, Coppola S, Liu SL (2003) Insight in the diagnosis and treatment of lysosomal storage diseases. Arch Neurol 60:322–328PubMedCrossRefGoogle Scholar
  61. 61.
    Wenger DA, Louie E (1991) Pseudodeficiencies of arylsulfatase A and galactocerebrosidase activities. Dev Neurosci 13:216–221PubMedCrossRefGoogle Scholar
  62. 62.
    Wenger DA, Rafi MA, Luzi P, Datto J, Constantino-Cerrarini E (2000) Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab 70:1–9PubMedCrossRefGoogle Scholar
  63. 63.
    Whitfield PD, Sharp PC, Johnson DW, Nelson P, Meikle PJ (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73:30–37PubMedCrossRefGoogle Scholar
  64. 64.
    Wiederschain G, Raghavan S, Kolodny E (1992) Characterization of 6-hexadecanoylamino-4-methylumbelliferyl-beta-D-galactopyranoside as fluorogenic substrate of galactocerebrosidase for the diagnosis of Krabbe disease. Clin Chim Acta 205:87–96PubMedCrossRefGoogle Scholar
  65. 65.
    Wraith JE (2002) Lysosomal storage disorders. Semin Neonatol 7:75–83PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Ben J.H.M. Poorthuis
    • 1
  • Johannes M.F.G. Aerts
    • 1
  1. 1.Department of Medical Biochemistry, K1University of AmsterdamAmsterdamNetherlands

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