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Journal of Lipid Research, Vol. 44, 1481-1488, August 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease

Anthony S. Wierzbicki^1,*,, Phillip D. Mayne^*, Matthew D. Lloyd, David Burston^*, Guam Mei^*, Margaret C. Sidey, Michael D. Feher and F. Brian Gibberd

^* Department of Chemical Pathology, Chelsea & Westminster Hospital, 369 Fulham Road, London, United Kingdom
Refsum Disease Clinic, Chelsea & Westminster Hospital, 369 Fulham Road, London, United Kingdom
Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom

Published, JLR Papers in Press, April 16, 2003. DOI 10.1194/jlr.M300121-JLR200

¹ To whom correspondence should be addressed. e-mail: anthony.wierzbicki{at}kcl.ac.uk

	ABSTRACT

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Adult Refsum disease (ARD) is associated with defective -oxidation of phytanic acid (PA). -Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, -oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the -oxidation pathway was 6.9 (2.8–19.4) mg [20.4 (8.3–57.4) µmol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. -Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 ± 58% in parallel with the 158 (125–603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The -oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration.

-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.

Abbreviations: 2,6-DMOA, 2,6-dimethyloctanedioic acid; 3-MAA, 3-methyl-adipic acid

Supplementary key words organic acid • -oxidation • -oxidation

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Adult Refsum disease (ARD) (Heredopathia atactica polyneutiformis) (On-line Mendelian Inheritance in Man; OMIM 265000) is an autosomal recessive disease that presents with retinitis pigmentosa, anosmia, peripheral neuropathy, deafness, and ataxia with additional ichthyosis and cardiomyopathy in severe cases (1–3). Many cases are caused by mutations in phytanoyl-CoA hydroxylase, resulting in increased plasma phytanic (3,7,11,15-tetramethylhexadecanoic) acid levels and accumulation of phytanic acid (PA) in all fat-containing tissues (1, 2). Normal metabolism of PA involves peroxisomal -oxidation, but an additional low-capacity pathway through -oxidation and subsequent cycles of ß-oxidation result in production of a variety of 3-methyl-organic acids, including 3-methyl-adipic acid (3-MAA; 3-methyl-hexanedioic acid) (4–6). Refsum disease is treated by the restriction of PA intake or physical removal of PA by plasmapheresis or apheresis (7–9). In patients on an appropriate diet, PA levels fall gradually due to -oxidation. In fasting and acutely ill patients, PA is mobilized from liver and adipose tissue pools as a result of the activation of lipolytic pathways, resulting in an acute increase in plasma levels and acute symptoms.

This study assessed the contribution made by the -oxidation pathway to the metabolism of PA by measuring 3-MAA excretion in patients with ARD.

	METHODS

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This study received ethical approval, and all patients and controls gave informed consent for the investigations performed.

Patient selection
Healthy controls and heterozygotes for ARD Four healthy volunteers [three male, one female; median age 32 (range 30–41) years] and two obligate heterozygotes (one male, one female) from a consanguineous family with Refsum disease were recruited. Each subject was stabilized on the low-PA diet (Westminster) for 24 h, and the next morning blood and urine samples were taken (7, 10, 11). Oral PA loading was performed using 25 ml of Maxepa oil (7.5 mg; 22.2 µmol PA/ml) in 75 ml orange juice. Blood and double-void technique urine samples were collected at 6 h intervals.

Dietary stabilization of patients with ARD Eleven patients with ARD diagnosed clinically and with plasma PA levels >200 µmol/l (normal <30 µmol/l) were recruited and had initial biochemical investigations performed. Patients were stabilized on a low-PA diet for over 12 weeks with a monthly dietetic review. Clinical biochemical analyses comprising blood PA, triglycerides, glucose, urinary 3-MAA, creatinine, and ketones were taken at the start and end of the dietary stabilization period. Serial blood and urine sampling on a more frequent basis was possible in one newly presented 24-year-old woman with ARD admitted over a 90 day period.

Ten patients underwent abdominal wall fat biopsy after dietary stabilization. Tissue PA content was measured and compared with blood and urine PA, creatinine and 3-MAA measurements.

Fasting studies in patients with ARD
A subset of five patients stabilized on the low-phytanic diet agreed to be admitted for investigation of their biochemical response to acute starvation. Patients agreed to be deprived of food and to be allowed only water to drink for a maximum period of 72 h. Clinical biochemical analyses comprising blood PA, triglycerides, and glucose and urinary 3-MAA, creatinine, and ketones were performed every 12 h. At the end of the study, patients were restarted on an oral low-PA diet, were discharged home after 3 days, and were reviewed monthly until well.

Biochemical assays
Measurement of PA PA was measured by established methods using methanol-chloroform extraction and gas chromatography (12). Plasma (0.5 ml) was extracted with 6 ml chloroform-methanol (2:1, v/v) and centrifuged at 1,900 g for 10 min at 4°C. One hundred microliters of 3-methyl-pentadecanoate (Sigma, Poole, UK) dissolved in hexane (0.728 mg/ml) was added as an internal standard to a 3 ml aliquot of the organic phase followed by 5 ml of 0.5 M methanoic sodium hydroxide (20 g/l methanol). The solution was heated at 100°C for 5 min, cooled, and 5 ml of boron trifluoride (14% w/v) was added and the sample was heat treated as before for 4 min. After cooling 30 ml of saturated sodium chloride, 15 ml of petroleum ether was added and the aqueous layer removed and filtered through phase separation paper (Whatman, Maidstone, UK). The aqueous layer was reextracted with 20 ml of petroleum ether and then the extract was evaporated to dryness, resuspended in 1 ml hexane, and reevaporated. The purified extract was dissolved in 0.3 ml hexane for injection.

PA was measured by gas chromatography (Varian 3700; Varian Ltd., Walton-on-Thames, UK) fitted with a 25 m BPX70 (70% cyanopropyl siloxane) capillary column (SGE; Milton Keynes, UK), with a temperature gradient from 150°C to 250°C. The injector temperature was 240°C and flame ionization detector temperature 300°C. Peaks were integrated on a Varian CDS100 integrator. The PA peak was identified from log retention time after injection of 1 µl and concentration calculated relative to methyl-phytanate (Phase Separations, Chester, UK) and methyl-pentadecanoate internal standards. The between-batch coefficient of variation was 5.6% (n = 5) and biological variation 7.7% (n = 9).

Measurement of 3-MAA 3-MAA was measured by standard gas chromatographic methods following ethyl-acetate extraction from acidified plasma. Lauric acid (50 µl; 1 mg/ml) and dodecanedioic acid (50 µl; 1 mg/ml) were added to 1 ml of fresh urine. The urine was acidified with three drops of concentrated hydrochloric acid and sodium chloride added in excess. The acidified urine was extracted with an equal volume of ethyl acetate, and phases were separated by centrifugation. The aqueous phase was reextracted twice more. Supernatant fractions were combined and dried down under nitrogen. The residue was redissolved in ethyl acetate and redried. The organic acids were derivatized in 30 µl of acetonitrile and 30 µl bis-(tri-methylsilyl)trifluoroacetamide.

Organic acids were analyzed by gas chromatography using a 25 m BP1 column (SGE). One microliter sample was injected with a split ratio of 1:100 and a temperature gradient from 90–250°C increasing at a rate of 8°C/min after an initial 4 min isothermal stage. Peaks were detected by flame ionization and integrated. 3-MAA concentrations were calculated from internal reference standards.

Triglycerides, glucose, and creatinine were measured by standard automated techniques on a Hitachi 717 analyzer (Boehringer-Mannheim; Lewes, UK).

Statistical analysis
Data from the studies were analyzed using GBStat 7.0 (Dynamic Microsystems, Silver Spring, MD). As only small numbers of patients were investigated and distributions of results were nonGaussian, data were analyzed by nonparametric statistics or after log transformation. Multiple regression analysis was performed to investigate the dependence of plasma PA and 3-MAA levels on demographic, anthropometric, and biochemical variables. P < 0.05 was considered significant. Kinetic plot analysis was conducted using sequential data in one newly presented patient and in five patients in response to fasting. Linearity of plots against time of natural logarithm plot of current to basal concentrations ([C]) (i.e., Ln [C]/[C_o]) and respective inverse concentrations (i.e., 1/[C] 1/[C_o]) were used to confirm first- or second-order kinetics, respectively.

	RESULTS

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Response to dietary therapy in a new patient
In one newly presented patient with ARD, it was possible to follow PA and 3-MAA elimination on a low-PA diet (Fig. 1) . PA elimination followed an approximately exponential course with first-order kinetics (ln {[S]/[So]} = -kt) over 40 days, with a plasma half-life for PA of 22.4 days. Plasma PA correlated weakly with 3-MAA excretion (r = 0.54; P = 0.02) over the period of admission in this patient (Fig. 1). Multiple regression analysis of the production of 3-MAA (r = 0.825) showed it was dependent on time (ß = -42; P < 0.001) and the log of concentration of PA (ß = -1,962; P = 0.05), but independent of other anthropometric and biochemical factors. Analysis of the kinetics of 3-MAA levels in this patient showed they were linear when plotted against 1/[C] - 1/[C_o], and therefore demonstrated second-order kinetics.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Plasma PA concentration in response to fasting in five patients with ARD assuming first-order kinetics.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Excretion of 3-MAA acid and plasma PA in 11 patients with adult Refsum disease (ARD).

View larger version (16K): [in this window] [in a new window]   Fig. 3. Fall in plasma phytanic acid (PA) (diamonds) and excretion of 3-methyl-adipic acid (3-MAA) (triangles) expressed as molar equivalent PA metabolized in a newly presented patient with Refsum disease presented as best-fit exponential and hyperbolic trend lines.

View larger version (14K): [in this window] [in a new window]   Fig. 4. Changes in plasma 3-MAA in response to fasting in three patients with ARD assuming second-order kinetics.

	DISCUSSION

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PA is derived by bacterial metabolism of chlorophyll in the digestive systems of ruminants and is not normally present in significant levels in human plasma or tissues. In contrast, in patients with ARD, PA is present in large quantities in plasma and accumulates in nervous and adipose tissues. Patients with ARD cannot metabolize PA by -oxidation and so rely on -oxidation, with the consequent production of 3-MAA (13).

This study included seven patients whose genetic defect has been mapped to chromosome 10, indicating they were likely to have mutations in phytanoyl-CoA hydroxylase (14). Family sizes were too small to allow mapping of the disease in four other patients. In one newly presenting ARD patient, long-term treatment with a low-PA diet that reduced intake from 60 mg (178 µmol)/day to <20 mg (60 µmol)/day resulted in a gradual fall in plasma and tissue PA levels, with a plasma half-life for PA of 22.4 days following classical first-order kinetics (1, 10). This study, like others, shows that significant -oxidation occurs in patients with acute and chronic ARD, with increased levels of 3-MAA compared with normal controls (5, 6, 13). After ingestion of a test load of PA, 3-MAA was detected in the urine of healthy controls and ARD heterozygotes, showing that -oxidation plays a significant role in postprandial metabolism of PA in humans.

The capacity of the -oxidation pathway has been measured by excretion of 2,6-dimethyloctanedioic acid (2,6-DMOA) derived from the C10 -2-methyl thioester derivative of PA (Fig. 5) . Based on 2,6-DMOA excretion in two patients, the capacity of the -oxidation pathway has been suggested to be 30 mg PA (89 µmol)/day (15). However, this present study measuring 3-MAA excretion showed a far lower capacity of 6.9 (2.8–19.4) mg [20.4(8.3–57.4) µmol]/day in patients consuming 2.7 (0–53) mg [8(0–16) µmol]/day of PA. The production of 3-MAA followed second-order kinetics, indicating that the activity of the pathway is dependent on initial plasma PA concentration. Patients in the original study underwent dietary PA restriction, compared with a normal daily intake of 165 mg (0.5 mmol)/day of PA, but no data were provided on the success of dietary therapy (15). However, these capacities may differ for an alternative reason. 2,6-DMOA and 3-hexanedioic acid are products of the initial steps of -oxidation and may be dependent on carnitine ester formation for activation for further metabolism. Phytanoyl-carnitines that occur in ARD (16) may impair the activation reaction through competition and lead to urinary excretion of excess 2,6-DMOA and 3-methylhexanedioic acid so that the initial steps of -oxidation may seem to have a greater capacity than that of the whole pathway.

View larger version (21K): [in this window] [in a new window]   Fig. 5. The metabolism of PA by -oxidation and subsequent ß-oxidation to 3-MAA.

PA loading was considered unethical in patients with established ARD, so the acute response of -oxidation in patients with ARD was assessed in a fasting state. Fasting induces ketosis, lipolysis, and acute mobilization of PA in hepatocyte and adipocyte fatty acid pools, resulting in secretion of VLDL enriched in PA. This process can induce release of 5,000 mg (14.8 mmol)/day of PA (50-fold normal) (2). In four individuals who developed ketosis following acute starvation, plasma PA increased as expected with a doubling time of 29 h, and in four patients (80%), a rise in urinary 3-MAA levels was seen, with the plasma PA following first-order kinetics and 3-MAA second-order kinetics, respectively. One other patient showed no change in PA or 3-MAA in response to fasting, possibly due to noncompliance. The release kinetics of PA showed a doubling time of 29.2 h, which is slower than that associated with secretion of VLDL (2–4 h) and implies that PA must be mobilized slowly from an internal hepatocyte pool or from adipose tissue. The acute stress used in this study was insufficient to saturate the -oxidation pathway as rises in PA levels paralleled those in 3-MAA. The findings suggest that -oxidation processes are similar in patients with ARD and healthy controls in response to acute PA loads. However, delayed symptoms associated with a relapse of disease were seen in three patients, with increases in two patients with plasma PA (10). Another patient showed an asymptomatic rise in plasma PA after the study. These findings confirm that the acute signs of ARD are secondary to increases in plasma levels rather than on total body PA stores.

In one patient studied, sequentially, PA clearance through -oxidation was initially 32% of total PA metabolism but rose to 100% by 40 days as PA levels fell. The exact enzymology of the -oxidation pathway in ARD is obscure, but in plants and humans, -oxidation of other fatty acids occurs through the microsomal cytochrome P₄₅₀CYP4A system (17, 18), while structurally related tocopherols (vitamin E) are metabolized by a cytochrome CYP3A enzyme (19). The stereochemistry of the -oxidation reaction may be relevant to its activity but has not been investigated. PA exists in a 2:1 racemic mixture of R- and S-epimers, and -oxidation occurs through initial nonstereospecific steps before -methylacyl-CoA racemase is required to allow entry of R-epimers into the ß-oxidation pathway (1). -Oxidation of the terminal methyl groups of PA introduces a new chiral center (Fig. 5). The stereochemistry of the -dicarboxylic acid would depend on whether the pro-R or pro-S methyl group was hydroxylated and oxidized to the corresponding carboxylic acid. It is unclear whether the initial hydroxylation step is stereospecific. In bile acid metabolism, an analogous reaction occurs in which 27-hydroxylation of cholesterol gives rise to 25S-alcohol and 25S-carboxylic acid derivatives (20). The cytochrome P₄₅₀ enzyme CYP27A that performs this reaction has a wide substrate range, but whether it has a role in the metabolism of PA is unknown. If the hydroxylation is not stereoselective, then the same racemase that functions in the -oxidation pathway may be able to convert the R-epimer to the S-epimer (as its CoA derivative). Degradation of the 15S-methyl fatty acyl-CoA derivative by ß-oxidation would give the C15 and C10 2-methyl fatty acyl-CoA esters with the S-stereochemistry. PA itself exists as a 2:1 mixture of 3R- and 3S-epimers, and it is anticipated that this stereochemistry will be preserved in 3-MAA (21). Since 3-MAA is significantly soluble in aqueous environments, it is likely that it will be excreted in preference to undergoing further ß-oxidation.

The data from the newly presented patient allow some suggestions to be made about the metabolism of PA in ARD. Initially, PA levels exceed the capacity of the residual - and -oxidation pathways. Excess PA is still excreted, so another alternative low-affinity pathway for PA excretion has to exist. PA is hydrophobic and is usually transported in lipoproteins, so it would need to be made into a hydrophilic metabolite for renal excretion (22). Hepatic conjugation would fulfill this function. One candidate for this role would be glucuronidation of PA, which would be consistent with the finding of PA in urine (23). Another possibility is nonspecific renal loss due to nephropathy. Though nephropathy has been described in some patients with ARD (24), only one of the patients studied here showed any evidence of hypokalaemia, but no evidence of aminoaciduria or glycosuria. Later, -oxidation is the principal route for PA excretion. This pathway is predominantly located in the liver, because fibroblasts from patients with ARD have only a limited capacity to metabolise PA (13, 25–27); therefore, the process of PA elimination is dependent on reverse PA transport from tissues, probably in HDL cholesterol (22). The relationship of -oxidation capacity to HDL was not assessed in this study. It is likely that long-term PA values in patients on stable diets are dependent on residual -oxidation capacity, because most mutations in phytanoyl-CoA hydroxylase do not completely inhibit activity (28) and PA concentration-dependent -oxidation. This may explain the large heterogeneity and variability in response to diet, despite high compliance seen in patients with ARD.

This study shows that the -oxidation pathway can theoretically metabolize all the PA ingested in patients with ARD on a low-PA diet. However, its main role seems to be to provide a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels. As -oxidation is capable of large increases in activity, and is most likely mediated through P₄₅₀ cytochrome enzymes, it forms a good candidate for therapeutic interventions to induce enzyme activity and reduce PA levels in ARD.

	ACKNOWLEDGMENTS

 
Professor J. Billimoria and Dr. M. Clemens developed the methods used to assay PA and 3-MAA. This study was supported by a grant from the North West Thames Regional Health Authority and European Community Biomed 5 grant RDDPT.

Manuscript received March 19, 2003 and in revised form April 9, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

1. Wierzbicki, A. S., M. D. Lloyd, C. J. Schofield, M. D. Feher, and F. B. Gibberd. 2002. Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J. Neurochem. 80: 727–735.[CrossRef][Medline]

2. Wanders, R. J. A., C. Jacobs, and O. H. Skjeldal. 2001. Refsum disease. In The Metabolic and Molecular Bases of Inherited Disease. 8th edition. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw Hill, New York. 3303–3321.

3. Gibberd, F. B., J. D. Billimoria, J. M. Goldman, M. E. Clemens, R. Evans, M. N. Whitelaw, S. Retsas, and R. M. Sherratt. 1985. Heredopathia atactica polyneuritiformis: Refsum's disease. Acta Neurol. Scand. 72: 1–17.[Medline]

4. Steinberg, D., J. H. Herndon, Jr., B. W. Uhlendorf, C. E. Mize, J. Avigan, and G. W. Milne. 1967. Refsum's disease: nature of the enzyme defect. Science. 156: 1740–1742.[Abstract/Free Full Text]

5. Billimoria, J. D., M. E. Clemens, F. B. Gibberd, and M. N. Whitelaw. 1982. Metabolism of phytanic acid in Refsum's disease. Lancet. 1: 194–196.[CrossRef][Medline]

6. Brenton, D. P., and S. Krywawych. 1982. 3-Methyladipate excretion in Refsum's disease. Lancet. 1: 624.

7. Brown, P. J., G. Mei, F. B. Gibberd, D. Burston, P. D. Mayne, J. E. McClinchy, and M. C. Sidey. 1993. Diet and Refsum's disease. The determination of phytanic acid and phytol in certain foods and application of this knowledge to the choice of suitable convenience foods for patients with Refsum's disease. J. Hum. Nutr. Diet. 6: 295–305.

8. Gibberd, F. B. 1993. Plasma exchange for Refsum's disease. Transfus. Sci. 14: 23–26.[CrossRef][Medline]

9. Gutsche, H. U., J. B. Siegmund, and I. Hoppmann. 1996. Lipapheresis: an immunoglobulin-sparing treatment for Refsum's disease. Acta Neurol. Scand. 94: 190–193.[Medline]

10. Masters-Thomas, A., J. Bailes, J. D. Billimoria, M. E. Clemens, F. B. Gibberd, and N. G. Page. 1980. Heredopathia atactica polyneuritiformis (Refsum's disease): 1. Clinical features and dietary management. J. Hum. Nutr. 34: 245–250.[Medline]

11. Masters-Thomas, A., J. Bailes, J. D. Billimoria, M. E. Clemens, F. B. Gibberd, and N. G. Page. 1980. Heredopathia atactica polyneuritiformis (Refsum's disease): 2. Estimation of phytanic acid in foods. J. Hum. Nutr. 34: 251–254.[Medline]

12. Moser, H. W., and A. B. Moser. 1991 Measurement of phytanic acid levels. In Techniques in Diagnostic Human Biochemical Genetics. 1st edition. F. A. Homme, editor. Wiley-Liss, Philadelphia. 193–203.

13. Try, K. 1968. The in vitro omega-oxidation of phytanic acid and other branched chain fatty acids by mammalian liver. Scand. J. Clin. Lab. Invest. 22: 224–230.[Medline]

14. Wierzbicki, A. S., J. Mitchell, M. Lambert-Hammill, M. Hancock, J. Greenwood, M. C. Sidey, J. de Belleroche, and F. B. Gibbens. 2000. Identification of genetic heterogeneity in Refsum's disease. Eur. J. Hum. Genet. 8: 649–651.[CrossRef][Medline]

15. Greter, J., S. Lindstedt, and G. Steen. 1983. 2,6-Dimethyloctanedioic acid—a metabolite of phytanic acid in Refsum's disease. Clin. Chem. 29: 434–437.[Abstract/Free Full Text]

16. Verhoeven, N. M., C. Jakobs, H. J. ten Brink, R. J. Wanders, and C. R. Roe. 1998. Studies on the oxidation of phytanic acid and pristanic acid in human fibroblasts by acylcarnitine analysis. J. Inherit. Metab. Dis. 21: 753–760.[CrossRef][Medline]

17. Salaun, J. P., and C. Helvig. 1995. Cytochrome P450-dependent oxidation of fatty acids. Drug Metabol. Drug Interact. 12: 261–83.[Medline]

18. Graham, I. A., and P. J. Eastmond. 2002. Pathways of straight and branched chain fatty acid catabolism in higher plants. Prog. Lipid Res. 41: 156–181.[CrossRef][Medline]

19. Birringer, M., D. Drogan, and R. Brigelius-Flohe. 2001. Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation. Free Radic. Biol. Med. 31: 226–232.[CrossRef][Medline]

20. Bjorkhem, I., S. Meaney, and U. Diczfalusy. 2002. Oxysterols in human circulation: which role do they have? Curr. Opin. Lipidol. 13: 247–253.[CrossRef][Medline]

21. Sita, L. R. 1993. Convenient highly stereoselective syntheses of (3R,7R,11R) and (3S,7R,11R)-3,7,11,15-tetramethylhexadecanoic acid (phytanic acid) and the corresponding tetramethylhexadecan-1-ols. J. Org. Chem. 58: 5285–5287.[CrossRef]

22. Wierzbicki, A. S., A. Sankaralingam, P. J. Lumb, T. C. Hardman, M. C. Sidey, and F. B. Gibberd. 1999. Transport of phytanic acid on lipoproteins in Refsum disease. J. Inherit. Metab. Dis. 22: 29–36.[CrossRef][Medline]

23. Little, J. M., L. Williams, J. Xu, and A. Radominska-Pandya. 2002. Glucuronidation of the dietary fatty acids, phytanic acid and docosahexaenoic acid, by human UDP-glucuronosyltransferases. Drug Metab. Dispos. 30: 531–533.[Abstract/Free Full Text]

24. Pabico, R. C., B. J. Gruebel, B. A. McKenna, R. C. Griggs, J. Hollander, J. Nusbacher, and B. J. Panner. 1981. Renal involvement in Refsum's disease. Am. J. Med. 70: 1136–1143.[CrossRef][Medline]

25. Verhoeven, N. M., and C. Jakobs. 2001. Human metabolism of phytanic acid and pristanic acid. Prog. Lipid Res. 40: 453–466.[CrossRef][Medline]

26. Vanhooren, J. C., S. Asselberghs, H. J. Eyssen, G. P. Mannaerts, and P. P. Van Veldhoven. 1994. Activation of 3-methyl-branched fatty acids in rat liver. Int. J. Biochem. 26: 1095–1101.[CrossRef][Medline]

27. Verhoeven, N. M., C. Jakobs, H. J. ten Brink, R. J. Wanders, and C. R. Roe. 1998. Studies on the oxidation of phytanic acid and pristanic acid in human fibroblasts by acylcarnitine analysis. J. Inherit. Metab. Dis. 21: 753–760.

28. Mukherji, M., W. Chien, N. J. Kershaw, I. J. Clifton, C. J. Schofield, A. S. Wierzbicki, and M. D. Lloyd. 2001. Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease. Hum. Mol. Genet. 10: 1971–1982.[Abstract/Free Full Text]

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