Refsums disease

Refsum's disease

Description, Causes and Risk Factors:

ICD-10: G60.1

Alternative Name: Hereditary motor and sensory

Refsum's disease is an inherited disorder of fatty acid oxidation. It is characterized by phytanic acid accumulation in the blood and tissues, causing a motor and sensory neuropathy.

Refsum's disease is caused by defective alpha oxidation of phytanic acid (3, 7, 11, 15 tetramethylhexadecanoic acid), a branched?chain fatty acid present in a wide range of foodstuffs including dairy products, some meats and fish. The defective enzyme is phytanoyl?coenzyme A hydroxylase, which normally catalyses the second step in the breakdown of phytanic to pristanic acid using the CoA derivative as a substrate (the first step in alpha oxidation is the conversion of phytanic acid to phytanoyl CoA by Phytanoyl CoA ligase). This results in accumulation of phytanic acid, with elevated levels in blood and other tissues including fat and neurons. Phytanic acid can also be catabolized from the non?carboxyl end by omega oxidation, but the capacity of this pathway is severely limited to ?10?mg of phytanic acid per day. The average diet contains ?50?mg/day, and this factor, in combination with limited excretory mechanisms (via the kidneys and skin), leads to phytanic acid accumulation. The mechanism of phytanic acid toxicity is unclear, but it may be incorporated into tissue lipids and result in impaired myelin function. An alternative hypothesis is that excess levels affect the metabolism of fat?soluble vitamins. Research suggested that high phytanic acid levels interfere with vitamin A esterification in the retinal pigment epithelium leading to the production of a toxic substance and progressive visual failure. The physiological role of phytanic acid is unknown.

Refsum's disease is inherited in an autosomal recessive manner. Each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being unaffected and not a carrier.

The disease affects males and females equally.

Classical Refsum's disease is one of a group of disorders of the peroxisome. There is a single enzyme deficiency, phytanoyl-CoA hydroxylase (phytanoyl-coenzyme A hydroxylase), the gene for which (PAHX, also called PHYH) is found on chromosome 10 (autosomal recessive).

Both point mutations and deletions have been described on PAHX associated with Refsum's disease.


    Symptoms begin by late childhood or adolescence, although there are reports of presentation as late as 50 years of age.

  • The disease is usually progressive, with periods of remission, although acute and subacute presentations have been reported, associated with rapid weight loss, fever and pregnancy.

  • The initial presentation is of unsteadiness and/or failing vision.

  • There is night blindness, progressive (nerve) deafness, loss of sense of smell, unsteady gait, and intention tremor, and there are bladder problems.

  • Atypical retinitis pigmentosa. Progressive concentric restriction of visual fields. Cataracts and photophobia caused by impaired pupillary light responses.

  • Peripheral polyneuropathy. Absent or diminished deep tendon reflexes. Palpable peripheral nerves secondary to hypertrophy.

  • Cerebellar ataxia. Loss of position sense and nystagmus.

  • Cardiomyopathy and conduction abnormalities. ECG changes are present.

  • Ichthyosis, hyperkeratosis plantaris and palmaris may be seen.

  • Epiphyseal dysplasia - leading to characteristic shortening of the fourth toe, hammer toe, pes cavus and osteochondritis.


Tests may include:

    Routine investigations of urine or blood do not show any consistent abnormality.

  • Plasma levels of phytanic acid of >800 mmol/L are not uncommon at presentation - normal levels <18 mmol/L.

  • CSF protein levels are usually elevated.

  • LDL and HDL cholesterol levels are decreased.


    Plain X-rays can monitor bone changes.

  • MRI scan may show symmetrical changes of the corticospinal tracts, cerebellar dentate nuclei and corpus callosum.

Other tests:

    Slow conduction velocities are found in nerve conduction studies.

  • Nerve biopsies from affected patients have onion bulb formation and targetoid inclusions have been described in Schwann's cells.

  • Electroretinogram may be grossly abnormal.


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.

NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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