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Sigvald Refsum first described the disease that bears his name in 1940's.Refsum's disease is an autosomal recessive disorder. It is caused by a defect in the metabolism of phytanic acid leading to accumulation of phytanic acid in plasma and tissues. This leads to the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma- and lipid-containing tissues.

Patients are deficient activity of phytanoyl-CoA hydroxyl-ase (PhyH), a peroxisomal enzyme catalysing the first step of phytanic acid alpha-oxidation. These enzymes are found in the peroxisome, a cell organelle, only visualized with electron microscopy.


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Hereditary motor sensory neuropathy type IV
Heredopathia atactica polyneuritiformis


Defect in phytanic acid metabolism

Phytanoyl-CoA 2-hydroxylase (PAHX) and 2-hydroxyphytanoyl-CoA lyasen in peroxisomes

PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13
Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease

Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a
Other atypical cases with low-plasma phytanic acid may be caused by alpha-methylacyl-CoA racemase deficiency


Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease.

Mukherji M, Chien W, Kershaw NJ, Clifton IJ, Schofield CJ, Wierzbicki AS, Lloyd MD.

The Oxford Centre for Molecular Science and The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK.


Hum Mol Genet. 2001 Sep 1;10(18):1971-82. Abstract quote

Refsum's disease is a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxisomal oxygenase phytanoyl-CoA 2-hydroxylase (PAHX) which catalyses the initial alpha-oxidation step in the degradation of phytanic acid.

Both pro and mature forms of recombinant PAHX were produced in Escherichia coli, highly purified, and shown to have a requirement for iron(II) as a co-factor and 2-oxoglutarate as a co-substrate. Sequence analysis in the light of crystallographic data for other members of the 2-oxoglutarate-dependent oxygenase super-family led to secondary structural predictions for PAHX, which were tested by site-directed mutagenesis. The H175A and D177A mutants did not catalyse hydroxylation of phytanoyl-CoA, consistent with their assigned role as iron(II) binding ligands. The clinically observed P29S, Q176K, G204S, N269H, R275Q and R275W mutants were assayed for both 2-oxoglutarate and phytanoyl-CoA oxidation. The P29S mutant was fully active, implying that the mutation resulted in defective targeting of the protein to peroxisomes.

Mutation of Arg-275 resulted in impaired 2-oxoglutarate binding. The Q176K, G204S and N269H mutations caused partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation. The results demonstrate that the diagnosis of Refsum's disease should not solely rely upon PAHX assays for 2-oxoglutarate or phytanoyl-CoA oxidation.

Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease.

Jansen GA, Hogenhout EM, Ferdinandusse S, Waterham HR, Ofman R, Jakobs C, Skjeldal OH, Wanders RJ.

Department of Pediatrics, Emma Children's Hospital, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands.

Hum Mol Genet. 2000 May 1;9(8):1195-200. Abstract quote

Refsum's disease (RD) is an inherited neurological syndrome biochemically characterized by the accumulation of phytanic acid in plasma and tissues.

Patients with RD are unable to degrade phytanic acid due to a deficient activity of phytanoyl-CoA hydroxyl-ase (PhyH), a peroxisomal enzyme catalysing the first step of phytanic acid alpha-oxidation.

To enable mutation analysis of RD at the genome level, we have elucidated the genomic organization of the PHYH gene. The gene is approximately 21 kb and contains nine exons and eight introns. Mutation analysis of PHYH cDNA from 22 patients with RD revealed 14 different missense mutations, a 3 bp insertion, and a 1 bp deletion, which were all confirmed at the genome level. A 111 bp deletion identified in the PHYH cDNA of several patients with RD was due to either one of two different mutations in the same splice acceptor site, which result in skipping of exon 3. Six mutations, including a large in-frame deletion and five missense mutations, were expressed in the yeast

Saccharomyces cerevisiae to study their effect on PhyH activity. The results showed that all these mutations lead to an enzymatically inactive PhyH protein.

Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.

Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muijsers AO, Skjeldal OH, Stokke O, Jakobs C, Besley GT, Wraith JE, Wanders RJ.

Department of Clinical Biochemistry, University of Amsterdam, The Netherlands.


Nat Genet. 1997 Oct;17(2):190-3. Abstract quote

Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF.

All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid.

We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation.

This analysis confirms our finding that Refsum disease is caused by a deficiency of PhyH.


Identification of PEX7 as the second gene involved in Refsum disease.

van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ.

Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.


Am J Hum Genet. 2003 Feb;72(2):471-7. Abstract quote

Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH).

In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder.

Biochemical analyses of the patients with RD revealed defects not only in phytanic acid alpha-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene.

Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.


Effects of phytanic acid on the vitamin E status, lipid composition and physical properties of retinal cell membranes: implications for adult Refsum disease.

Young SP, Johnson AW, Muller DP.

Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

Clin Sci (Lond). 2001 Dec;101(6):697-705. Abstract quote

Adult Refsum disease is an inherited disorder in which phytanic acid accumulates in tissues and serum.

Two hypotheses have been proposed to explain the pathogenesis of this condition. The molecular distortion hypothesis suggests that phytanic acid may alter membrane composition and structure, thereby affecting membrane function(s). The anti-metabolite hypothesis suggests that an accumulation of phytanic acid in membranes may interfere with vitamin E function.

These two hypotheses were investigated by studying the effects of modulating phytanic acid and alpha-tocopherol concentrations on the fatty acid composition and certain physical parameters of cultured retinal cells.

Results showed that (a) the phospholipid fraction of retinal cells readily incorporated phytanic acid, (b) the incorporation of phytanic acid increased membrane fluidity, (c) there was no competition for uptake between phytanic acid and alpha-tocopherol, and (d) the incorporation of phytanic acid did not increase the susceptibility of membranes to lipid peroxidation in vitro.

These results obtained with cultured retinal cells suggest that the molecular distortion hypothesis, but not the anti-metabolite hypothesis, could explain the pathogenesis of adult Refsum disease. In vitro tissue culture models can, however, only approximate to the much more complex situation that occurs in vivo.

Transport of phytanic acid on lipoproteins in Refsum disease.

Wierzbicki AS, Sankaralingam A, Lumb PJ, Hardman TC, Sidey MC, Gibberd FB.

Department of Chemical Pathology, St Thomas' Hospital, London, UK.

J Inherit Metab Dis. 1999 Feb;22(1):29-36. Abstract quote

Patients with Refsum disease accumulate significant quantities of phytanic acid in adipose and neural tissue. The accumulation can be reversed by following a diet low in phytanic acid, yet the mechanism of transport of this fatty acid is obscure.

We investigated the distribution of phytanic acid in different lipoprotein subfractions in 11 patients with Refsum disease and 9 unaffected siblings. Plasma phytanic acid was distributed on VLDL (16.2% +/- 12.2%), IDL (1.77% +/- 1.64%), LDL (34.8% +/- 12.6%) and HDL (14.3% +/- 7.87%). No correlations with any parameter were seen with total phytanic acid content. Weak nonsignificant correlations were found with the fractional distribution of phytanic acid and VLDL triglyceride (r = 0.35; p = 0.12) and plasma HDL-cholesterol (r = 0.32; p = 0.16) and with LDL:HDL cholesterol ratio (r = 0.33; p = 0.14). Significant correlation of the fractional distribution of phytanic acid on lipoprotein particles was noted with the ratio of apolipoprotein B: apolipoprotein A1-containing particles (r = 0.46; p = 0.03) and apolipoprotein B: apolipoprotein A1 in HDL2 (r = 0.53; p = 0.01).

This suggests that the import-export balance for phytanic acid in plasma is related to forward and reverse cholesterol transport on lipoprotein particles, and only weakly to plasma cholesterol and triglycerides. These ratios of apolipoprotein particles may play a significant role in determining the rate of phytanic acid elimination in patients with Refsum disease.




The optimized use of gas chromatography-mass spectrometry and high performance liquid chromatography to analyse the serum bile acids of patients with metabolic cholestasis and peroxisomal disorders.

Courillon F, Gerhardt MF, Myara A, Rocchiccioli F, Trivin F.

Service de Biochimie, Hopital Saint-Joseph, Paris, France.


Eur J Clin Chem Clin Biochem. 1997 Dec;35(12):919-22. Abstract quote

We have measured the bile acids in human serum as methyl ester-trimethylsilyl ethers by gas chromatography-mass spectrometry (GC-MS) using an electron ionization procedure.

The overall method was validated and the detection limit (0.4 mumol/l), linearity (2-30 mumol/l), intra-day and inter-day precision, accuracy and recovery (96.2% for nor-23-deoxycholic acid as internal standard) were measured. Serum C24-bile acids profiles from 43 cholestatic patients were measured by GC-MS and by HPLC. The results obtained with the two methods were well correlated and the criteria for selecting either HPLC or GC-MS identified.

The serum C24- and C27-bile acids and C29 dicarboxylic bile acid profiles for patients with generalized peroxisomal deficiencies, like Zellweger syndrome (n = 5), neonatal adrenoleukodystrophy (n = 1), infantile Refsum disease (n = 2) and from a single peroxisomal deficiency (n = 1) were also measured by GC-MS.


Refsum disease diagnostic marker phytanic acid alters the physical state of membrane proteins of liver mitochondria.

Schonfeld P, Struy H.

Institute of Biochemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, D-39120, Magdeburg, Germany.

FEBS Lett. 1999 Aug 27;457(2):179-83. Abstract quote

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a branched chain fatty acid accumulating in Refsum disease to high levels throughout the body, induces uncoupling of rat liver mitochondria similar to non-branched fatty acids (e.g. palmitic acid), but the contribution of the ADP/ATP carrier or the aspartate/glutamate carrier in phytanic acid-induced uncoupling is of minor importance.

Possible deleterious effects of phytanic acid on membrane-linked energy coupling processes were studied by ESR spectroscopy using rat liver mitochondria and a membrane preparation labeled with the lipid-specific spin probe 5-doxylstearic acid (5-DSA) or the protein-specific spin probe MAL-TEMPO (4-maleimido-2,2,6, 6-tetramethyl-piperidine-1-oxyl). The effects of phytanic acid on phospholipid molecular dynamics and on the physical state of membrane proteins were quantified by estimation of the order parameter or the ratio of the amplitudes of the weakly to strongly immobilized MAL-TEMPO binding sites (W/S ratio), respectively.

It was found, that phytanic acid (1) increased the mobility of phospholipid molecules (indicated by a decrease in the order parameter) and (2) altered the conformational state and/or the segmental mobility of membrane proteins (indicated by a drastic decrease in the W/S ratio).

Unsaturated fatty acids with multiple cis-double bonds (e.g. linolenic or arachidonic acid), but not non-branched FFA (ranging from chain length C10:0 to C18:0), also decrease the W/S ratio.

It is hypothesized that the interaction of phytanic acid with transmembrane proteins might stimulate the proton permeability through the mitochondrial inner membrane according to a mechanism, different to a protein-supported fatty acid cycling.



Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation.

Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB.

Department of Chemical Pathology, St. Thomas' Hospital, London, UK.

J Neurochem. 2002 Mar;80(5):727-35 Abstract quote

Refsum's disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma- and lipid-containing tissues.

The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, phytanoyl-CoA 2-hydroxylase (PAHX) and 2-hydroxyphytanoyl-CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2-oxoglutarate-dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsum's disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low-plasma phytanic acid may be caused by alpha-methylacyl-CoA racemase deficiency. A sterol-carrier protein-2 (SCP-2) knockout mouse model shares a similar clinical phenotype to Refsum's disease, but no mutations in SCP-2 have been described to-date in man.

This review describes the clinical, biochemical and metabolic features of Refsum's disease and shows how the biochemistry of the alpha-oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating alpha-receptor.


Atypical refsum disease with pipecolic acidemia and abnormal catalase distribution.

Baumgartner MR, Jansen GA, Verhoeven NM, Mooyer PA, Jakobs C, Roels F, Espeel M, Fourmaintraux A, Bellet H, Wanders RJ, Saudubray JM.

Department of Pediatrics, Hopital Necker-Enfants Malades, Paris, France.

Ann Neurol. 2000 Jan;47(1):109-13. Abstract quote

We describe an 18-year-old patient with psychomotor retardation and abnormally short metatarsi and metacarpals but no other signs of classic Refsum disease.

Molecular analysis of the phytanoyl-coenzyme A hydroxylase gene revealed a homozygous deletion causing a frameshift. Surprisingly, L-pipecolic acid was elevated in plasma, and microscopy of the liver showed a reduced number of peroxisomes per cell and a larger average peroxisome size.

These abnormal peroxisomes lacked catalase as did peroxisomes in fibroblasts of this patient. Such generalized peroxisomal abnormalities are not present in classic Refsum disease.


Hearing loss in adult Refsum's disease.

Bamiou DE, Spraggs PR, Gibberd FB, Sidey MC, Luxon LM.

Neuro-otology Department, National Hospital for Neurology and Neurosurgery, London, UK.

Clin Otolaryngol. 2003 Jun;28(3):227-30 Abstract quote

Refsum's disease is characterized by defective peroxisomal alpha oxidation of phytanic acid, with clinical features that include retinitis pigmentosa, polyneuropathy, anosmia and hearing loss.

Although hearing loss in Refsum's disease is common, there are few detailed assessments of the site of the abnormality. We examined the audiometric findings in patients with biochemically diagnosed Refsum's disease in order to assess the site of origin of the hearing loss.

We found hearing loss, ranging from mild, predominantly high frequency to moderate degree, in seven out of nine patients with biochemically diagnosed adult Refsum's disease. In addition, we found evidence to suggest subtle auditory nerve involvement in six out of the seven patients with hearing loss and in one out of the two patients with a normal pure tone audiogram, on the basis of the ABR test results.

We conclude that patients with Refsum's disease who report hearing difficulties should have full audiometric investigations in order to provide appropriate audiological rehabilitation.


Phytanic acid alpha-oxidase deficiency (Refsum disease) presenting in infancy.

Herbert MA, Clayton PT.

Hospital for Sick Children, London, UK.

J Inherit Metab Dis. 1994;17(2):211-4 Abstract quote

This report describes a patient with high serum phytanic acid concentration due to phytanic acid alpha-oxidase deficiency (classical Refsum disease).

He presented unusually early, hypotonia and developmental delay being apparent by 7 months. A generalized peroxisomal disorder (so-called 'infantile Refsum disease') was excluded by analyses of pristanic acid, very long-chain fatty acids, bile acids and plasmalogen synthesis.

The early presentation raises the possibility of in utero exposure to phytanate.



Phytanic acid storage disease (Refsum's disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management.

Weinstein R.

Department of Medicine, Division of Hematology/Oncology, Section of Hematology and Transfusion Medicine, St. Elizabeth's Medical Center of Boston, Tufts University School of Medicine, Boston, MA 02135, USA.

J Clin Apheresis. 1999;14(4):181-4. Abstract quote

Phytanic acid storage disease (known also as Refsum's Disease) is caused by inherited defects in the metabolic pathway for phytanic acid, a dietary branched-chain fatty acid. Poorly metabolized phytanic acid accumulates in fatty tissues, including myelin sheaths, and in organs including the liver and kidneys. Over time, affected individuals may develop classical diagnostic features of retinitis pigmentosa, cerebellar ataxia, peripheral polyneuropathy and an elevated protein content in the cerebrospinal fluid.

Liver, kidney, and heart disease may also develop. Dietary restriction of phytanic acid is useful in preventing acute attacks and arresting the progression of organ impairment, especially in the peripheral nervous system.

Therapeutic plasma exchange has been shown to be particularly useful for rapidly lowering plasma phytanic acid levels during acute attacks and may play a significant role as maintenance therapy as well.

Lipapheresis: an immunoglobulin-sparing treatment for Refsum's disease.

Gutsche HU, Siegmund JB, Hoppmann I.

Institute of Clinical Nephrology, Heide, Germany.

Acta Neurol Scand. 1996 Sep;94(3):190-3. Abstract quote

Toxic phytanic acid concentrations in patients with Refsum's disease can be reduced by plasma separation, performed either as plasmapheresis, or as cascade filtration. The latter procedure is as efficient and safe as plasmapheresis, and eliminates the need for albumin replacement. This study investigates the loss of immunoglobulins associated with the procedure.

MATERIAL AND METHODS: Immunoglobulin- and phytanic acid serum concentrations before and after cascade filtration (n = 16) were measured in a patient with Refsum's disease and their removal determined. Filters with sieving coefficients for immunoglobulin G of 70% and 30% were compared with each other and with historical data on plasmapheresis.

RESULTS: While differences in immunoglobulin M loss are negligible, the loss of immunoglobulin G in cascade filtration is significantly less than that reported for plasmapheresis and depends upon the pore size of the employed filters. The loss is least with larger pore size, but this advantage becomes statistically insignificant if immunoglobulin G loss is related to the lesser decrease in phytanic acid concentration that was achieved simultaneously in this study.

CONCLUSION: Unless transplantation of a-hydroxylase containing tissue can be established as treatment for Refsum's disease, cascade filtration appears to be the treatment of choice in order to avoid loss of albumin and to reduce the loss of immunoglobulin G.

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