Refsum Disease

What is Refsum Disease?

Adult Refsum disease is a metabolic disorder caused by a number of faulty genes (principally PHYH) which affect the ability to metabolize phytanic acid, a type of fat found in certain foods. In humans, if phytanic acid is not degraded it accumulates in nerves, liver and fat.  Refsum disease can be life threatening if undiagnosed.

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.

Symptoms

The most common symptoms of Refsum disease include:

• 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. 

Inheritance

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.

Treatments

There are currently two available treatment regimens 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. 

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. 

Research and Clinical Trials

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.

The 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. 

To learn more about the Global DARE Foundation mission and priorities, visit their website at https://www.defeatadultrefsumeverywhere.org/

Global DARE Foundation recently hosted Dr. Bart Leroy, MD, PhD, in an educational webinar on Refsum Disease from an Ophthalmology Perspective. Dr. Leroy presented on the benefits of early diagnosis by clinicians. Check out the recording here.