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Infantile Refsum disease: an inherited peroxisomal disorder

Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy

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Abstract

Three patients affected by infantile Refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical Zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile Refsum disease, neonatal adrenoleukodystrophy or Zellweger syndrome who survived for several years. Attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to Zellweger syndrome.

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Abbreviations

IRD:

infantile Refsum disease

ZS:

Zellweger syndrome

NALD:

neonatal adrenoleukodystrophy

ERG:

electroretinogram

VEP:

visual evoked potentials

BAEP:

brainstem auditory evoked potentials

SSEP:

somatosensory evoked potentials

ACTH:

adrenocorticotropin hormone

VLCFA:

very long chain fatty acids

THCA:

trihydroxycoprostanoic acid

DHCA:

dihydroxycoprostanoic acid

DHAP-AT:

acyl-CoA: dihydroxyacetone phosphate acyltransferase

References

  1. Aubourg P, Robain O, Rocchiccioli F, Dancea S, Scotto J (1985) The cerebro-hepato-renal (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 69:9–25

    Google Scholar 

  2. Boltshauser F, Spycher MA, Stelnmann B, Briner J, Isler W, Kusler T, Poulos A, Pollard AC (1982) Infantile phytanic acid storage disease: a variant of Refsum's disease?, Eur J Pediatr 139:317

    Google Scholar 

  3. Borst P (1983) Animal peroxisomes (microbodies), lipid biosynthesis and the Zellweger syndrome. Trends Biochem Sci 8: 269–272

    Google Scholar 

  4. Bowen P, Lee CSN, Zellweger H, Lindenberg R (1964) A familial syndrome of multiple congenital defects. Bull Johns Hopkins Hosp 114:402–414

    Google Scholar 

  5. Brown FR III, McAdams AJ, Cummins JW, Konkol R Singh I, Moser AB, Moser HW (1982) Cerebro-hepato-renal (Zellweger) syndrome and neonatal adrenoleukodystrophy: similarities in phenotype and accumulation of very long chain fatty acids Johns Hopkins Med J 151:344–351

    Google Scholar 

  6. Budden SS, Kennaway NG, Buist NRM, Poulos A, Weleber KG (1986) Dysmorphic syndrome with phytanic acid oxidase deficiency, abnormal very long chain fatty acids, and pipecolic acidemia: studies in four children. J Pediatr 108:33–39

    Google Scholar 

  7. Burton BK, Reed SP, Remy WT (1981) Hyperpipecolic acidemia: clinical and biochemical observations in two male siblings. J Pediatr 99:729–734

    Google Scholar 

  8. Goldfischer S, Moore CL, Johnson AB, Spiro AJ, Valsamis MP, Wisniewski HK, Ritch RH, Norton WT, Papin I, Gartner LM (1973) Peroxisomal and mitochondrial defects in the cerebrohepato-renal syndrome. Science 182:62–64

    Google Scholar 

  9. Goldfischer S, Collins J, Rapin I, Coltoff-Schiller B, Chang CH, Nigro M, Black VH, Javitt NB, Moser HW, Lazarow PB (1985) Peroxisomal defects in neonatal-onset and X-linked adrenoleukodystrophies. Science 227:67–70

    Google Scholar 

  10. Goldfischer S, Collins J, Rapin I, Neumann P, Neglia W, Spiro AJ, Ishii T, Roels F, Vamecq J, van Hoof F (1986) Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. J Pediatr 108:25–32

    Google Scholar 

  11. Govaerts L, Monnens L, Tegelaers W, Trijbels F, van Raay-Selten A (1982) Cerebro-hepato-renal syndrome of Zellweger: clinical symptoms and relevant laboratory findings in 16 patients. Eur J Pediatr 139:125–128

    Google Scholar 

  12. Govaerts L, Monnens L, Melis T, Trijbels F (1984) Disturbed adrenocortical function in cerebro-hepato-renal syndrome of Zellweger. Eur J Pediatr 143:10–12

    Google Scholar 

  13. Haas JE, Johnson ES, Farrell DL (1982) Neonatal-onset adrenoleukodystrophy in a girl. Ann Neurol 12:449–457

    Google Scholar 

  14. Hajra AK, Datta NS, Jackson LG, Moser AB, Moser HW, Larsen JW, Powers J (1985) Prenatal diagnosis of Zellweger cerebrohepato-renal syndrome. N Engl J Med 312:445–446

    Google Scholar 

  15. Hanson RF, Szczepanik-Van Leeuwen P, Williams GC, Gabrowski G, Sharp HL (1979) Defects of bile acid synthesis in Zellweger's syndrome. Science 203:1107–1108

    Google Scholar 

  16. Heymans HSA, Schutgens RBH, Tan R, van den Bosch H, Borst P (1983) Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome). Nature 306:69–70

    Google Scholar 

  17. Heymans HSA, Oorthuys JWE, Nelck G, Wanders RJA, Schutgens RBH (1985) Rhizomelic chondrodysplasia punctata: another peroxisomal disorder. N Engl J Med 313:187–188

    Google Scholar 

  18. Jaffe R, Crumrine P, Hashida Y, Moser HW (1982) Neonatal adrenoleukodystrophy. Clinical, pathologic and biochemical delincation of a syndrome affecting both males and females. Am J Pathol 108:100–111

    Google Scholar 

  19. Kahlke W, Goerlich R, Feist D (1974) Erhöhte Phytansäurespiegel in Plasma und Leber bei einem Kleinkind mit unklarem Hirnschaden. Klin Wochenschr 52:651–653

    Google Scholar 

  20. Kelley RI (1983) Review. The cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 16:503–517

    Google Scholar 

  21. Kelley RI, Moser HW (1984) Hyperpipecolic acidemia in neonatal adrenoleukodystrophy. Am J Med Genet 19:791–795

    Google Scholar 

  22. Manz HJ, Schuelein M, McCullough DC, Kishimoto Y, Eiben RM (1980) New phenotypic variant of adrenoleukodystrophy. Pathologic, ultrastructural and biochemical study in two brothers. J Neurol Sci 45:245–260

    Google Scholar 

  23. Moser HW, Moser AB, Powers JM, Nitowski HM, Schaumburg HH, Norum RA, Migeon BR (1982) The prenatal diagnosis of adrenoleukodystrophy. Demonstration of increase hexacosanoic acid levels in cultured amniocytes and fetal adrenal gland. Pediatr Res 16:172–175

    Google Scholar 

  24. Moser AE, Singh I, Brown FR III, Solish GI, Kelley RI, Benke PJ, Moser HW (1984) The cerebro-hepato-renal (Zellweger) syndrome. Increased levels and impaired degradation of very long chain fatty acids and their use in prenatal diagnosis. N Engl J Med 310:1141–1146

    Google Scholar 

  25. Noetzel MJ, Clark HB, Moser HW (1983) Neonatal adrenoleukodystrophy with prolonged survival. Ann Neurol 14:379

    Google Scholar 

  26. Ogier H, Roels F, Cornelis A, Poll-The BT, Scotto JM, Odièvre M, Saudubray JM (1985) Absence of hepatic peroxisomes in a case of infantile Refsum's disease. Scand J Clin Lab Invest 45: 767–768

    Google Scholar 

  27. Opitz JM, Zu Rhein GM, Vitale L, Shahidi NT, Howe JJ, Chon SM, Shanklin DR, Sybers HD, Dood AT, Gerritsen T (1969) The Zellweger syndrome (cerebro-hepato-renal syndrome). Birth Defects 5/2:144–158

    Google Scholar 

  28. Partin JS, McAdams AJ (1983) Absence of hepatic peroxisomes in neonatal onset adrenoleukodystrophy. Pediatr Res 17:294A

    Google Scholar 

  29. Poll-The BT, Poulos A, Sharp P, Boué J, Ogier H, Odièvre M, Saudubray JM (1985) Antenatal diagnosis of infantile Refsum's disease. Clin Genet 27:524–526

    Google Scholar 

  30. Poll-The BT, Ogier H, Saudubray JM, Schutgens RBH, Wanders RJA, van den Bosch H, Schrakamp G (1986) Impaired plasmalogen metabolism in infantile Refsum's disease. Eur J Pediatr 144:513–514

    Google Scholar 

  31. Poll-The BT, Saudubray JM, Ogier H, Schutgens RBH, Wanders RJA, Schrakamp G, van den Bosch H, Trijbels F, Poulos A, Moser HW, van Elderen J, Eyssen H (1986) Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction. J Inherited Metab Dis 9:169–174

    Google Scholar 

  32. Poll-The BT, Saudubray JM, Rocchiccioli F, Scotto J, Roels F, Bove J, Ogier H, Dumez Y, Wanders RJA, Schutgens RBH, Schram AW, Tager JM (1987) Prenatal diagnosis and confirmation of infantile Refsum's disease. J Inherited Metab Dis [Suppl 2] 10

  33. Poulos A, Sharp P (1984) Plasma and skin fibroblasts C26 fatty acids in infantile Refsum's disease. Neurology 34:1606–1609

    Google Scholar 

  34. Poulos A, Whiting MJ (1985) Identification of 3α, 7α, 12α-trihydroxy-5β-cholestan-26-oic acid, an intermediate in cholic acid synthesis, in the plasma of patients with infantile Refsum's disease. J Inherited Metab Dis 8:13–17

    Google Scholar 

  35. Poulos A, Sharp P, Whiting M (1984) Infantile Refsum's disease (phytanic acid storage disease). A variant of Zellweger syndrome? Clin Genet 26:579–586

    Google Scholar 

  36. Roels F, Goldfischer S (1979) Cytochemistry of human catalase: the demonstration of hepatic and renal peroxisomes by a high temperature procedure. J Histochem Cytochem 27:1471–1477

    Google Scholar 

  37. Roels F, Cornelis A, Poll-The BT, Aubourg P, Ogier H, Scotto JM, Saudubray JM (1986) Hepatic peroxisomes are deficient in infantile Refsum disease. A cytochemical study of 4 cases. Am J Med Genet 25:257–271

    Google Scholar 

  38. Schutgens RBH, Scharkamp G, Wanders RJA, Heymans HSA, Moser HW, Moser AE, Tager JM, van den Bosch H, Aubourg P (1985) The cerebro-hepato-renal (Zellweger) syndrome: prenatal detection based on impaired biosynthesis of plasmalogens. Prenat Diagn 5:337–344

    Google Scholar 

  39. Schutgens RBH, Heymans HSA, Wanders RJA, van den Bosch H, Tager JM (1986) Peroxisomal disorders: a newly recognized group of genetic diseases. Eur J Pediatr 144:430–440

    Google Scholar 

  40. Scotto JM, Hadchouel M, Odièvre M, Laudat MH, Saudubray JM, Dulac O, Beucler I, Beaune P (1982) Infantile phytanic acid storage disease, a possible variant of Refsum's disease: three cases, including ultrastructural studies of the liver. J Inherited Metab Dis 5:83–90

    Google Scholar 

  41. Stokke O, Skrede S, Ek J, Björkhem I (1984) Refsum's disease, adrenoleukodystrophy, and the Zellweger syndrome. Scand J Clin Lab Invest 44:463–464

    Google Scholar 

  42. Tager JM, Ten Harmsen van der Beek WA, Wanders RJA, Hashimoto T, Heymans HSA, van den Bosch H, Schutgens RBH, Schram AW (1985) Peroxisomal β-oxidation enzyme proteins in the Zellweger syndrome. Biochem Biophys Res Commun 126: 1269–1275

    Google Scholar 

  43. Trijbels J, Monnens L, Bakkeren J, van Raay-Selten A (1979) Biochemical studies in the cerebro-hepato-renal syndrome of Zellweger: a disturbance in the metabolism of pipecolic acid. J Inherited Metab Dis 2:39–42

    Google Scholar 

  44. Ulrich J, Herschkowitz N, Heitz P, Sigrist TH, Baerlocher P (1978) Adrenoleukodystrophy: preliminary report of a connatal case: light-and-electron microscopical, immunohistochemical and biochemical findings. Acta Neuropathol (Berl) 43:77–83

    Google Scholar 

  45. Wanders RJA, Kos M, Roest B, Meijer AJ, Schrakamp G, Heymans HSA, Tegelaers WHH, van den Bosch H, Schutgens RBH, Tager JM (1984) Activity of peroxisomal enzymes and intracellular distribution of catalase in Zellweger syndrome. Biochem Biophys Res Commun 123:1054–1061

    Google Scholar 

  46. Wanders RJA, Schutgens RBH, Schrakamp G, van den Bosch H, Tager JM, Schram AW, Hashimoto T, Poll-The BT, Saudubray JM (1986) Infantile Refsum disease: deficiency of catalase-containing particles (peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal β-oxidation enzyme proteins. Eur J Pediatr 145:172–175

    Google Scholar 

  47. Wanders RJA, Schrakamp G, van den Bosch H, Tager JM, Schutgens RBH (1986) A prenatal test for the cerebro-hepatorenal (Zellweger) syndrome by the demonstration of the absence of catalase-containing particles (peroxisomes) in cultured amniotic fluid cells. Eur J Pediatr 145:136–138

    Google Scholar 

  48. Wanders RJA, Saelman D, Heymans HSA, Schutgens RBH, Westerveld A, Poll-The BT, Saudubray JM, Van den Bosch H, Strijland A, Schram AW, Tager JM (1986) Genetic relationship between the Zellweger syndrome, infantile Refsum disease and rhizomelic chondrodysplasia punctala. N Engl J Med 314:787–788

    Google Scholar 

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Poll-The, B.T., Saudubray, J.M., Ogier, H.A.M. et al. Infantile Refsum disease: an inherited peroxisomal disorder. Eur J Pediatr 146, 477–483 (1987). https://doi.org/10.1007/BF00441598

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  • DOI: https://doi.org/10.1007/BF00441598

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