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Zellweger syndrome: Biochemical procedures in diagnosis, prevention and treatment

  • R. B. H. Schutgens
  • R. J. A. Wanders
  • H. S. A. Heymans
  • A. W. Schram
  • J. M. Tager
  • G. Schrakamp
  • H. van den Bosch
Section II: Peroxisomal Function And Dysfunction

Abstract

In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes in which peroxisomes are normally involved. These include the catabolism of very long chain (>C22) fatty acids, the biosynthesis of ether-phospholipids and of bile acids, the catabolism of phytanic acid and the catabolism of pipecolic acid. Many diagnostic tests for Zellweger syndrome have become available in recent years. In classic Zellweger syndrome abnormal C27-bile acids, very long chain fatty acids, dicarboxylic acids and pipecolic acid accumulate in the plasma of the patients. Moreover, depending upon the diet, plasma phytanic acid concentrations may be elevated. In platelets the activity of acyl-CoA: dihydroxyacetone phosphate acyltransferase is deficient; in erythrocytes from young (<4 months) patients the plasmalogen content of the phospholipids is decreased.

In cultured fibroblasts from skin and from chorionic villus and cultured amniotic fluid cells from Zellweger patients the plasmalogen level is lowered; there is a decreased activity of acyl-CoA: dihydroxyacetone phosphate acyltransferase, alkyl dihydroxyacetonephosphate synthase and phytanic acid oxidase; thede novo biosynthesis of plasmalogens and the peroxisomal β-oxidation of fatty acids are impaired and the intracellular localization of catalase is abnormal.

Dietary treatment of patients with Zellweger syndrome has not so far resulted in an objective clinical improvement. As Zellweger syndrome is usually fatal in early life, prenatal diagnosis of the disease is important.

Keywords

Dicarboxylic Acid Phytanic Acid Acid Oxidase Dihydroxyacetone Phosphate Pipecolic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Barth, P. G., Schutgens, R. B. H., Bakkeren, J. A. J. M., Dingemans, K. P., Heymans, H. S. A., Douwes, A. C. and van der Klei-van Moorsel, J. M. A milder variant of Zellweger syndrome.Eur. J. Pediatr. 144 (1985) 338–342PubMedGoogle Scholar
  2. Beard, M. E., Baker, R., Conomos, P., Pugatch, D. and Holtzman, E. Oxidation of oxalate and polyamines by rat peroxisomes.J. Histochem. Cytochem. 33 (1985) 460–464PubMedGoogle Scholar
  3. Benveniste, J., Henson, P. M. and Cochrane, C. G. Leukocyte-dependent histamine release from rabbit platelets: the role of IgE, basophils, and a platelet activating factor.J. Exp. Med. 136 (1972) 1356–1377PubMedGoogle Scholar
  4. Bleeker-Wagemakers, E. M., Oorthuys, J. W. E., Wanders, R. J. A. and Schutgens, R. B. H. Long term survival of a patient with the cerebro-hepato-renal (Zellweger) syndrome.Clin. Genet. 29 (1986) 160–164PubMedGoogle Scholar
  5. Borst, P. Animal peroxisomes (microbodies), lipid biosynthesis and the Zellweger syndrome.Trends Biol. Sci. 8 (1983) 269–272Google Scholar
  6. Borst, P. Review. How proteins get into microbodies (peroxisomes, glyoxysomes, glycosomes).Biochim. Biophys. Acta 866 (1986) 179–203PubMedGoogle Scholar
  7. Carey, W. F., Robertson, E. F., van Crugten, C., Poulos, A. and Nelson, P. V. Prenatal diagnosis of Zellweger syndrome by chorionic villus sampling — and a caveat.Prenat. Diagn. 6 (1986) 227–229PubMedGoogle Scholar
  8. Datta, N. S., Wilson, G. N. and Hajra, A. Deficiency of enzymes catalyzing the biosynthesis of glycerol-ether lipids in Zellweger syndrome.N. Engl. J. Med. 311 (1984) 1080–1083PubMedGoogle Scholar
  9. Farrell, K., Dimmick, J. E., Applegarth, D. A., Wong, L. E., Tze, W. J., McCormick, A. Q., Jan, J. E. and Moser, H. W. Peroxisomal abnormalities in neonatal adrenoleukodystrophy.Ann. Neurol. 14 (1983) 379Google Scholar
  10. Goetzl, E. J., Derian, C. K., Tauber, A. I. and Valone, F. H. Novel effects of l-O-alkylhexadecyl-2-acyl-sn-glycero-3-phosphocholine mediators on human leukocyte function: delineation of the specific roles of the acyl substituents.Biochem. Biophys. Res. Commun. 94 (1980) 881–888PubMedGoogle Scholar
  11. Goldfischer, S., Moore, C. L., Johnson, A. B.et al. Peroxisomal and mitochondrial defects in the cerebrohepatorenal syndrome.Science 132 (1973) 62–64Google Scholar
  12. Goldfischer, S. and Reddy, J. K. Peroxisomes (microbodies) in cell pathology.Int. Rev. Exp. Pathol. 26 (1984) 45–84PubMedGoogle Scholar
  13. Goldfischer, S., Collins, J., Rapin, I.et al. Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities.J. Pediatr. 108 (1986) 25–32PubMedGoogle Scholar
  14. Govaerts, L., Monnens, L., Melis, T. and Trijbels, F. Disturbed adrenocortical function in cerebro-hepato-renal syndrome of Zellweger.Eur. J. Pediatr. 143 (1984) 10–12PubMedGoogle Scholar
  15. Hagey, L. R. and Krisans, S. K. Degradation of cholesterol to propionic acid by rat liver peroxisomes.Biochem. Biophys. Res. Commun. 107 (1982) 834–841PubMedGoogle Scholar
  16. Hajra, A. K. and Bishop, J. E. Glycerolipid biosynthesis in peroxisomes via the acyl dihydroxyacetone phosphate pathway.Ann. NY Acad. Sci. 386 (1982) 170–182PubMedGoogle Scholar
  17. Hajra, A. K., Datta, N. S., Jackson, L. G., Moser, A. B., Moser, H. W., Larsen Jr., J. W. and Powers, J. Prenatal diagnosis of Zellweger cerebrohepatorenal syndrome.N. Engl. J. Med. 312 (1985) 445–446PubMedGoogle Scholar
  18. Hanson, R. F., Szczepanik-van Leeuwen, P., Williams, G. C., Grabowski, G. and Sharp, H. L. Defects of bile acid synthesis in Zellweger's syndrome.Science 203 (1979) 1107–1108PubMedGoogle Scholar
  19. Hashimoto, T. Individual peroxisomal β-oxidation enzymes.Ann. NY Acad. Sci. 386 (1982) 5–12PubMedGoogle Scholar
  20. Heymans, H. S. A., Schutgens, R. B. H., Tan, R., van den Bosch, H. and Borst, P. Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome).Nature 306 (1983) 69–70PubMedGoogle Scholar
  21. Heymans, H. S. A. Cerebro-hepato-renal (Zellweger) syndrome. Clinical and biochemical consequences of peroxisomal dysfunction. PhD Thesis. University of Amsterdam (1984)Google Scholar
  22. Kase, B. F., Björkhem, I. and Pedersen, J. I. Formation of cholic acid from 3α,7α,12α-trihydroxy-5β-cholestanoic acid by rat liver peroxisomes.J. Lipid. Res. 24 (1983) 1560–1567PubMedGoogle Scholar
  23. Kase, B. F., Prydz, K., Björkhem, I., Pedersen, J. I.In vitro formation of bile acids from di- and trihydroxy-5β-cholestanoic acid in human liver peroxisomes.Biochim. Biophys. Acta 877 (1986) 37–42PubMedGoogle Scholar
  24. Kelley, R. I. Review: the cerebro-hepato-renal syndrome of Zellweger, morphologic and metabolic aspects.Am. J. Genet. 16 (1983) 503–517Google Scholar
  25. Kondrup, J. and Lazarow, P. Flux of palmitate through the peroxisomal and mitochondrial β-oxidation systems in isolated rat hepatocytes.Biochim. Biophys. Acta 835 (1985) 147–153PubMedGoogle Scholar
  26. Lazarow, P. B. and de Duve, C. A fatty acyl-CoA oxidizing system in rat liver peroxisomes: enhancement by clofibrate, a hypolipidemic drug.Proc. Natl. Acad. Sci. USA 73 (1976) 2043–2046PubMedGoogle Scholar
  27. Lazarow, P. B., Black, V., Shio, H., Fujiki, Y., Hajra, A. K., Datta, N. S., Bongaru, B. S. and Dancig, J. Zellweger syndrome: biochemical and morphological studies on two patients treated with clofibrate.Pediatr. Res. 19 (1985) 1356–1364PubMedGoogle Scholar
  28. Mannaerts, G. P., Debeer, L. J., Thomas, J. and de Schepper, P. J. Mitochondrial and peroxisomal fatty acid oxidation in rat liver homogenates and isolated hepatocytes from control and clofibrate-treated rats.J. Biol. Chem. 245 (1979) 4585–4595Google Scholar
  29. Mooi, W. J., Dingemans, K. P., van den Bergh, M. A., Jöbsis, A. C., Heymans, H. S. A. and Barth, P. G. Ultrastructure of the liver in the cerebro-hepato-renal syndrome of Zellweger.Ultrastruct. Pathol. 5 (1983) 135–144PubMedGoogle Scholar
  30. Mortensen, P. B., Gregersen, N. and Rasmussen, K. The β-oxidation of dicarboxylic acids in isolated mitochondria and peroxisomes.J. Inher. Metab. Dis. 6 Suppl. 2 (1983) 123–124PubMedGoogle Scholar
  31. Ogier, H., Roels, F., Cornelis, A., Poll-Thé, B. T., Odièvre, M. and Saudubray, J. M. Absence of hepatic peroxisomes in a case of infantile Refsum's disease.Scand. J. Clin. Lab. Invest. 45 (1985) 767–768PubMedGoogle Scholar
  32. Parmentier, G. P., Janssen, G. A., Eggermont, E. A. and Eyssen, H. J. C27 Bile acids in infants with coprostanoic acidemia and occurrence of a 3α,7α,12α-trihydroxy-5β-C29 dicarboxylic bile acid as a major component in their serum.Eur. J. Biochem. 102 (1979) 173–183PubMedGoogle Scholar
  33. Pedersen, J. I. and Gustafsson, J. I. Conversion of 3α,7α,12α-trihydroxy-5β-cholestanoic acid into cholic acid by rat liver peroxisomes.FEBS Lett. 121 (1980) 345–348PubMedGoogle Scholar
  34. Poll-Thé, B. T., Poulos, A., Sharp, P., Boué, J., Ogier, H., Odièvre, M. and Saudubray, J. M. Antenatal diagnosis of infantile Refsum disease.Clin. Genet. 27 (1985) 524–525PubMedGoogle Scholar
  35. Poulos, A., Sharp, P. and Whiting, M. Infantile Refsum's disease (phytanic acid storage disease): a variant of Zellweger's syndrome?Clin. Genet. 26 (1984) 579–586PubMedGoogle Scholar
  36. Santos, M. J., Ojeda, J. M., Garrido, J. and Leighton, F. Peroxisomal organisation in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts.Proc. Natl. Acad. Sci. USA 82 (1985) 6556–6560PubMedGoogle Scholar
  37. Schrakamp, G., Schutgens, R. B. H., Wanders, R. J. A., Heymans, H. S. A., Tager, J. M., and van den Bosch, H. The cerebro-hepato-renal (Zellweger) syndrome. Impairedde novo biosynthesis of plasmalogens in cultured skin fibroblasts.Biochim. Biophys. Acta 833 (1985a) 170–174PubMedGoogle Scholar
  38. Schrakamp, G., Rooseboom, C. F. P., Schutgens, R. B. H., Wanders, R. J. A., Heymans, H. S. A., Tager, J. M. and van den Bosch, H. Alkyl dihydroxyacetone phosphate synthase in human fibroblasts and its deficiency in Zellweger syndrome.J. Lipid Res. 26 (1985b) 867–873PubMedGoogle Scholar
  39. Schram, A. W., Strijland, A., Hashimoto, T.et al. Biosynthesis and maturation of peroxisomal β-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease.Proc. Natl. Acad. Sci. USA 83 (1986) 6156–6158PubMedGoogle Scholar
  40. Schutgens, R. B. H., Romeijn, G. J., Wanders, R. J. A., van den Bosch, H., Schrakamp, G. and Heymans, H. S. A. Deficiency of acyl-CoA: dihydroxyacetone phosphate acyltransferase in patients with Zellweger (cerebro-hepato-renal) syndrome.Biochem. Biophys. Res. Commun. 120 (1984) 179–184PubMedGoogle Scholar
  41. Schutgens, R. B. H., Schrakamp, G., Wanders, R. J. A., Heymans, H. S. A., Moser, H. W., Moser, A. E., Tager, J. M., van den Bosch, H. and Aubourgh, P. The cerebrohepato-renal (Zellweger) syndrome: prenatal detection based on impaired biosynthesis of plasmalogens.Prenat. Diagn. 5 (1985) 337–344PubMedGoogle Scholar
  42. Schutgens, R. B. H., Heymans, H. S. A., Wanders, R. J. A., van den Bosch, J. and Tager, J. M. Peroxisomal disorders: A newly recognised group of genetic diseases.Eur. J. Pediatr. 144 (1986) 430–440PubMedGoogle Scholar
  43. Singh, I., Moser, A. E., Goldfischer, S. and Moser, H. W. Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy.Proc. Natl. Aci. USA 81 (1984) 4203–4207Google Scholar
  44. Skjeldal, O., Stokke, O., Norseth, J. and Lie, S. O. Phytanic acid oxidase activity in cultured skin fibroblasts.Scand. J. Clin. Lab. Invest. 46 (1986) 283–287PubMedGoogle Scholar
  45. Solish, G. I., Moser, H. W., Ringer, L. D., Moser, A. E., Tiffany, C. and Schutta, E. The prenatal diagnosis of the cerebro-hepato-renal syndrome of Zellweger.Prenat. Diagn. 5 (1985) 27–34PubMedGoogle Scholar
  46. Stokke, O., Skrede, S., Ek, J. and Björkhem, I. Refsum disease, adrenoleukodystrophy, and the Zellweger syndrome.Scand. J. Clin. Lab. Invest. 44 (1984) 463–464PubMedGoogle Scholar
  47. Tager, J. M., ten Harmsen van der Beek, W. A., Wanders, R. J. A.et al. Peroxisomal β-oxidation enzyme proteins in the Zellweger syndrome.Biochem. Biophys. Res. Commun. 126 (1985) 1269–1275PubMedGoogle Scholar
  48. Trijbels, J., Monnens, L., Bakkeren, J. and van Raay-Selten, A. Biochemical studies in the cerebro-hepato-renal syndrome of Zellweger: a disturbance in the metabolism of pipecolic acid.J. Inher. Metab. Dis. 2 (1979) 39–42Google Scholar
  49. Vamecq, J. and van Hoof, F. Implication of a peroxisomal enzyme in the catabolism of glutaryl-CoA.Biochem. J. 221 (1984) 203–211PubMedGoogle Scholar
  50. Wanders, R. J. A., Kos, M., Roest, B.et al. Activity of peroxisomal enzymes and intracellular distribution of catalase in Zellweger syndrome.Biochem. Biophys. Res. Commun. 123 (1984) 1054–1061PubMedGoogle Scholar
  51. Wanders, R. J. A., van Weringh, G., Schrakamp, G., Tager, J. M., van den Bosch, H. and Schutgens, R. B. H. Deficiency of acyl-CoA: dihydroxyacetone phosphate acyltransferase in thrombocytes of Zellweger patients: a simple postnatal diagnostic test.Clin. Chim. Acta 151 (1985a) 217–221PubMedGoogle Scholar
  52. Wanders, R. J. A., Schutgens, R. B. H. and Tager, J. M. Peroxisomal matrix enzymes in Zellweger syndrome: activity and subcellular localisation in liver.J. Inher. Metab. Dis. 8 Suppl. 2 (1985b) 151–152Google Scholar
  53. Wanders, R. J. A., van Roermund, C. M. T., de Vries, C. T., van den Bosch, H., Schrakamp, G., Tager, J. M., Schram, A. W. and Schutgens, R. B. H. Peroxisomal β-oxidation of palmitoyl-CoA in human liver homogenates and its deficiency in the cerebro-hepatorenal (Zellweger) syndrome.Clin. Chim. Acta 159 (1986a) 1–10PubMedGoogle Scholar
  54. Wanders, R. J. A., Purvis, Y. R., Heymans, H. S. A., Bakkeren, J. A. J. M., Parmentier, G. G.et al. Age-related differences in plasmalogen content of erythrocytes from patients with the cerebro-hepato-renal (Zellweger) syndrome: implications for postnatal detection of the disease.J. Inher. Metab. Dis. 9 (1986b) 335–342PubMedGoogle Scholar
  55. Wanders, R. J. A., Heymans, H. S. A., Schutgens, R. B. H., van Eldere, J. and Eyssen, H. J. Impaired cholesterol side chain cleavage activity in liver from patients with the cerebro-hepato-renal (Zellweger) syndrome in relation to the accumulation of di- and trihydroxy-coprostanoic in serum from the patients.J. Inher. Metab. Dis. 9, Suppl. 2 (1986c) 321–324PubMedGoogle Scholar
  56. Wanders, R. J. A., Schrakamp, G., van den Bosch, H., Tager, J. M. and Schutgens, R. B. H. A prenatal test for the cerebro-hepato-renal (Zellweger) syndrome by demonstration of the absence of catalase-containing particles (peroxisomes) in cultured amniotic fluid cells.Eur. J. Pediatr. 145 (1986d) 136–138PubMedGoogle Scholar
  57. Wilson, G. N., Holmes, R. G., Custer, J., Lipkowitz, J. L., Stover, J., Datta, N. and Hajra, A. Zellweger syndrome: Diagnostic assays, syndrome delineation, and potential therapy.Am. J. Med. 24 (1986) 69–82PubMedGoogle Scholar
  58. Woody, N. C. and Pupene, M. B. Excretion of pipecolic acid by infants and by patients with hyperlysinemia.Pediatr. Res. 4 (1970) 89–95PubMedGoogle Scholar

Copyright information

© SSIEM and MTP Press Limited 1987

Authors and Affiliations

  • R. B. H. Schutgens
    • 1
  • R. J. A. Wanders
    • 1
  • H. S. A. Heymans
    • 1
  • A. W. Schram
    • 2
  • J. M. Tager
    • 2
  • G. Schrakamp
    • 3
  • H. van den Bosch
    • 3
  1. 1.Department of PediatricsUniversity Hospital AmsterdamAmsterdamThe Netherlands
  2. 2.Department of BiochemistryUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of BiochemistryState University UtrechtUtrechtThe Netherlands

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