Refsum disease is an inherited disorder in which the enzyme responsible for processing phytanic acid is defective. Accumulation of phytanic acid in the tissues and the blood leads to damage of the brain, nerves, eyes, skin, and bones.
Refsum disease was first characterized by the Norwegian physician, Sigvald Refsum, in the 1940s and is known by other names, such as classical Refsum disease, adult Refsum disease, phytanic acid alpha-hydroxylase deficiency, phytanic acid storage disease, hypertrophic neuropathy of Refsum, heredopathia atactica polyneuritiformis, and hereditary motor and sensory neuropathy IV. Refsum disease should not be confused with infantile Refsum disease , which was once thought to be a variant of the disorder but is now known to be a genetically and biochemically distinct entity. Sometimes infantile Refsum disease is simply referred to as "Refsum disease," furthering the confusion.
Living bodies are made up of millions of individual cells that are specifically adapted to carry out particular functions. Within cells are even smaller structures, called organelles, that perform jobs and enable the cell to serve its ultimate purpose. One type of organelle is the peroxisome, whose main function is to break down waste materials or to process materials that, if allowed to accumulate, would prove toxic to the cells.
Phytanic acid is a substance found in foods, such as dairy products, beef, lamb, and some fish. Normally, phytanic acid is processed by a set of enzymes within the cell to convert it to another form. In the past, scientists were unsure where in the cell this process took place, hypothesizing that it may occur in the peroxisome or another organelle, called the mitochondrion. However, recent research has definitively determined that the enzymes responsible for processing phytanic acid are located in the peroxisome.
Refsum disease is an inherited disorder in which one of the peroxisomal enzymes, phytanic acid hydroxylase (also called phytanic acid oxidase, or phytanyl CoA hydroxylase), is defective, resulting in unprocessed phytanic acid. Consequently, high levels of phytanic acid build up in the tissues of the body and the bloodstream, causing damage to different organ systems.
Refsum disease is a genetic condition and can be inherited or passed on in a family. The genetic defect for the disorder is inherited as an autosomal recessive trait, meaning that two abnormal genes are needed to display the disease. A person who carries one abnormal gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to his or her children. A child must inherit the same abnormal gene from each parent to display the disease.
Refsum disease is caused by a deficiency in an enzyme, phytanic acid hydroxylase. The gene encoding for this enzyme, called PAHX or PHYH, was identified in 1997 and mapped to human chromosome 10 (locus: 10pter-p11.2). Several common mutations have been identified in the gene that result in Refsum disease.
Refsum disease is rare, but the exact incidence and prevalence of the disorder in the general population is not known. Refsum disease may not be distributed equally among geographical areas or different ethnic groups, as most of the diagnosed cases have been found in children and young adults of Scandinavian heritage.
Signs and symptoms
Patients with Refsum disease generally do not show obvious defects at birth, and growth and development initially appears normal. The onset of clinical symptoms varies from early childhood to age 50, but symptoms usually appear before 20 years of age. The manifestations of Refsum disease primarily involve the nervous system, the eye, the skin, the bones, and, in rare cases, the heart and kidneys.
Phytanic acid deposits in the fatty sheaths surrounding nerves, causing damage and resulting in peripheral neuropathy in 90% of patients with Refsum disease. Peripheral neuropathy is the term for dysfunction of the nerves outside of the spinal cord, causing loss of sensation, muscle weakness, pain, and loss of reflexes. Nerves leading to the nose and ears can also be affected, resulting in anosmia (loss of the sense of smell) in 35% of patients and hearing loss or deafness in 50% of patients. Finally, Refsum disease results in cerebellar ataxia in 75% of patients. Cerebellar ataxia is a defect in a specific part of the brain (the cerebellum), resulting in loss of coordination and unsteadiness. In contrast to infantile Refsum disease, people with Refsum disease do not show mental retardation and generally have normal intelligence.
Accumulation of phytanic acid also results in disorders of the eye. The most common finding is retinitis pigmentosa , a degeneration of the retina resulting in poor nighttime vision and sometimes blindness. Disorders of pupil movement and nystagmus (uncontrollable movements of the eye) may also be present due to related nervous system damage. Other eye manifestations of Refsum disease may include glaucoma (abnormally high pressure in the eye, leading to vision loss) and cataracts (clouding of the lens of the eye).
People with Refsum disease often develop dry, rough, scaly skin. These skin changes, called ichthyosis , can occur over the entire body, but sometimes will appear only on the palms and soles of the feet. In addition to these skin abnormalities, 60% of affected people may experience abnormal bone growth, manifesting as shortened limbs or fingers, or abnormal curvatures of the spine.
Patients with Refsum disease usually first present to a physician complaining of weakness in the arms and legs, physical unsteadiness and/or nightblindness or failing vision. The symptoms associated with Refsum disease are progressive and, if untreated, will become more numerous and severe as the patient ages. For reasons that are not completely understood, clinical deterioration can be sometimes be interrupted by periods of good health without symptoms.
Refsum disease is diagnosed though a combination of consistent medical history, physical exam findings, and laboratory and genetic testing . When patients with Refsum disease present to their physicians complaining of visual problems or muscle weakness, physical signs of retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, or skin and bone changes (as discussed above) are often noted. These findings raise suspicion for a genetic syndrome or metabolic disorder, and further tests are conducted.
Laboratory tests reveal several abnormalities. Normally, phytanic acid levels are essentially undetectable in the plasma. Thus, the presence of high levels of phytanic acid in the bloodstream is highly indicative of Refsum disease. If necessary, a small portion of the patient's connective tissue can be sampled and grown in a laboratory and tested to demonstrate a failure to process phytanic acid appropriately. Other associated laboratory abnormalities include the presence of high amounts of protein in the fluid that bathes the spinal cord, or abnormal electrical responses recorded from the brain, muscles, heart, ears, retina, and various nerves as a result of nervous system damage.
Genetic testing can also be performed. When a diagnosis of Refsum disease is made in a child, genetic testing of the PAHX/PHYH gene can be offered to determine if a specific gene change can be identified. If a specific change is identified, carrier testing can be offered to relatives. In families where the parents have been identified to be carriers of the abnormal gene, diagnosis of Refsum disease before birth is possible. Prenatal diagnosis is performed on cells obtained by amniocentesis (withdrawal of the fluid surrounding a fetus in the womb using a needle) at about 16–18 weeks of pregnancy or from the chorionic villi (a part of the placenta) at 10–12 weeks of pregnancy.
Treatment and management
There is no cure for Refsum disease, thus treatment focuses on reducing levels of phytanic acid in the bloodstream to prevent the progression of tissue damage. Phytanic acid is not made in the human body and comes exclusively from the diet. Restriction of phytanic acid-containing foods can slow progress of the disease or reverse some of the symptoms. Patients are advised to maintain consumption of phytanic acid below 10 mg/day (the normal intake is approximately 100 mg/day). Sources of high levels of phytanic acid to be avoided include meats (beef, lamb, goat), dairy products (cream, milk, butter, cheese), and some fish (tuna, cod, haddock). Plasma levels of phytanic acid can be monitored periodically by a physician to investigate the effectiveness of the restricted diet and determine if changes are required. As a result of dietary restriction, nutritional deficiencies may result. Consultation with a nutritionist is recommended to assure proper amounts of calories, protein, and vitamins are obtained through the diet, and nutritional supplements may be required.
Because phytanic acid is stored in fat deposits within the body, it is important for patients with Refsum disease to have regular eating patterns; with even brief periods of fasting, fat stores are converted to energy, resulting in the release of stored phytanic acid into the blood stream. Thus, unless a patient assumes a regular eating pattern, repeated and periodic liberation of phytanic acid stores results in greater tissue damage and symptom development. For these same reasons, intentional weight loss though calorie-restricted diets or vigorous exercise is discouraged.
Another useful adjunct to dietary treatment is plasmapheresis. Plasmapheresis is a procedure by which determined amounts of plasma (the fluid component of blood that contains phytanic acid) is removed from the blood and replaced with fluids or plasma that do not contain phytanic acid. Regular utilization of this technique allows people who fail to follow a restricted diet to maintain lower phytanic acid levels and experience less tissue damage and symptoms.
Patients with Refsum disease should be seen regularly by a multidisciplinary team of health care providers, including a pediatrician, neurologist, ophthalmologist, cardiologist, medical geneticist specializing in metabolic disease, nutritionist, and physical/occupational therapist. People with Refsum disease, or those who are carriers of the abnormal gene or who have an relative with the disorder, can be referred for genetic counseling to assist in making reproductive decisions.
The prognosis of Refsum disease varies dramatically. The disorder is slowly progressive and, if left untreated, severe symptoms will develop with considerably shortened life expectancy. However, if diagnosed early, strict adherence to a phytanic acid-free dietary regimen can prevent progression of the disease and reverse skin disease and some of the symptoms of peripheral neuropathy. Unfortunately, treatment cannot undo existing damage to vision and hearing.
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Oren Traub, MD, PhD