Advertisement

Zellweger Cerebrohepatorenal Syndrome

  • Jacob Valk
  • Marjo S. van der Knaap

Abstract

The cerebrohepatorenal syndrome (CHRS), also called Zellweger syndrome, is a fatal autosomal recessive disorder. After birth the affected children show profound muscular hypotonia or even atonia. Most patients lie motionless with weak or absent Moro reflex, tendon reflexes and sucking and swallowing reflexes. Typically, the children’s faces have a high and bulging forehead, upslanting palpebral fissures, pufffy eyelids, hypoplastic supraorbital ridges, hypertelorism, and epicanthus folds, giving them a mongoloid appearance. Besides Brushfield spots, peripheral pigmentary retinopathy, optic atrophy or hypoplasia, glaucoma, corneal clouding, cataracts, low-set malformed ears, high arched palate, round face, micrognathia, and widely patent sutures and fontanels are present. Hepatomegaly, prolonged neonatal or later-onset icterus, and hemorrhages due to hypoprothrombinemia are common. Limb anomalies include cubitus valgus, camptodactyly, and talipes equinovarus. Failure to thrive and severe psychomotor retardation are conspicuous. Convulsions are frequent. Cardiac defects are not frequent, but a ventricular septum defect, a patent ductus arteriosus, and a patent foramen ovale may occur. Cryptorchidism is frequently observed in boys, clitoromegaly, and labial hypoplasia in girls. About 85% of patients die within the first year of life, death occurring in the majority within the first few months.

Keywords

Phytanic Acid Patent Ductus Arteriosus Peroxisomal Membrane Pipecolic Acid Peroxisomal Enzyme 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Agamanolis DP, Patre S (1979) Glycogen accumulation in the central nervous system in the cerebrohepatorenal syndrome. J Neurol Sci 41: 325–342PubMedCrossRefGoogle Scholar
  2. Agamanolis DP, Robinson HB, Timmons CD (1976) Cerebrohepatorenal syndrome. J Neuropath Exp Neurol 35: 226–246PubMedCrossRefGoogle Scholar
  3. Applegarth DA, Dimmick JE (1985) Annotated Bibliography: adrenoleukodystrophy, cerebrohepatorenal syndrome ( Zellweger Syndrome), and peroxisomes. Pediatr Pathol 3: 377–378PubMedCrossRefGoogle Scholar
  4. Arias JA, Moser AB, Goldfischer SL (1985) Ultrastructural and cytochemical demonstration peroxisomes in cultured fibroblasts from patients with peroxisomal deficiency disorders. J Cell Biol 100: 1789–1792PubMedCrossRefGoogle Scholar
  5. Aubourg P, Robain O, Rocchiccioli F, Dancea S, et al. (1985) The cerebrohepatorenal (Zellweger) syndrome: lamellar lipid profiles in adrenocortical, hepatic mesenchymal, astrocyte cells and increased levels of very long chain fatty acids and phytanic acid in the plasma. J Neurol Sci 69: 9–25PubMedCrossRefGoogle Scholar
  6. Bart PG, Schutgens RBH, Bakkeren JAJM, Dingemans KP, et al. (1985) A milder variant of Zellweger syndrome. Eur J Pediatr 144: 338–342CrossRefGoogle Scholar
  7. Beard ME, Baker R, Conomos P, Pugatch D, et al. (1985) Oxidation of oxalate and polyamines by rat peroxisomes. J Histochem Cytochem 33: 460–464PubMedCrossRefGoogle Scholar
  8. Clayton PT, Lake BD, Hall NA, Shortland DB, et al. (1987) Plasma bile acids in patients with peroxisomal dysfunction syndromes: analysis by capillary gas chromatography-mass spectrometry. Eur J Pediatr 146: 166–173PubMedCrossRefGoogle Scholar
  9. Cohen SMZ, Brown FR, Marlyn L, Moser HW, et al. (1983) Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome ( Zellweger’s syndrome) and its relationship to neonatal adrenoleukodystrophy. Am J Ophthalmol 96: 488–501Google Scholar
  10. Datta NS, Wilson GN, Hajra AK (1984) Deficiency of enzymes catalyzing the biosynthesis of glycerol-ether lipids in Zellweger syndrome. N Engl J Med 311: 1080–1083PubMedCrossRefGoogle Scholar
  11. Ek J, Kase BF, Reith A, Björkhem I, et al. (1986) Peroxisomal dysfunction in a boy with neurologic symptoms and amaurosis (Leber disease): clinical and biochemical findings similar to those observed in Zellweger syndrome. J Pediatr 108: 19–24PubMedCrossRefGoogle Scholar
  12. Evrard P, Caviness VS, Prats-Vinas J, Lyon G (1978) The mechanism of arrest of neuronal migration in the Zell-weger malformation: an hypothesis bases upon cytoarchitectonic analysis. Acta Neuropath 41: 109–117PubMedCrossRefGoogle Scholar
  13. Goldfischer S, Johnson AB, Essner E, Moore C, et al. (1973) Peroxisomal abnormalities in metabolic diseases. J Histochem Cytochem 21: 972–977PubMedCrossRefGoogle Scholar
  14. Goldfischer S, Moore CL, Johnson AB, Spiro A, et al. (1973) Peroxisomal and mitochondrial defects in the cerebrohepatorenal syndrome. Science 182: 62–64PubMedCrossRefGoogle Scholar
  15. Goldfischer S, Powers JM, Johnson JM, Johnson AB, et al. (1983) Striated adrenocortical cells in cerebrohepatorenal ( Zellweger) syndrome. Virchows Arch 401: 355–361Google Scholar
  16. Heymans HSA, Schutgens RBH, Tan R, Bosch van den H, et al. (1983) Severe plasmalogen deficiency in tissues of infants without peroxisomes ( Zellweger syndrome ). Nature 306: 69–70Google Scholar
  17. Kelley R (1983) Review: the cerebrohepatorenal syndrome of Zellweger morphologic and metabolic aspects. Am J Med Genet 16: 503–517PubMedCrossRefGoogle Scholar
  18. Lawson AM, Madigan MJ, Shortland D, Clayton PT (1986) Rapid diagnosis of Zellweger’s syndrome and infantile Refsum’s disease by fast atom bombardment-mass spectrometry of urine bile salts. Clin Chim Acta 161: 221–231PubMedCrossRefGoogle Scholar
  19. Léon de GA, Grover WD, Huff DS, Morinigo-Mestre G, et al. (1977) Globoid cells, glial nodules, and peculiar fibrilla.(changes in the cerebrohepatorenal syndrome of Zellweger. Ann Neurol 2: 473–484PubMedCrossRefGoogle Scholar
  20. Mei Liu H, Bangaru BS, Kidd J, Boggs J (1976) Neuropatho-logical considerations in cerebrohepatorenal syndrome ( Zellweger’s syndrome ). Acta Neuropath 34: 115–123Google Scholar
  21. Molzer B, Korschinsky M, Bernheimer H, Schmid R, et al. (1986) Very long chain fatty acids in genetic peroxisomal disease fibroblasts: differences between the cerebrohepatorenal ( Zellweger) syndrome and adrenoleukodystrophy variants. Clin Chim Acta 161: 81–90Google Scholar
  22. Mortensen PB, Gregersen N, Rasmussen K, Kr lvraa S (1983) The /3-oxidation of dicarboxylic acids in isolated mitochondria and peroxisomes. J lnher Metab Dis 6: 123–124CrossRefGoogle Scholar
  23. Moser AE, Singh I, Brown FR, Solish GI, et al. (1984) The cerebrohepatorenal ( Zellweger) syndrome. N Engl J Med 310: 1141–1146PubMedCrossRefGoogle Scholar
  24. Müller-Höcker J, Walther JU, Bise K, Pongratz, et al. (1984) Mitochondrial myopathy with loosely coupled oxidative phosphorylation in a case of Zellweger syndrome. Virchows Arch 45: 125–138CrossRefGoogle Scholar
  25. Passarge E, McAdams AJ (1967) Cerebrohepatorenal syndrome. J Pediatr 71: 691–702PubMedCrossRefGoogle Scholar
  26. Pedersen JI, Gustafsson J (1980) Conversion of 3a, 7a, 12atrihydroxy-5/-cholestanoic acid into cholic acid by rat liver peroxisomes. Febs Lett 21: 345–348CrossRefGoogle Scholar
  27. Poulos A, Sharp P, Fellenberg AJ, Danks DM (1985) Cerebrohepatorenal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum’s disease: plasma changes and skin fibroblast phytanic acid oxidase. Hum Genet 70: 172–177PubMedCrossRefGoogle Scholar
  28. Poulos A, Singh H, Paton B, Sharp P, et al. (1986) Accumulation and defective /1-oxidation of very long chain fatty acids in Zellweger’s syndrome, adrenoleukodystrophy and Refsum’s disease variants. Clin Genet 29: 397–408PubMedCrossRefGoogle Scholar
  29. Powers JM, Moser HW, Moser AB, Upshur JK, et al. (1985) Fetal cerebrohepatorenal (Zellweger) syndrome: dysmorphic, radiologic, biochemical and pathologic findings in four affected fetuses. Hum Pathol 16: 610–620PubMedCrossRefGoogle Scholar
  30. Powers JM, Tummons RC, Moser AB, Moser HW, et al. (1987) Neuronal lipidosis and neuroaxonal dystrophy in cerebro-hepato-renal ( Zellweger) syndrome. Acta Neuropathol 73: 333–343PubMedCrossRefGoogle Scholar
  31. Rachubinski R, Fujiki Y, Mortensen RM, Lazarow PB (1984) Acyl-CoA oxidase and hydratase-dehydrogenase, two enzymes of the peroxisomal fi-oxidation system, are synthesized on free polysomes of clofibrate-treated rat liver. J Cell Biol 99: 2241–2246PubMedCrossRefGoogle Scholar
  32. Rocchiccioli F, Cartier PH, Aubourg P, Bougnères PF (1986) Mass spectrometric identification of 2-hydroxy-sebacic acid in the urines of patients with neonatal adrenoleukodystrophy and Zellweger syndrome. Biomed Environ Mass Spectrom 13: 315–318PubMedCrossRefGoogle Scholar
  33. Roscher A, Molzer B, Bernheimer H, Stöckler S, et al. (1985) The cerebrohepatorenal (Zellweger) syndrome: an improved method for the biochemical diagnosis and its potential value for prenatal detection. Pediatr Res 19: 930–933PubMedCrossRefGoogle Scholar
  34. Santos M, Leighton F (1984) Subcellular distribution of peroxisomal enzymes in Zellweger syndrome fibroblasts. Int Cell Biology 1273Google Scholar
  35. Santos MJ, Imanaka T, Shio H, Small GM, et al. (1988) Peroxisomal membrane ghosts in Zellweger syndrome–aberrant organelle assembly. Science 239: 1536–1538PubMedCrossRefGoogle Scholar
  36. Schram AW, Strijland A, Hashimoto T, Wanders RJA, et al. (1986) Biosynthesis and maturation of peroxisomal fi-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum’s disease. Proc Natl Acad Sci 83: 6156–6158PubMedCrossRefGoogle Scholar
  37. Schutgens RBH, Romeyn GJ, Wanders RJA, Bosch van den H, et al. (1984) Deficiency of acyl-CoA: dihydroxyacetone phosphate acyl transferase in patients with Zellweger (cerebro-hepato-renal) syndrome. Biochem Biophys Res Comm 120: 179–184PubMedCrossRefGoogle Scholar
  38. Schutgens RBH, Wanders RJA, Heymans HSA, Schram AW, et al. (1987) Zellweger syndrome: biochemical procedures in diagnosis, prevention and treatment. J Inherited Metab Dis 10: 33–45PubMedCrossRefGoogle Scholar
  39. Singh I, Moser AE, Goldfischer S, Moser HW (1984) Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebrohepatorenal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci 81: 4203–4207PubMedCrossRefGoogle Scholar
  40. Stokke O, Skrede S, Ek J, Björkhem I (1984) Refsum’s disease, adrenoleucodystrophy, and the ‘Zellweger syndrome. Scand J Clin Lab Invest 44: 463–464PubMedCrossRefGoogle Scholar
  41. Trijbels JMF, Berden JA, Monnens LAH, Willems JL, et al. (1983) Biochemical studies in the liver and muscle of patients with Zellweger syndrome. Pediatr Res 17: 514–517PubMedCrossRefGoogle Scholar
  42. Vamecq J, Draye JP, Hoof van F, Misson JP, et al. (1986) Multiple peroxisomal enzymatic deficiency disorders. Am J Pathol 125: 524–535PubMedGoogle Scholar
  43. Versmold HT, Bremer HJ, Herzog V, Siegel G, et al. (1977) A metabolic disorder similar to Zellweger syndrome with hepatic acatalasia and absence of peroxisomes, altered content and redox state of cytochromes, and infantile cirrhosis with hemosiderosis. Eur J Pediatr 124: 261–275PubMedCrossRefGoogle Scholar
  44. Volpe JJ, Adams RD (1972) Cerebrohepatorenal syndrome of Zellweger: an inherited disorder of neuronal migration. Acta Neuropath 20: 175–198PubMedCrossRefGoogle Scholar
  45. Wanders RJA, Kos M, Roest B, Meijer AJ, et al. (1984) Activity of peroxisomal enzymes and intracellular distribution of catalase in Zellweger syndrome. Biochem Biophys Res Comm 123: 1054–1061PubMedCrossRefGoogle Scholar
  46. Wanders RJA, Saelman D, Heymans HS, Schutgens RB, et al. (1986) Genetic relation between the Zellweger syndrome, infantile Refsum’s disease, and rhizomelic chondrodysplasia punctata. N Engl J Med 314: 787–788PubMedCrossRefGoogle Scholar
  47. Wanders RJA, Roermund van CWT, Wijland van MJA, Heikoop J, et al. (1987) Peroxisomal very long-chain fatty acid fl-oxidation in human skin fibroblasts: activity in Zellweger syndrome and other peroxisomal disorders. Clin Chim Acta 166: 255–263PubMedCrossRefGoogle Scholar
  48. Wanders RJA, Schutgens RBH, Tager JM (1985) Peroxisomal matrix enzymes in Zellweger syndrome: activity and sub-cellular localization in liver. J Inher Metab Dis 8: 151–152PubMedCrossRefGoogle Scholar
  49. Wilson GN, Holmes RG, Custer J, Lipkowitz JL, et al. (1986) Zellweger syndrome: diagnostic assays, syndrome delineation, and potential therapy. Am J Med Genet 24: 69–82PubMedCrossRefGoogle Scholar
  50. Zellweger H (1982) Cerebrohepatorenal syndrome. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, vol 43. Amsterdam: North Holland Publishing Company: 338–340Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • Jacob Valk
    • 1
  • Marjo S. van der Knaap
    • 2
  1. 1.Department of Diagnostic Radiology and NeuroradiologyFree University HospitalAmsterdamThe Netherlands
  2. 2.Department of Child NeurologyAcademic HospitalUtrechtThe Netherlands

Personalised recommendations