Refsum's disease

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Refsum's disease
File:Phytanic acid.png
Phytanic acid
ICD-10 G60.1
ICD-9 356.3
OMIM 266500
DiseasesDB 11213
eMedicine derm/705 
MeSH D012035

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Refsum's disease (Refsum-Thiébaut disease, Refsum-Thiébaut-Klenk-Kahlke disease), named after Norwegian neurologist Sigvald Bernhard Refsum (1907-1991),[1][2] is neurological disease that results in the malformation of myelin sheaths around nerve cells. It is a peroxisomal disorder.


Refsum's disease is caused by faulty enzymes during the alpha-oxidation of phytanic acid resulting in buildup of phytanic acid and its unsaturated fatty acid derivatives in the plasma and tissues.

This in turn can be due to deficiencies of phytanoyl-CoA hydroxylase (chromosome 10) or peroxin-7 (chromosome 6).


Patients with Refsum's Disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation/remission occur.

Differential diagnosis

Refsum's disease must be differentiated from other diseases that cause neurological manifestations in infants.

Diseases Type of motor abnormality Clinical findings Laboratory findings and diagnostic tests Radiographic findings
Spasticity Hypotonia Ataxia Dystonia
Leigh syndrome - - + +
Niemann-Pick disease type C - - + +
  • Abnormal liver function tests
  • Fibroblast cell culture with filipin staining
Infantile Refsum disease - + + - Elevated plasma VLCFA levels --
Adrenoleukodystrophy + - - -
  • Elevated plasma VLCFA levels
  • Molecular genetic testing for mutations in the ABCD1 gene
Zellweger syndrome - + - - --
Pyruvate dehydrogenase deficiency + + + -
  • Elevated lactate and pyruvate levels in blood and CSF
  • Abnormal PDH enzymatic activity in cultured fibroblasts
Arginase deficiency + - - - --
Holocarboxylase synthetase deficiency - + - - Elevated levels of:
  • Beta-hydroxyisovalerate
  • Beta-methylcrotonylglycine
  • Beta-hydroxypropionate
  • Methylcitrate
  • Tiglylglycine
Glutaric aciduria type 1 - - - + Elevated levels of:
Ataxia telangiectasia - - + - --
Pontocerebellar hypoplasias - + - - Genetic testing for PCH gene mutations
Metachromatic leukodystrophy - + + -
  • Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts
Pelizaeus-Merzbacher + - + -
Angelman syndrome - - + -
  • Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations
Rett syndrome + - - +
  • Occurs almost exclusively in females
  • Normal development during first six months followed by regression and loss of milestones
  • Loss of speech capability
  • Stereotypic hand movements
  • Seizures
  • Autistic features
  • Clinical diagnosis
  • Genetic testing for MECP2 mutations
Lesch-Nyhan syndrome + - - + --
Miller-Dieker lissencephaly + + - -
  • Cytogenetic testing for 17p13.3 microdeletion
Dopa-responsive dystonia + - - +
  • Onset in early childhood
  • Symptoms worsen with fatigue and exercise
  • Positive response to a trial of levodopa


The most effective therapy in the classic Refsum disease is dietary treatment with a phytanic acid-restricted diet, such as exclusively avoiding consumption of beef, lamb, fatty fish such as tuna, cod, and haddock [3]. Recent research has shown that CYP4 isoform enzymes could eliminate the phytanic acid storage in vivo [4] and patients could try alternative natural remedies with either eatable marine invertebrates or with clofibrate supplement of which the component is usually rich in the excretion of high plant [5], [6], [7]. Currently, there is no clinical data to approve using this xenonbiotic drug for the treatment, perhaps due to its serious adverse effect [8]and the major medical treatment of the disease only relies on the plasmapheresis.


Phytol (from chlorophyll in plant foods) ---> phytanic acid -x-> pristanic acid ---> propionyl CoA

See also


  1. S. Refsum: "Heredoataxia hemeralopica polyneuritiformis - et tidligere ikke beskrevet familiært syndrom? En foreløbig meddelelse." Nordisk Medicin,1945, 28: 2682-2686 (in norwegian).
  2. S. Refsum: "Heredopathia atactica polyneuritiformis. A familial syndrome not hitherto described. A contribution to the clinical study of hereditary diseases of the nervous system". Acta psych. neur., 1946. Suppl.38: 1-303.
  3. National Institutes of Health. "Synonym(s): Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis <Internet>". Retrieved 8 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  4. Xu, Fengyun; et al. "CYP4 Isoform Specificity in the {omega}-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease <Internet>". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  5. Snyder, Mark J. "Cytochrome P450 enzymes belonging to the CYP4 family from marine invertebrates <Internet>". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  6. Rewitz, Kim F. "Marine invertebrate cytochrome P450: Emerging insights from vertebrate and insect analogies <Internet>". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  7. Raucy, Judy L. "Regulation of CYP2E1 by Ethanol and Palmitic Acid and CYP4A11 by Clofibrate in Primary Cultures of Human Hepatocytes <Internet>". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  8. "Atromid-S: Indication & Dosage <Internet>". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

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