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Treatment of infantile phytanic acid storage disease: clinical, biochemical and ultrastructural findings in two children treated for 2 years

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Abstract

Two patients with infantile phytanic acid storage disease (infantile Refsum disease), one of whom showed the presence of morphologically normal peroxisomes in a liver biopsy, were treated with a low phytanic acid diet for more than 2 years and the effects of treatment on certain clinical, biochemical and ultrastructural parameters were examined. Both patients showed evidence of either an improvement or stabilisation in their clinical condition. Plasma phytanic acid levels decreased to near normal values in approximately 6 weeks after the introduction of the diet; plasma pipecolic acid also declined markedly but the decrease was not so rapid and its level remained abnormal. C26∶C22 fatty acid ratios decreased very slowly and even after 2 years the values remained grossly abnormal. Despite the marked reduction of phytanic acid in the liver, there was an increase in the C26∶C22 fatty acid ratios and this appeared to be paralleled by an increase in inclusion bodies. Our data suggest that some patients with the infantile form of Refsum disease may show some clinical benefit from dietary management and this is reflected biochemically by decreases in the plasma levels of phytanic acid and pipecolic acid.

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Abbreviations

VLCFA:

very long chain fatty acids

ALD:

adrenoleukodystrophy

References

  1. Barka T, Anderson PJ (1962) Histochemical methods for acid phosphatase using hexazonium pararosanilin as coupler. J Histochem Cytochem 10:741–753

    Google Scholar 

  2. Barth PG, Schutgens RB, Bakkeren JAJM, Dingemans KP, Heymans HSA, Douwes AC, Van der Klei-Van Moorsel JM (1980) A milder variant of Zellweger syndrome. Eur J Pediatr 144:338–342

    Google Scholar 

  3. Berkovic SF, Zajak JD, Warburton DJ, Merory JD, Fellenberg AJ, Poulos A, Pollard AC (1983) Adrenomyeloneuropathy: Clinical and biochemical diagnosis. Aust NZ J Med 13:594–600

    Google Scholar 

  4. Budden SS, Kennaway NG, Buist N, Poulos A, Weleber RG (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 

  5. Chang YF (1978) Lysine metabolism in the rat brain: the pipecolic acid forming pathway. J Neurochem Res 30:347–354

    Google Scholar 

  6. Chang YF (1982) Lysine metabolism in the human and the monkey. Demonstration of pipecolic acid formation in the brain and other organs. Neurochem Res 7:577–588

    Google Scholar 

  7. Eldjarn L, Stokke O (1979) Biochemical and dietary aspects of Refsum disease. In: Dyck PJ, Thomas PK, Lambert EH (eds) Peripheral neuropathy. Saunders, Philadelphia

    Google Scholar 

  8. Eldjarn L, Try K, Stokke E, Munthe-Kaas WA, Refsum S, Steinberg D, Avigan J, Mize C (1966) Dietary effects of serum phytanic acid levels and on clinical manifestations in heredopathia atactica polyneuritiformis. Lancet I:691–693

    Google Scholar 

  9. Folch J, Lees M, Sloane-Stanley G (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509

    Google Scholar 

  10. Giacobini E (1976) Piperidine: a new neuromodulator or a hypogenic substance. Adv Biochem Psychopharmacol 15:17–56

    Google Scholar 

  11. Giacobini E, Nomura Y, Schmidt-Glenewinkel T (1980) Pipecolic acid: origin biosynthesis and metabolism in the brain. Cell Mol Biol 26:135–146

    Google Scholar 

  12. Gibberd FB, Page NGR, Billimoria JD, Retsas S (1979) Heredopathia atactica polyneuritiformis (Refsum disease) treated by diet and plasma-exchange. Lancet I:575–578

    Google Scholar 

  13. Goldfischer S, Moore CL, Johnson AB (1973) Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. Science 182:62–64

    Google Scholar 

  14. Goldfischer S, Collins J, Rapin I, Colthoff-Schiller G, Chang CH, Nigro M, Black VH, Javitt N, Moser HW, Lazarow PB (1985) Peroxisomal defects in neonatal onset and X-linked adrenoleukodystrophies. Science 227:67–69

    Google Scholar 

  15. Kase Y, Okano Y, Yamanishi Y (1970) In vivo production of piperidine from pipecolic acid in the rat. Life Sci 9:1381–1387

    Google Scholar 

  16. Kase Y, Takahama K, Hashimoto T, Kaisaku J, Okano Y, Miyata T (1980) Electrophoretic study of pipecolic acid, a biogenic amino acid, in the mammalian brain. Brain Res 193:608–613

    Google Scholar 

  17. Masters-Thomas A, Barles J, Billimoria JD, Clemens ME, Gibberd AB, Page NR (1980) Heredopathia atactica polyneuritiformis (Refsum disease). Clinical features and dietary management. J Hum Nutr 34:245–250

    Google Scholar 

  18. Novikoff AB, Goldfischer S (1969) Visualisation of peroxisomes (microbodies) and mitochondria with diaminobenzidine. J Histochem Cytochem 17:675–680

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  21. Poulos A (1981) Diagnosis of Refsum disease using [1-14C] phytanic acid as substrate. Clin Genet 20:247–253

    Google Scholar 

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

    Google Scholar 

  23. Poulos A, Whiting M (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 disease. J Inherited Metab Dis 8:13–17

    Google Scholar 

  24. Poulos A, Sharp P, Whiting M (1984) Infantile Refsum disease: a variant of Zellweger syndrome? Clin Genet 26:579–586

    Google Scholar 

  25. Poulos A, Sharp P, Fellenberg AJ, Danks DM (1985) Cerebrohepato-renal (Zellweger) syndrome, adrenoleukodystrophy and Refsum disease: plasma changes and fibroblast phytanic acid oxidase. Hum Genet 70:172–177

    Google Scholar 

  26. Poulos A, Singh H, Paton B, Sharp P, Derwas N (1986) Accumulation and defective β-oxidation of very long chain fatty acids in Zellweger syndrome, adrenoleukodystrophy and Refsum disease variants. Clin Genet 29:397–408

    Google Scholar 

  27. Refsum S (1975) Heredopathia atactica polyneuritiformis: phytanic acid storage disease (Refsum disease). In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology. 21:181–229

  28. Refsum S (1980) Heredopathica atactica polyneuritiformis. Phytanic acid storage disease (Refsum disease) In: Sobne I (ed) Spinocerebellar degenerations. University of Tokyo Press, Tokyo, pp 313–338

    Google Scholar 

  29. Roels F, Cornelis A, Poll-The BT, Aubourg P, Ogier H, Scotto J, 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 

  30. Schutgens RBH, Romeyn GJ, Wanders RJA, Van den Bosch H, Schrakamp G, Heymans HSA (1984) Deficiency of acyl-CoA: dihydroxyacetone phosphate acyl transferase in patients with Zellweger (cerebro-hepato-renal) syndrome. Biochem Biophys Res Commun 120:179–184

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  33. Steinberg D (1978) Phytanic acid storage disease. Refsum syndrome. In: Stanbury JB, Wyngaarden JB, Fredrickson DS (eds) Metabolic basis of inherited disease, 4th edn. McGraw-Hill, New York, pp 688–706

    Google Scholar 

  34. Steinberg D, Mize CE, Herndon JH, Fales HM, Engel WK, Vroom FQ (1970) Phytanic acid in patients with Refsum syndrome and response to dietary treatment. Arch Intern Med 125:75–87

    Google Scholar 

  35. Stokke O, Eldjarn L (1979) Toxicity of phytanic acid in Refsum disease. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, vol 36. North Holland, Amsterdam, pp 347–349

    Google Scholar 

  36. Stokke O, Skrede S, Ek J, Bjorkhem I (1984) Refsum disease, adrenoleukodystrphy and the Zellweger syndrome. Scand J Clin Lab Invest 44:463–464

    Google Scholar 

  37. Tsuji S, Sano T, Ariga T, Miyatake T (1981) Increased synthesis of hexacosanoic acid (C26∶0) by cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). J Biochem 90:1233–1236

    Google Scholar 

  38. Van Crugten JT, Paton B, Poulos A (1986) Partial deficiency of dihydroxyacetone phosphate acyltransferase in both classical and infantile Refsum diseases. J Inherited Metab Dis 9:163–168

    Google Scholar 

  39. Van Duyn MA, Moser AB, Brown FT, Sacktor N, Liv A, Moser HW (1984) The design of a diet restricted in saturated very long chain fatty acids: therapeutic application in adrenoleukodystrophy. Am J Clin Nutr 40:277–284

    Google Scholar 

  40. 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 relation between the Zellweger syndrome, infantile Refsum disease and rhizomelic chondrodysplasia punctata. N Engl J Med 314:787–788

    Google Scholar 

  41. 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 

  42. Wilson GN, Holmes RG, Custer J, Lykowitz JL, Stover J, Datta N, Hajra A (1986) Zellweger syndrome: diagnostic assays, syndrome delineation and potential therapy. Am J Med Genet 24:69–82

    Google Scholar 

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Authors and Affiliations

  1. Department of Chemical Pathology, Adelaide Children's Hospital, King William Road, 5006, North Adelaide, Australia

    E. F. Robertson, A. Poulos & P. Sharp

  2. Department of Neurology, Adelaide Children's Hospital, King William Road, 5006, North Adelaide, Australia

    J. Manson

  3. Department of Histopathology, Adelaide Children's Hospital, King William Road, 5006, North Adelaide, Australia

    A. Jaunzems & R. Carter

  4. Department of Neurology, The Prince of Wales Children's Hospital, High Street, 2031, Randwick, New South Wales, Australia

    G. Wise

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  1. E. F. Robertson
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  2. A. Poulos
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  3. P. Sharp
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  4. J. Manson
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  5. G. Wise
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  6. A. Jaunzems
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  7. R. Carter
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Robertson, E.F., Poulos, A., Sharp, P. et al. Treatment of infantile phytanic acid storage disease: clinical, biochemical and ultrastructural findings in two children treated for 2 years. Eur J Pediatr 147, 133–142 (1988). https://doi.org/10.1007/BF00442210

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  • DOI: https://doi.org/10.1007/BF00442210

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