NORD gratefully acknowledges Kathleen Renna, Scientific Program Analyst, Division of Genomics and Society, National Human Genome Research Institute, Anthony S. Wierzbicki, PhD, Consultant in Metabolic Medicine/Chemical Pathology at Guy’s & St. Thomas’ Hospitals and Honorary Professor in Cardiometabolic Disease at King’s College, London, and the Global DARE Foundation, for assistance in the preparation of this report.
Refsum disease is a metabolic disorder characterized by the build-up of a fat (lipid) called phytanic acid in blood plasma and tissues. Individuals with Refsum disease are usually normal at birth, but between the ages of 10 and 20 years old, symptoms begin to develop starting with loss of night vision (retinitis pigmentosa), and eventually including weakness in arms and legs or unsteadiness (cerebellar ataxia). Other common symptoms include a loss of sense of smell (anosmia), rough, scaly skin (ichthyosis) and after many years, deafness.
Treatment for Refsum disease is based on limiting the intake of foods high in phytanic acid. Our bodies cannot make phytanic acid; rather, it is found in foods such as dairy, beef, lamb, and some seafoods. Refsum disease is caused by a change (mutation) in the gene that makes an enzyme responsible for breaking down phytanic acid, a particular type of fatty acid which is derived by bacterial fermentation of green plants or algae. The lack of function of the enzyme (phytanoyl-CoA hydroxylase) leads to a build-up of phytanic acid in blood plasma and tissues. The disorder is inherited in an autosomal recessive manner.
Refsum disease is a member of a family of genetic disorders known as leukodystrophies, which result due to errors in lipid metabolism. This error affecting a single process prevents the myelin sheath, the insulating layer that consists of fats and proteins surrounding our nerve cells including those in the eye, from growing or functioning properly.
Refsum disease is sometimes called adult Refsum disease or classic Refsum disease. It was first described by Dr. Sigwald Refsum in 1946. This condition is different from infantile Refsum disease, which has a different cause and is in the group of conditions called Zellweger spectrum disorders (see Related Disorders below) caused by defects in assembling cell sub-compartments called peroxisomes.
At birth, individuals with Refsum disease generally appear normal although they may show shorter bones in the hands and feet (metacarpals and metatarsals, respectively). Between 10 and 20 years old, individuals may show their first symptom which is most frequently the loss of night vision (retinitis pigmentosa). Some people may not show any symptoms until up to 50 years of age. Retinitis pigmentosa occurs because light-sensing cells in the retina, a layer in the back of the eye, gradually deteriorate. The initial loss of night vision usually occurs during childhood, and the progression toward loss of peripheral vision and full blindness may occur over the course of years.
Individuals with Refsum disease often present with retinitis pigmentosa and a combination of other symptoms. Other possible issues in the eye include abnormally small pupils, rapid, involuntary eye movement (nystagmus) and cloudiness in the eye that causes individuals to see starburst-type haloes around bright objects (cataracts). Individuals may experience a loss of their sense of smell and taste (anosmia) and after many years, deafness. Affected individuals also may experience numbness, weakness, a tingling sensation or loss of reflexes in their hands and feet (peripheral polyneuropathy) associated with an unsteady gait (cerebellar ataxia) as they deteriorate. Additionally, individuals with Refsum disease may have rough, scaly patches of skin (ichthyosis) and general weakness throughout the body. Shortening of bones in the hands and feet and abnormal growth plate formation affecting the knees, shoulders and elbows (skeletal dysplasia) may be seen. Although it is rare, if phytanic acid levels become very high in people with Refsum disease, then a cardiac arrhythmia (irregular heartbeat) can occur which could be life threatening.
The type and number of symptoms present in individuals with Refsum disease varies greatly from person to person and the severity depends on the level of phytanic acid in the body. If a person has a greater build-up of phytanic acid, they are expected to show more severe symptoms. The number and severity of symptoms also may increase with age.
Most cases (90%) of Refsum disease result from a change (mutation) in the PHYH gene. Most of the remaining cases result from a mutation in the PEX7 gene which transports PHYH into the peroxisomal compartment in cells. Mutations in PHYH and PEX7 genes cause abnormal functioning of peroxisomes, which are structures that allow for the breakdown of fatty acids, including phytanic acid. Specifically, PHYH codes for the phytanoyl-CoA hydroxylase enzyme that is used in the peroxisome to break down phytanic acid. Phytanic acid comes from the diet and is derived from bacterial fermentation of green plants or algae. It is commonly found in dairy, beef, lamb and other ruminant animal-derived food stuffs as well as some seafood. The improper functioning of the peroxisome and related enzymes means that phytanic acid cannot be broken down and thus accumulates in the cell. It is currently unclear how the buildup of phytanic acid is toxic and affects vision or how it causes other features of the disease.
Refsum disease is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Refsum disease occurs in approximately 1 in 1,000,000 people. Males and females are affected in equal numbers.
Refsum disease can be diagnosed based on the finding of highly raised phytanic acid in a blood sample. Levels of pristanic acid, the next step in the pathway, are usually low. This initial diagnosis must then be confirmed with either molecular genetic testing for mutations in either the PHYH or PEX7 genes or by enzyme analysis in a skin biopsy to determine if there is abnormal activity of the enzyme phytanoyl-CoA hydroxylase pathway.
Treatment of Refsum disease requires minimizing intake of beef, lamb, certain seafood, and dairy products while maintaining carbohydrate intake, which helps prevent phytanic acid from entering the blood from fat or liver stores. Removal and reinfusion of blood (plasmapheresis or apheresis) may also be necessary if levels are very high or general symptoms such as profound weakness are present. Other treatments are tailored based on symptoms and are usually supportive measures. Patients with Refsum disease should avoid fasting and rapid weight loss because this causes release of phytanic acid stored in the body. Patients should using ibuprofen as this may interfere with the degradation pathway of phytanic acid.
Patients should receive guidance from a trained dietician and physician on how to minimize risks of acute phytanic acid release and how to manage a low phytanic acid diet.
Genetic counseling is recommended for affected individuals and their family members.
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Refsum Disease. Genetic and Rare Diseases Information Center. Last updated: 11/9/2011. https://rarediseases.info.nih.gov/diseases/5691/refsum-disease Accessed June 1, 2020.
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Wanders RJA, Waterham HR, Leroy BP. Refsum Disease. 2006 Mar 20 [Updated 2015 Jun 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1353/ Accessed June 1, 2020.
Wanders RJA and Wierzicki A. About Refsum. Global DARE Foundation. https://www.defeatadultrefsumeverywhere.org/about-refsum Accessed June 8, 2020.
Refsum Disease video. Global DARE Foundation. April, 2021. https://youtu.be/0s68Z5Talvw. Accessed April 12, 2021.
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