Correspondence

Phytanoyl–Coenzyme a Hydroxylase Deficiency — The Enzyme Defect in Refsum's Disease

N Engl J Med 1997; 337:133-134July 10, 1997

Article

To the Editor:

Heredopathia atactica polyneuritiformis was first identified as a distinct clinical entity by Refsum in the 1940s. Patients with this disorder usually present in the second decade of life or later with visual difficulties, distal limb weakness, and ataxia. The syndrome is characterized by atypical retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and high concentrations of protein in cerebrospinal fluid.1

Phytanic acid, an unusual branched-chain fatty acid (3,7,11,15-tetramethyl-hexadecanoic acid), accumulates in tissues and body fluids of patients with Refsum's disease.1 The patients are unable to metabolize phytanic acid, which is exclusively derived from exogenous sources. Normally, phytanic acid undergoes α-oxidation in which the chain is shortened by one carbon atom, yielding pristanic acid and carbon dioxide.1 Pristanic acid can be degraded by β-oxidation to yield three molecules of acetyl-coenzyme A (CoA), three of propionyl-CoA, and one of isobutyryl-CoA. Patients with Refsum's disease have deficient α-oxidation of [1-¹⁴C]phytanic acid to pristanic acid, whereas the subsequent β-oxidation of pristanic acid is normal (Table 1Table 1Metabolism of Phytanic Acid in Tissues from Normal Subjects and Patients with Refsum's Disease.).

We have recently found that phytanic acid needs to be activated to its CoA ester, phytanoyl-CoA, before it can be oxidized,4 and we have identified an enzyme activity (phytanoyl-CoA hydroxylase) in rat-liver peroxisomes by which phytanoyl-CoA is converted to 2-hydroxyphytanoyl-CoA.5 We now report that phytanoyl-CoA hydroxylase activity was undetectable in liver tissue from a patient with Refsum's disease (Table 1). On the basis of these findings, Refsum's disease can be classified as a true peroxisomal disorder.

Gerbert A. Jansen, M.Sc.
Ronald J.A. Wanders, Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands

Paul A. Watkins, M.D., Ph.D.
Stephanie J. Mihalik, Ph.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21205

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   K. Rüther. (2005) Die Adulte Refsum-Erkrankung. Der Ophthalmologe 102:8, 772-777
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   J.C. Komen, M. Duran, R.J.A. Wanders. (2005) Characterization of phytanic acid ω-hydroxylation in human liver microsomes. Molecular Genetics and Metabolism 85:3, 190-195
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   Sinan Cakirer, Mahmut R. Savas. (2005) Infantile Refsum disease: serial evaluation with MRI. Pediatric Radiology 35:2, 212-215
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   Ronald J.A. Wanders. (2004) Metabolic and molecular basis of peroxisomal disorders: A review. American Journal of Medical Genetics 126A:4, 355-375
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    Gerbert A. Jansen, Hans R. Waterham, Ronald J. A. Wanders. (2004) Molecular basis of Refsum disease: Sequence variations in Phytanoyl-CoA Hydroxylase (PHYH) and the PTS2 receptor (PEX7). Human Mutation 23:3, 209-218
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    Mridul Mukherji, Nadia J. Kershaw, Christopher J. Schofield, Anthony S. Wierzbicki, Matthew D. Lloyd. (2002) Utilization of Sterol Carrier Protein-2 by Phytanoyl-CoA 2-Hydroxylase in the Peroxisomal α Oxidation of Phytanic Acid. Chemistry & Biology 9:5, 597-605
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    Nanda M Verhoeven, Cornelis Jakobs. (2001) Human metabolism of phytanic acid and pristanic acid. Progress in Lipid Research 40:6, 453-466
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    G.A. Jansen, D.M. van den Brink, R. Ofman, O. Draghici, G. Dacremont, R.J.A. Wanders. (2001) Identification of Pristanal Dehydrogenase Activity in Peroxisomes: Conclusive Evidence That the Complete Phytanic Acid α-Oxidation Pathway Is Localized in Peroxisomes. Biochemical and Biophysical Research Communications 283:3, 674-679
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    T.J. Sadusky, T.J. Kemp, M. Simon, N. Carey, G.R. Coulton. (2001) Identification of Serhl, a New Member of the Serine Hydrolase Family Induced by Passive Stretch of Skeletal Muscle in Vivo. Genomics 73:1, 38-49
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    M. R. Baumgartner, G. A. Jansen, N. M. Verhoeven, P. A. W. Mooyer, C. Jakobs, F. Roels, M. Espeel, A. Fourmaintraux, H. Bellet, R. J. A. Wanders, J. M. Saudubray. (2000) Atypical Refsum disease with pipecolic acidemia and abnormal catalase distribution. Annals of Neurology 47:1, 109-113
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    Robert Weinstein. (1999) Phytanic acid storage disease (Refsum's disease): Clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. Journal of Clinical Apheresis 14:4, 181-184
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    M. R. Baumgartner, B. T. Poll-The, N. M. Verhoeven, C. Jakobs, M. Espeel, F. Roels, D. Rabier, T. Levade, M. O. Rolland, M. Martinez, R. J. A. Wanders, J. M. Saudubray. (1998) Clinical approach to inherited peroxisomal disorders: A series of 27 patients. Annals of Neurology 44:5, 720-730
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    Hugo W. Moser, Gerald V. Raymond. (1998) Genetic peroxisomal disorders: Why, when, and how to test. Annals of Neurology 44:5, 713-715
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    Wierzbicki, Hardman, Lumb, Sankaralingam, Morrish, Patel, Sidey, Gibberd. (1998) Influence of plasma phytanic acid levels in Refsum's disease on the behaviour of the erythrocyte membrane sodium-lithium countertransporter. European Journal of Clinical Investigation 28:4, 334-338
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    Gerbert A. Jansen, Stephanie J. Mihalik, Paul A. Watkins, Cornelis Jakobs, Hugo W. Moser, Ronald J.A. Wanders. (1998) Characterization of phytanoyl-Coenzyme A hydroxylase in human liver and activity measurements in patients with peroxisomal disorders. Clinica Chimica Acta 271:2, 203-211
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    Udo Seedorf. (1998) Peroxisomes in lipid metabolism. Journal of Cellular Biochemistry 72:S30-31, 158-167
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    Stephanie J. Mihalik, James C. Morrell, Do Kim, Katherine A. Sacksteder, Paul A. Watkins, Stephen J. Gould. (1997) Identification of PAHX, a Refsum disease gene. Nature Genetics 17:2, 185-189
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