What is Refsum Disease: Causes, Symptoms, Treatment, Complications, Prognosis, Diagnosis

What is Refsum Disease?

Refsum disease is named after a Norwegian neurologist Sigvald Bernhard Refsum. It is a neurological disorder mainly caused by the deposition of phytanic acid in different tissues of human body. Let us understand about the symptoms, causes and treatment of Refsum disease.

Before going to discuss about the disease, we shall know something about the source and metabolism of the phytanic acid. Phytanic acid also called 3,7,11,15-tetramethylhexadecanoic acid, is found in dairy products, some fishes and in herbivores like ruminants. Humans who consume the above foods get sufficient amount of phytanic acid in the diet. In humans, metabolism of fatty acids takes place mainly by two methods namely, α (alpha) oxidation and β (beta) oxidation. Most of the fatty acids undergo β oxidation and produce carbon dioxide and water; whereas phytanic acid unlike other fatty acids undergoes α oxidation in peroxisomes. This oxidation reaction is brought about by an enzyme called phytanic acid oxidase, which results in the formation of another fatty acid 2,6,10,14-tetramethylpentadecanoic acid which is commonly called pristanic acid by the removal of one carbon. Pristanic acid on the other hand undergoes β oxidation to form medium chain fatty acids. All these reactions take place in peroxisomes. Then these fatty acids are brought to mitochondria to form carbon dioxide and water.

In some individuals, due to the deficiency of the enzyme phytanic acid oxidase, this phytanic acid is not oxidized and instead, stored in blood and tissues giving rise to a neurological disorder called Refsum disease. It is an autosomal recessive disorder which is expressed if the individuals have 2 copies of the defected gene. The disease is usually detected in adults. Refsum disease is also known as

  • Adult Refsum disease
  • Phytanic acid oxidase deficiency
  • Heredopathia atactica polyneuritiformis
  • Phytanic acid storage disease
  • HMSN type IV
  • Hereditary motor and sensory neuropathy type IV

Symptoms of Refsum Disease

This is an adolescent onset disease. Some of the important signs and symptoms of Refsum disease include the following,

  • Lack of coordination of voluntary muscles (muscles which normally brings about desired action) leading to ataxia1
  • Changes in speech
  • Abnormalities in the eye and its movements which include retinitis pigmentosa, cataract, night blindness, abnormality in the pupil1
  • Ichthyosis (dry thickened scaly skin) is a noninflammatory condition where palm, sole and trunk would have scaliness
  • Hearing loss or difficulty in hearing
  • Damage to the cerebrum
  • Peripheral polyneuropathy where normal sensation of skin in arms and legs is altered due to damage of nerves which connect brain and other parts of the body
  • Neuronal degeneration
  • Anosmia (Loss of sense of smell)
  • Size of limbs is decreased due to abnormalities in epiphysis (epiphyseal dysplasia)

Causes for Refsum Disease

Refsum disease is caused due to the accumulation of phytanic acid in blood and tissues. This disease is also referred to as peroxisomal disorder since the α oxidation is altered because of the deficiency of an enzyme called phytanic acid oxidase particularly known as phytanoyl-CoA hydroxylase.2

The main causes of Refsum disease is genetic changes. The reason for this deficiency is the mutations caused in PHYH gene or PEX7 gene. This gene codes for peroxin 7 protein receptor. Hence the mutation alters the transportation of proteins which are responsible for development of different parts of the body. This results in impaired development of body parts which is a major symptom of rhizomelic chondrodysplasia punctata type 1.

Diagnosis of Refsum Disease

Diagnosis of Refsum disease includes a thorough history takin, clinical examination and investigations. Refsum disease is mainly characterized by deposition of phytanic acid in blood and tissues. Hence, the disease can be confirmed by the following tests:

  • Blood Tests: The level of phytanic acid can be measured by simple blood test.
  • Genetic Tests for Refsum Disease: This test is done to confirm the disease as well as it tells about the chance of getting any genetic disorder. These test include molecular genetic tests, chromosomal genetic tests, biochemical genetic tests, etc.

Complications of Refsum Disease

At a later stage in life in patients of Refsum disease, some more complications can be expected because of cardiomyopathy such as cardiac arrhythmia and/or cardiac arrest. The possibility and severity of the complications of Refsum disease may vary from person to person, hence medical advice and follow-up is essential.

Is Refsum Disease Inherited?

Refsum disease is an autosomal recessive disorder. The individuals get Refsum disease if they have defected genes in 2 copies in each cell. It means, both the parents should contribute one copy of defected gene, in which case the person may inherit Refsum disease. The individuals would be the carriers if only one copy of defected gene is present in them. In such cases, the disease is not expressed.

Treatment of Refsum Disease

Important thing to note while treating the patients with Refsum disease is that, since it is caused by the deposition of phytanic acid in the body, the doctors would advise the patients to avoid the foods that have high levels of phytanic acid.3 This is called phytanic acid restricted diet.

Hence, as a part of the treatment of Refsum disease, the foods to be avoided include:

  • Fish like tuna, cod, haddock, etc., should be avoided.
  • Ruminants and their milk are also rich in phytanic acid, hence should be avoided.
  • Fats of other grass eating animals also to be avoided.
  • Enzyme therapy which includes CYP4 isoform is found to reduce the level of phytanic acid.

An eye should be kept on weight management. This is because; the reduction in weight may release the accumulated phytanic acid to the plasma from the fat tissues. This increases the level of phytanic acid in blood plasma which is thought to worsen the symptoms of Refsum disease. In such condition, plasmapheresis is done. It is a medical intervention which involves the filtering of blood or replacement of plasma which reduces the level of phytanic acid or completely removes it.

Prognosis of Refsum Disease

In many cases who suffer from Refsum disease, death is commonly recorded before reaching the age of 30 years. In cases where Refsum disease is diagnosed very soon and treatment is started the number of deaths could be controlled. In patients where diet therapy is started immediately and if the patients strictly follow the prescribed diet chart, dramatic improvement can be seen. A strict phytanic acid restricted diet is found to reduce weakness, reduce the neurological symptoms and reduce the scales of the skin. This is also found to improve the response to the stimulus, nerve response, walking etc.


Refsum disease is a rare autosomal recessive disorder caused by the accumulation of phytanic acid in the body. Although there are records and researches regarding Refsum disease in general, attempts are to be made to manage Refsum disease in pregnant women. Biological sources of phytanic acid are to be avoided in diet to manage the disease. It is an added advantage for humans that phytanic acid cannot be derived in them from chlorophyll present in plants. A well planned phytanic acid restricted diet would be helpful if started well in time and followed for life time.

  1. https://www.ncbi.nlm.nih.gov/books/NBK22208/
  2. https://www.ncbi.nlm.nih.gov/pubmed/9326940
  3. https://www.ncbi.nlm.nih.gov/pubmed/20547622