Refsum's Disease

Author: Francesca Bona
Date: 27/02/2011



Refsum's Disease is an autosomal recessive disorder of lipid metabolism in which deficiency of phytanic acid alpha-hydroxylase results in accumulation of phytanic acid; manifested chiefly by chronic polyneuritis, retinitis pigmentosa, cerebellar ataxia and elevation of protein in cerebrospinal fluid.

The Diseases DatabaseRefsum disease
MedlinePlusRefsum disease
OMIM single geneRefsum disease
WikigenesRefsum disease
GeneCardsRefsum disease
Kegg PathwayRefsum disease
Orpha.netRefsum disease)


Prevalence of the disease is of 1 case per 1.000.000 and males and females are equally affected. Initial signs usually appear around the age of 15, but they can also manifest during childhood or at the age of 30-40 years.
Refsum disease may not be distributed equally among geographical areas or different ethnic groups, as most of the diagnosed cases have been found in children and young adults of Scandinavian heritage. (


The onset of symptoms is typically in late childhood or adolescence, usually following a progressive course.
The cardinal manifestations involve the nervous system: demyelinating neuropathy, pes cavus (Wikipedia), cerebellar ataxia, sensorineural deafness, anosmia and cranial nerve involvement. The neurological symptoms are often preceded by the ophthalmic ones, like nyctalopia, cataracts, photophobia and retinitis pigmentosa- related visual failure. Both a generalized dysautonomia and high lipid levels in the iris can lead to myosis.

Patiens can also present with cardiac involvement (conduction abnormalities or cardiomyopathy) and reversible renal involvement, especially in association with extremely high phytanic acid levels.
Scaly thickening over the extremities and syndactyly (with the characteristic shortening of the fourth toe) can be useful for the diagnosis.

A.J. Wills, N.J. Manning, M.S. Reilly. Refsum's disease. Q J Med 2001; 94: 403-406


  • Lab results:
    • CSF protein levels are usually elevated;
    • Plasma levels of phytanic acid measured by gas chromatography-mass spectroscopy are consistently elevated (normal range < 19 mmol/l). Phytanc acid levels > 800 mmol/l are not uncommon at presentation. Phytanic acid also accumulates to a lesser degree in the plasma of patients with peroxisomal deficiency disorders such as Zellweger disease, neonatal adrenoleukodystrophy and infantile Refsum’s disease. It has been reported at 941 mmol/l in rhizomelic chondrodysplasia punctate. Pristanic acid is also known to be elevated in peroxisomal deficiency disorders and peroxisomal branched chain oxidation defects, but should be low/normal in Refsum’s disease due to a lack of production from phytanate. However, it has been seen a patient where the pristanate to phytanate ratio was 0,005, far exceeding the Refsum’s range (< 0,007) and suggesting a biochemical variant of this disorder.
  • ENG: nerve conduction studies are abnormal, with slowing of conduction velocities.
  • Electroretinogram: may be grossly abnormal.
  • Histopathology: nerve biopsies from affected have shown onion bulb formation, and targetoid inclusion have been described in Schwann cells which have a similar appearance on electron microscopy to those seen in cultured fibroblast.

DD: Friedreich’s ataxia, mithocondrial cytopathies, other hereditary and sensory neuropathies, abetalipoproteinemia and vitamin E deficiency can usually be differentiated on clinical grounds or by appropriate investigations.


The pathogenesis of this disease is releated to a defective enzyme involved into the catabolism of phytanic acid, namely the phytanol-coenzyme A hydroxylase.
Phytanic acid (Wikipedia) is a branched-chain fatty acid present in many foods, as some meats and fish. Its physiological role is yet unknown.
The defective enzyme normally catalyses the second step of the alpha oxidation of this acid, which leads to the formation of pristanic acid, as shown in the figure.

There is another pathway involved in the catabolism of phytanic acid (via omega oxidation), but its capacity is of 10 mg/day, compared to the 50 mg/day contained in an average diet.
Phytanic acid will consequently accumulate in blood and tissues, causing a toxicity which mechanism is still only hypothesized. It could be incorporated into tissue lipids, therefore impairing myelin function; alternatively, it could affect the metabolism of fat-soluble vitamins. Levy suggested that the excess of phytanic acid may interfere with vitamin A esterification in the retina, leading to the production of a toxic substance that causes a progressive visual failure.


The disease affects males and females equally. Adult Refsum's disease is not a common condition and therefore the chance of a patient with retinitis pigmentosa having adult Refsum's disease is small. A person with retinitis pigmentosa and no other problems, such as a loss of smell or difficulty in walking, is unlikely to have adult Refsum's disease.
The disease is a recessive genetic disorder, which means the abnormal gene causing the disease has to come from both parents. Therefore the disease is unlikely to be passed from a parent with the illness to his or her child unless the two parents were related before marriage (e.g. cousins) or both come from families with a case of adult Refsum's disease. (


Some problems, such as Retinitis pigmentosa, the poor sense of smell and the deafness, are considered to be slowly progressive.
Retinitis pigmentosa is the most important abnormality in adult Refsum's disease, but it has not been possible to show a relationship between the severity of the retinitis and the level of phytanic acid in the blood although there is some evidence that, if the level of phytanic acid in the body can be kept low, the blindness will not get worse. Hence, if one is to prevent blindness in adult Refsum's disease, it will be necessary to treat the illness early and prevent retinal damage, rather than to treat it when it is severe.
As for the hyposmia, all patients with adult Refsum's disease have a poor sense of smell from a young age. In order to detect this the sensation of smell must be tested appropriately by a suitable medical technique. It is not sufficient to ask a patient if he/she can smell normally as these patients may not know what normal smell is and be unaware that their ability to smell is well below the normal.

On the other hand, some problems can change rapidly.
The weakness and unsteadiness of gait, due to the peripheral neuropathy, can come on quickly, and if treated can improve quickly. Only if it has been present and untreated for a long time will it fail to improve with treatment. It is this symptom which may immobilize a patient, especially if vision is severely affected. There are also other less common problems in this group including a dry rash, ichthyosis.


Reducing daily intake of phytanic acid to 10-20 mg/day through dietary restriction is the first measure to take. Phytanic acid is found in foods obtained from animals which live mainly on green plants and fish. In developed Countries, this typically means beef, lamb, goat, fish, milk and milk products, and fish oils (often contained in processed fats). It is also important to prevent loss of weight, as, when the weight falls, body fat stores are used to provide energy and the stored phytanic acid is released into the blood, increasing serum levels. This may even happen over a short timescale, so a regular eating pattern of three meals a day, plus snacks if necessary, is better than long periods without food followed by a large meal. The release from adipose stores might also be held responsible for the time lag occurring before serum levels start to fall.

A recent analysis of a sample of foods of different groups showed that foods can be divided into three groups, according to the levels of phytanic acid they contain:

Group I - Low-risk foods
Foods where no phytanic acid was found.
These foods can be eaten freely.

Group II - Medium-risk foods
Foods found to contain up to about 8 mg phytanic acid in a normal serving. Althought adult Refsum's patients can break down some phytanic acid (10-30 mg per day), they should aim to take in as little as possible. If their phytanic acid level is low, and either decreasing or stable, they may take one food from this group each day, though preferably not on a regular basis. During illness, or when the phytanic acid levels are high, these foods should be avoided completely.

Group III - High-risk foods
Foods found to contain high levels of phytanic acid - above 10 mg and up to 700 mg/100 g (in fish oils). Also those processed foods containing ingredients known to be high in phytanic acid, namely cream, butter and 'animal fats', which are often from fish oils.
Foods in this group should be avoided completely.

Some examples of food of different degrees of risk:

  • Meat: Phytanic acid is found in foods obtained from animals which live mainly on green plants (i.e. cows, sheep and goats)
    • Low-risk: pig, chicken, duck, turkey
    • Medium-risk: rabbit
    • High-risk: cow, sheep, goose
  • Fish: All fish contain phytanic acid, proportionally to their fat content. Fish oil medicines, as cod liver oil capsules, must be avoided.
    • Low-risk: none
    • Medium-risk: white fish, shellfish
    • High-risk: fish oils, salmon, sardines
  • Fruit and vegetables: No phytanic acid was found in a selection of fruit and vegetables and none in any vegetable oil. Previous studies have shown to be little danger from free phytol. In view of the protective effect of fruit and vegetables in maintaining general good health patients are recommended to take average amounts of fruits and vegetables every day.
    There is a possible exception in the case of spinach and dried fruit, due to the high levels of phytol they contain - these might be a problem if eaten in quantity. Potatoes cooked in animal fat must be avoided as well.
  • Dairy products: The fats in milk from cows, sheep and goats all contain phytanic acid, so great care must be taken with dairy products. All traditional cheeses, processed cheese and cheese spreads contain phytanic acid and should never be eaten. Even lower fat or fat-reduced cheese should be avoided.

Into the low-risk group we can also put: savoury flavourings, hen's eggs, sodas, nuts, cereals, sweets.

Since adult Refsum's disease also affects the nervous system, alcohol should be kept to a minimum. US National Guidelines give 21 units of alcohol per week for a man and 14 for a woman (1 unit = ½ pint beer, 1 glass of wine).

When a rapid clinical improvement is needed, plasma exchange can be useful. It should also be considered in patients in which dietary control is inadequate.
Although the neurological, cardiac and dermatological sequelae can be reversed by reduction of phytanic acid levels, visual and hearing impairments are less responsive to treatment.


The causative mutation can be found in:

  • PHYH gene (or PAXH, localised in 10pter-p11.2) encoding the peroxysomal enzyme phytanoyl-CoA hydroxylase (PhyH), which alpha-oxidises phytanic acid and allows the first step of its degradation. It is the most common case.
Your Favorite Gene SigmaPHYHPHYHIPPEX7
  • PHYHIP (Phytanoyl-CoA hydroxylase-interacting protein) is a 330 amino acid protein that is strongly expressed in brain, with weak expression in ovary, small intestine and ovary. PHYHIP interacts with the Refsum disease gene product, PAHX, indicating that PHYHIP may play a role in the CNS deficits of Refsum disease.
  • PEX7 gene, localised in 6q22-24. It codes for the peroxine 7 receptor, which allows the import of PhyH in peroxysomes.


AddThis Social Bookmark Button