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Refsum's disease: characterization of the enzyme defect in cell culture.

The Journal of Clinical Investigation, 01 Jun 1969, 48(6):1017-1032
https://doi.org/10.1172/jci106058 PMID: 4181593 PMCID: PMC322316

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Abstract 

Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-(14)C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to alpha-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled alpha-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the alpha-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.

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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1969 Jun; 48(6): 1017–1032.
PMCID: PMC322316
PMID: 4181593

Refsum's disease: characterization of the enzyme defect in cell culture

James H. Herndon, Jr., Daniel Steinberg, B. William Uhlendorf, and Henry M. Fales
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Abstract

Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-14C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to α-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled α-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the α-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.

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Selected References

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