What is Refsum Disease?
Adult Refsum disease is a metabolic disorder caused by a number of faulty genes (principally PHYH) which affect the pathway that degrades a plant-derived chemical called phytol which some bacteria found in ruminant animals turn into Phytanic Acid. In humans if phytanic acid is not degraded it accumulates in nerves, liver and fat. Phytanic acid is not produced in the body but found in many foods. The highest concentration of phytanic acid is found in dairy products, beef, lamb and some fish. Refsum disease can be life threatening if undiagnosed.
What are the clinical symptoms of Refsum Disease?
Patients with Refsum disease do not generally show any obvious defects at birth except maybe short metacarpals and metatarsals (shorten thumbs or shorten 4th toes). Other bones and joints may be affected, but growth and development appears normal. Initial symptoms will generally appear between the age of 10 to 20 with the loss of night vision being common. Patients have also been known to not display symptoms until around age 50. The initial complaints usually involve vision problems, weakness in the arms and legs or unsteadiness. Below is a list of the most common symptoms of Refsum disease.
Retinitis pigmentosa: Retinitis pigmentosa is an expression of degenerative eye disease as the visual receptors are lost in the retina and the background structure of the eye is exposed. It manifests as a failure of night vision and later decreased peripheral vision, and eventually can lead to low vision or blindness.
Anosmia: loss of the sense of smell and many aspects of the subtleties of taste
Peripheral polyneuropathy: Peripheral polyneuropathy is the term for dysfunction of the nerves outside of the spinal cord. Symptoms may include numbness, weakness, burning pain, and loss of reflexes occurring initially at the body extremes (feet or hands).
Deafness: loss of hearing
Cerebellar ataxia: Ataxia is a nerve-derived form of unsteadiness. Cerebellar ataxia refers to the fact that the defect is in a specific part of the brain (the cerebellum) that coordinates muscle functions. As a result the brain fails to regulate the body posture, as well as the strength and direction of movements.
Skeletal dysplasia: Bone abnormalities including shortening or deformity of the tubular bones in the hands and feet and abnormal growth plates (epiphyseal dysplasia) at the knees, elbows and shoulders may be found.
Ichthyosis: A distinct type of scaliness of the skin different in appearance from eczema or psoriasis. These symptoms can range anywhere from fish-like scaliness of the palms and soles of the feet to being present on the trunk of the body.
Pupillary abnormalities: The pupil of the eye is often small in Refsum disease and does not respond well to light or drugs used to ‘open’ the eye by optometrists.
Cataract: a clouding of the lens in the eye causing deterioration in vision often associated with starburst haloes around bright objects.
Nystagmus: rapid, involuntary, rhythmic eye movements
Cardiac Arrhythmia: Heart rhythm abnormalities are a rare but serious complication of very high phytanic acid levels and can be a cause of death in Refsum disease.
Weakness: significant slow-recovering weakness after illness is a feature of Refsum disease
The impact on an individual of these symptoms can increase based on their plasma phytanic acid level. Higher levels will generally increase the severity of symptoms. Phytanic acid accumulates in the fat tissue of Refsum patients throughout their lives before their diagnosis. This means that even with a strict diet low in phytanic acid an individual can still have higher levels of plasma phytanic acid throughout their lives due to release of phytanic acid from their fat cells into their blood.
How do you get Refsum Disease?
Refsum disease is a familial (genetic) disorder that occurs in 1 in 1,000,000 people. Most cases are sporadic though the risks are increased if there is a history of consanguineous marriage in the family. It is classified as an autosomal recessive. This means that if both parents are carriers of the disease, each child has a 1 in 4 chance of developing Refsum disease.
When both parents are carriers of a specific mutated gene, such as those for Refsum disease, their children have a 25% chance of being affected by the disease, a 25% chance of neither being a carrier nor affected, and a 50% chance of being an unaffected carrier, just like their parents. (See illustration below.)
How is Refsum Disease Diagnosed?
The diagnosis of Refsum disease is based on clinical findings and the finding of a raised blood phytanic acid level. Most people with Refsum disease have phytanic acid levels 10-100 fold above those found in the general population, though a few have lower but still abnormal levels. The diagnosis is typically confirmed through genetic (DNA) testing but in a few cases direct measurement of enzyme activities in skin biopsy samples may be required.
Is there a treatment for Refsum Disease?
There are currently two available treatment regimes for Refsum Disease. The first treatment is a strict diet low in phytanic acid and is used for long-term management. Dietary restriction of phytanic acid intake helps lessen or resolve ichthyosis, sensory neuropathy, and ataxia. A low phytanic acid diet is suspected to slow the progression of vision and hearing loss. Click here to learn more about the diet.
The second treatment is the direct removal from the blood stream of phytanic acid by a dialysis-type process (plasmapheresis or lipid apheresis) and is typically used in acute management of people hospitalized as a result of Refsum disease where it helps to resolve acute heart arrhythmias or extreme weakness. It may be done on a chronic regular basis in some patients whose phytanic acid levels do not fall sufficiently on diet.
In addition to the strict diet, patients with Refsum disease must try to minimize the acute release of stored phytanic acid from their fat cells. Sickness, planned hospital procedures involving fasting (e.g. surgery) or rapid weight loss can mobilize fat as part of the body’s stress response which in turn can release phytanic acid from a patient’s liver or fat stores. Patients should receive guidance from a trained dietician and physician on how to minimize risks of acute phytanic acid release and how to manage Refsum disease.
What research is being done to support improving the quality of life for patients with Refsum Disease?
Past research in this area clarified the clinical features of Refsum disease, helped devise a dietary intervention and identified responses to fasting. Before the establishment of the diet and plasmapheresis, patients with the disease had a shortened life expectancy. Basic science clarified the pathways involved in degrading phytanic acid and also the genetic defects that cause the condition. All of these contributed to the understanding of Refsum disease which established the treatments that are currently available.
Research has slowed in the more recent years due to funding challenges. Global DARE Foundation was established in 2019 to help drive research and find better therapies to improve the quality of life of Refsum patients.
Global DARE Foundation is starting a research project to test more foods for their phytanic acid content and to update the previous measurements as dietary habits, farming practices and food manufacturing processes have changed dramatically in the last 30 years. To date only 150 foods have been tested which limits the foods that Refsum patients can eat. The foundation is also in early conversations on a proof of concept study for gene therapy in this inherited disorder.
References for this summary
See Gene Review for additional details
Summary reviewed by Prof. Ronald Wanders, PhD & Prof. Anthony Wierzicki, PhD