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
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
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
Borst P (1983) Animal peroxisomes (microbodies), lipid biosynthesis and the Zellweger syndrome. Trends Biochem Sci 8: 269–272
Bowen P, Lee CSN, Zellweger H, Lindenberg R (1964) A familial syndrome of multiple congenital defects. Bull Johns Hopkins Hosp 114:402–414
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
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
Burton BK, Reed SP, Remy WT (1981) Hyperpipecolic acidemia: clinical and biochemical observations in two male siblings. J Pediatr 99:729–734
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
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
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
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
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
Haas JE, Johnson ES, Farrell DL (1982) Neonatal-onset adrenoleukodystrophy in a girl. Ann Neurol 12:449–457
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
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
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
Heymans HSA, Oorthuys JWE, Nelck G, Wanders RJA, Schutgens RBH (1985) Rhizomelic chondrodysplasia punctata: another peroxisomal disorder. N Engl J Med 313:187–188
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
Kahlke W, Goerlich R, Feist D (1974) Erhöhte Phytansäurespiegel in Plasma und Leber bei einem Kleinkind mit unklarem Hirnschaden. Klin Wochenschr 52:651–653
Kelley RI (1983) Review. The cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet 16:503–517
Kelley RI, Moser HW (1984) Hyperpipecolic acidemia in neonatal adrenoleukodystrophy. Am J Med Genet 19:791–795
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
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
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
Noetzel MJ, Clark HB, Moser HW (1983) Neonatal adrenoleukodystrophy with prolonged survival. Ann Neurol 14:379
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
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
Partin JS, McAdams AJ (1983) Absence of hepatic peroxisomes in neonatal onset adrenoleukodystrophy. Pediatr Res 17:294A
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
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
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
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
Poulos A, Sharp P (1984) Plasma and skin fibroblasts C26 fatty acids in infantile Refsum's disease. Neurology 34:1606–1609
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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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