Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1967 Mar;46(3):313–322. doi: 10.1172/JCI105533

Studies on the Metabolic Error in Refsum's Disease*

Daniel Steinberg 1,2,†, Charles E Mize 1,2, Joel Avigan 1,2, Henry M Fales 1,2, Lorentz Eldjarn 1,2, Kenneth Try 1,2, Oddvar Stokke 1,2, Sigvald Refsum 1,2
PMCID: PMC297052  PMID: 4164676

Abstract

Studies utilizing mevalonic acid-2-14C and D2O as precursors failed to provide evidence for an appreciable rate of endogenous biosynthesis of phytanic acid in a patient with Refsum's disease.

Orally administered tracer doses of phytol-U-14C were well absorbed both by seven normal control subjects (61 to 94%) and by two patients with Refsum's disease (74 and 80%).

The fraction of the absorbed dose converted to 14CO2 in 12 hours was 3.5 and 5.8% in Refsum's disease patients and averaged 20.9% in seven control subjects.

Labeled phytanic acid was demonstrated in the plasma of both control subjects and patients given phytol-U-14C, establishing phytol in the diet as a potential precursor of phytanic acid. This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days.

We conclude that the phytanic acid accumulating in Refsum's disease is primarily of exogenous origin and that patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds. This may relate to a deficiency in mechanisms for release of phytanic acid from stored ester forms or, more probably, to reactions essential to oxidative degradation of the carbon skeleton.

Full text

PDF
313

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Avigan J., Steinberg D., Gutman A., Mize C. E., Milne G. W. Alpha-decarboxylation, an important pathway for degradation of phytanic acid in animals. Biochem Biophys Res Commun. 1966 Sep 22;24(6):838–844. doi: 10.1016/0006-291x(66)90324-x. [DOI] [PubMed] [Google Scholar]
  2. Avigan J. The presence of phytanic acid in normal human and animal plasma. Biochim Biophys Acta. 1966 Apr 4;116(2):391–394. doi: 10.1016/0005-2760(66)90022-1. [DOI] [PubMed] [Google Scholar]
  3. Bloch K. The biological synthesis of cholesterol. Science. 1965 Oct 1;150(3692):19–28. doi: 10.1126/science.150.3692.19. [DOI] [PubMed] [Google Scholar]
  4. ELDJARN L. HEREDOPATHIA ATACTICA POLYNEURITIFORMIS (REFSUM'S DISEASE)--A DEFECT IN THE OMEGA-OXIDATION MECHANISM OF FATTY ACIDS. Scand J Clin Lab Invest. 1965;17:178–181. doi: 10.1080/00365516509077305. [DOI] [PubMed] [Google Scholar]
  5. Eldjarn L., Try K., Stokke O., Munthe-Kaas A. W., Refsum S., Steinberg D., Avigan J., Mize C. Dietary effects on serum-phytanic-acid levels and on clinical manifestations in heredopathia atactica polyneuritiformis. Lancet. 1966 Mar 26;1(7439):691–693. doi: 10.1016/s0140-6736(66)91632-1. [DOI] [PubMed] [Google Scholar]
  6. Eldjarn L., Try K., Stokke O. The ability of patients with herdopathia atactica polyneuritiformis to alpha-oxidize and degrade several isoprenoid branch-chained fatty structures. Scand J Clin Lab Invest. 1966;18(2):141–150. doi: 10.3109/00365516609051810. [DOI] [PubMed] [Google Scholar]
  7. Eldjarn L., Try K., Stokke O. The existence of an alternative pathway for the degradation of branch-chained fatty acids, and its failure in heredopathia atactica polyneuritiformis (Refsum's disease). Biochim Biophys Acta. 1966 Apr 4;116(2):395–397. doi: 10.1016/0005-2760(66)90023-3. [DOI] [PubMed] [Google Scholar]
  8. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  9. FOSTER D. W., BLOOM B. The synthesis of fatty acids by rat liver slices in tritiated water. J Biol Chem. 1963 Mar;238:888–892. [PubMed] [Google Scholar]
  10. Hansen R. P. 3,7,11,15-tetramethylhexadecanoic acid: its occurrence in the tissues of humans afflicted with Refsum's syndrome. Biochim Biophys Acta. 1965 Oct 4;106(2):304–310. doi: 10.1016/0005-2760(65)90038-x. [DOI] [PubMed] [Google Scholar]
  11. Hansen R. P. Occurrence of 3,7,11,15-tetramethylhexadecanoic acid in ox perinephric fat. Chem Ind. 1965 Feb 13;7:303–304. [PubMed] [Google Scholar]
  12. Hansen R. P., Shorland F. B., Prior I. A. The fate of phytanic acid when administered to rats. Biochim Biophys Acta. 1966 Feb 1;116(1):178–180. doi: 10.1016/0005-2760(66)90108-1. [DOI] [PubMed] [Google Scholar]
  13. JAGANNATHAN S. N. THE DETERMINATION OF PLASMA TRIGLYCERIDES. Can J Biochem. 1964 Apr;42:566–570. doi: 10.1139/o64-067. [DOI] [PubMed] [Google Scholar]
  14. JOVER A., GORDON R. S., Jr Procedure for quantitative analysis of faces with special reference to facal fatty acids. J Lab Clin Med. 1962 May;59:878–884. [PubMed] [Google Scholar]
  15. KAHLKE W. REFSUM-SYNDROM.--LIPOIDCHEMISCHE UNTERSUCHUNGEN BEI 9 FAELLEN. Klin Wochenschr. 1964 Oct 15;42:1011–1016. doi: 10.1007/BF01479444. [DOI] [PubMed] [Google Scholar]
  16. KLENK E., KAHIKE W. UBER DAS VORKOMMEN DER 3.7.11.15-TETRAMETHYL-HEXADECANSAEURE (PHYTANSAEURE) IN DEN CHOLESTERINESTERN UND ANDEREN LIPOIDFRAKTIONEN DER ORGANE BEI EINEM KRANKHEITSFALL UN- BEKANNTER GENESE (VERDACHT AUF HEREDOPATHIA ATACTICA POLYNEURITIFORMIS. Hoppe Seylers Z Physiol Chem. 1963;333:133–139. doi: 10.1515/bchm2.1963.333.1.133. [DOI] [PubMed] [Google Scholar]
  17. KREMER G. J. UBER DAS VORKOMMEN DER 3,7,11,15-TETRAMETHYLHEXADECANSAEURE IN DEN LIPOIDEN VON NORMALSEREN. Klin Wochenschr. 1965 May 1;43:517–518. doi: 10.1007/BF01486095. [DOI] [PubMed] [Google Scholar]
  18. Klenk E., Kremer G. J. Untersuchungen zum Stoffwechsel des Phytols, Dihydrophytols und der Phytansäure. Hoppe Seylers Z Physiol Chem. 1965;343(1):39–51. [PubMed] [Google Scholar]
  19. Mize C. E., Avigan J., Baxter J. H., Fales H. M., Steinberg D. Metabolism of phytol-U-14C and phytanic acid-U-14C in the rat. J Lipid Res. 1966 Sep;7(5):692–697. [PubMed] [Google Scholar]
  20. Mize C. E., Steinberg D., Avigan J., Fales H. M. A pathway for oxidative degradation of phytanic acid in mammals. Biochem Biophys Res Commun. 1966 Nov 11;25(3):359–365. doi: 10.1016/0006-291x(66)90786-8. [DOI] [PubMed] [Google Scholar]
  21. NANDI D. L., PORTER J. W. THE ENZYMATIC SYNTHESIS OF GERANYL GERANYL PYROPHOSPHATE BY ENZYMES OF CARROT ROOT AND PIG LIVER. Arch Biochem Biophys. 1964 Apr;105:7–19. doi: 10.1016/0003-9861(64)90230-9. [DOI] [PubMed] [Google Scholar]
  22. NATHAN D. G., DAVIDSON J. D., WAGGONER J. G., BERLIN N. I. The counting of barium carbonate in a liquid scintillation spectrometer. J Lab Clin Med. 1958 Dec;52(6):915–917. [PubMed] [Google Scholar]
  23. RICHTERICH R., KAHLKE W., VAN MECHELEN, ROSSI E. REFSUM'S SYNDROM (HEREDOPATHIA ATACTICA POLYNEURITIFORMIS): EIN ANGEBORENER DEFEKT IM LIPID-STOFFWECHSEL MIT SPEICHERUNG VON 3,7,11,15-TETRAMETHYL-HEXADECANSAEURE. Klin Wochenschr. 1963 Aug 15;41:800–801. doi: 10.1007/BF01789071. [DOI] [PubMed] [Google Scholar]
  24. Richterich R., Moser H., Rossi E. Refsum's disease (heredopathia atactica polyneuritiformis). An inborn error of lipid metabolism with storage of 3,7,11,15 tetramethyl hexadecanoic acid. A review of the clinical findings. Humangenetik. 1965;1(4):322–332. doi: 10.1007/BF00273974. [DOI] [PubMed] [Google Scholar]
  25. Richterich R., Rosin S., Rossi E. Refsum's disease (heredopathia atactica polyneuritiformis). An inborn error of lipid metabolism with storage of 3,7,11,15 tetramethyl hexadecanoic acid formal genetics. Humangenetik. 1965;1(4):333–336. doi: 10.1007/BF00273975. [DOI] [PubMed] [Google Scholar]
  26. STEINBERG D. A new approach to radioassay of aqueous solutions in the liquid scintillation spectrometer. Anal Biochem. 1960 Jun;1:23–39. doi: 10.1016/0003-2697(60)90016-6. [DOI] [PubMed] [Google Scholar]
  27. STEINBERG D., AVIGAN J., MIZE C., BAXTER J. PHYTANIC ACID FORMATION AND ACCUMULATION IN PHYTOL-FED RATS. Biochem Biophys Res Commun. 1965 May 3;19:412–416. doi: 10.1016/0006-291x(65)90138-5. [DOI] [PubMed] [Google Scholar]
  28. Steinberg D., Avigan J., Feigelson E. B. EFFECTS OF TRIPARANOL (MER-29) ON CHOLESTEROL BIOSYNTHESIS AND ON BLOOD STEROL LEVELS IN MAN. J Clin Invest. 1961 May;40(5):884–893. doi: 10.1172/JCI104323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Steinberg D., Avigan J., Mize C. E., Baxter J. H., Cammermeyer J., Fales H. M., Highet P. F. Effects of dietary phytol and phytanic acid in animals. J Lipid Res. 1966 Sep;7(5):684–691. [PubMed] [Google Scholar]
  30. Steinberg D., Avigan J., Mize C., Eldjarn L., Try K., Refsum S. Conversion of U-C14-phytol to phytanic acid and its oxidation in heredopathia atactica polyneuritiformis. Biochem Biophys Res Commun. 1965 Jun 9;19(6):783–789. doi: 10.1016/0006-291x(65)90328-1. [DOI] [PubMed] [Google Scholar]
  31. Stewart C. P., Hendry E. B. The phospholipins of blood. Biochem J. 1935 Jul;29(7):1683–1689. doi: 10.1042/bj0291683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. WOELLER F. H. Liquid scintillation counting of C-14-labelled CO2 with phenethylamine. Anal Biochem. 1961 Oct;2:508–511. doi: 10.1016/0003-2697(61)90056-2. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES