In 1946 Professor Refsum of Oslo University in Norway described two families with impaired vision, due to retinitis pigmentosa, and an unsteady gait.  Professor Refsum suggested that this association was not a chance finding but the manifestation of a single disease.  This disease, which he called Heredopathia Atactica Polyneuritiformis, is now usually referred to as Adult Refsum’s Disease.  At about the same time scientists in New Zealand identified the fatty acid, phytanic acid, in milk fat.  In 1963 Klenk and Kahlke discovered that patients with Refsum’s disease had a raised phytanic acid level in their blood.  The finding of a specific chemical abnormality in these patients has been of importance in the understanding of the disease and in devising a rational treatment.

Phytanic Acid

The fats in the body are made up of several fatty acids, one of which is called phytanic acid.  It comes from chlorophyll, the green pigment of plants, which contains a phytol side chain.  Man, carnivores and most omnivores do not absorb chlorophyll with its attached phytol.  However many herbivores which live on green plants, for example cows and sheep and some fish, have specially adapted digestive systems containing bacteria which can break down chlorophyll thus releasing phytol, which is absorbed and metabolised into phytanic acid. The phytanic acid is then incorporated into the fat and milk of these herbivores.  Man is able to absorb phytanic acid from the milk and the fat of herbivores and other animals which can digest chlorophyll. Phytanic acid requires a special enzyme in the body for its breakdown and the release of energy and this is done easily by the majority of human beings.  However those with, or liable to, Adult Refsum’s Disease are unable to break down phytanic acid and hence as they eat food containing phytanic acid, the amount of phytanic acid in the body gradually rises.

There is a second minor pathway for the removal of phytanic acid from the body but it is unable to remove the amount of phytanic acid that most people eat in a normal diet. However if the patient takes a diet with a very low level of phytanic acid, the phytanic acid level in the body will fall slowly over  months and years due to this second pathway.

The Medical Condition

Small amounts of phytanic acid in the body are harmless but when the level rises in the blood it is a poison. Phytanic acid in the fat stores is less dangerous. It is not known exactly how phytanic acid or related compounds poison the body, although the problems that occur in Refsum’s disease are well recognized.  The problems that occur in patients with Adult Refsum’s Disease can be divided into 3 categories:

1. Bony abnormalities: 

These occur early in life, but only in a proportion of patients and are rarely a major problem.  The commonest congenital abnormalities are short fingers and toes but other bones and joints may be affected. 

2. Slowly progressive problems 

(a) The most important and serious abnormality in Refsum’s Disease is retinitis pigmentosa, a degeneration of the retina, which usually begins mildly in childhood and then slowly progresses. The main symptoms of retinitis pigmentosa are poor vision in the dark and contraction of the visual fields, which means that only objects in the centre of vision are easily seen. 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.  Unfortunately the retina of the eye is a very sensitive structure and when damaged does not have powers of recovery.  Hence, if one is to prevent blindness in 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. Other eye pathology can occur in Refsum’s Disease.

(b) 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.
(c) Some patients develop deafness.

3. Problems which can change rapidly: 

The weakness and unsteadiness of gait which patients with Refsum’s disease get can come on quickly, and if treated can improve quickly.  The unsteadiness is due to damage to the nerves.  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.  The heart muscle can be damaged in severe Adult Refsum’s Disease, but this is rare in patients whose phytanic acid is controlled by appropriate management. There are other rarer complications in this category.

Epidemiology.

The disease affects males and females equally. Refsum’s disease is not a common condition and therefore the chance of a patient with retinitis pigmentosa having Refsum’s disease is small.  A person with retinitis pigmentosa and no other problem, such as a loss of smell or difficulty in walking, is unlikely to have 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 Refsum’s Disease.

Diagnosis.

There are a few other rare conditions with a raised phytanic acid but these are usually present at birth or early infancy and may be associated with severe multiple abnormalities. Sometime they are called Infantile Refsum’s Disease but they do not have the same cause or genetic abnormality as Adult Refsum’s Disease. 
Patients with Adult Refsum’s Disease usually present to a doctor with visual symptoms and are diagnosed as having Retinitis Pigmentosa. Adult Refsum’s Disease should be considered in all such cases even though the likelihood is small. If the patient has poor sensation for smell Adult Refsum’s Disease becomes much more likely and the blood phytanic acid level should always be measured. If the patient also has a short digit and neurological symptoms or signs in the legs then Refsum’s Disease is very likely. 

Treatment

The main treatment for Refsum’s disease is dietary and requires the expertise of a dietitian.  The principles are clear.  First, the patient should eat sufficiently well to prevent loss of weight.  When the weight falls the fat stores are used up for energy, but the phytanic acid released from these stores is not removed, so it accumulates in the blood and makes the patient ill.  Second, the patient should avoid foods containing significant phytanic acid, which means fat from animals which live chiefly on green plants.  In Europe, this is mostly milk products and fat from mutton and beef and fish. Many prepared foods contain such products. By reducing the intake of these fats the intake of phytanic acid is lessened considerably and the patient is likely to improve or remain well, although the retina will not regenerate.  Other methods of treatment, such as plasma exchange, may be needed if the patient is very ill and the disease is life threatening. This requires a specialist service.  In addition one of the most important things a patient can do is to keep in good general health by eating, resting and exercising sensibly.

A patient with Refsum’s Disease is best managed by doctors and dietitians with a working knowledge of the illness.

The Future

Refsum’s Disease is a complex illness and this account gives only a summary of the main aspects.
There are many things about Refsum’s disease that are not known by doctors, scientists or dietitians, but as research continues one can be cautiously optimistic that further help will become available for patients with this condition.