Refsum disease refers to two rare inherited disorders that are considered unrelated and have symptoms that vary depending on classification: infantile Refsum disease (IRD) or adult Refsum disease (ARD)
Infantile Refsum disease (IRD) is characterized by a mutation in the genes responsible for development of peroxisomes, structures within cells that are responsible for the breakdown of fatty acids. As a result, fatty acids (very long chain fatty acids, or VLCFA, and branched chain fatty acids, or BCFA) accumulate and impair the normal function of multiple organ systems. In addition, these children can show deficient levels of phospholipids that are especially important for brain, lung and heart functions. It is one of three peroxisome development disorders: IRD, Zellweger Syndrome and neonatal adrenoleukodystrophy.
Children with IRD may have craniofacial (head and face) abnormalities and enlarged livers. Progressive adrenal dysfunction and progressive loss of hearing and vision are common. Newborns may present with profound hypotonia (low muscle tone) and a poor ability to feed. Currently, there is no cure for infantile Refsum disease syndrome, nor is there a standard course of treatment. Survival varies depending on severity and complications, most commonly pneumonia. Some patients may live into adulthood and beyond.
Both IRD and ARD are included in the family of rare inherited disorders called leukodystrophies that cause progressive degeneration of the white matter of the brain. The disease results in imperfect growth or destruction of the myelin sheath, a fatty covering that insulates nerve fibers in the brain and spinal cord and promotes rapid transmission of nerve impulses. Without myelin, nerve cells cease to function and eventually die. As myelin deteriorates in leukodystrophies such as Refsum disease, nervous system function is impaired. The leukodystrophies are often referred to as “demyelinating” diseases. The most common leukodystrophies include Canavan disease, Krabbe disease, metachromatic leukodystrophy (MLD), childhood ataxia with central nervous system hypomyelination (CACH), Alexander disease and Refsum disease.
People with adult Refsum disease (ARD), sometimes referred to as classic Refsum disease (CRD), lack the enzyme in peroxisomes needed to break down phytanic acid, a type of fat found in foods like beef and dairy products. As a result, toxic levels of phytanic acid build up in the brain, blood and other tissues. The first symptoms of disease generally appear at puberty, but may appear anywhere from infancy to middle age. It is generally diagnosed in late childhood or early adulthood with increasing night blindness due to degeneration of the retina (retinitis pigmentosa) and a loss of the sense of smell (anosmia). Other symptoms may include deafness, weakness or numbness of the hands and feet (peripheral neuropathy), problems with balance and coordination (ataxia), dry and scaly skin (ichthyosis) and heartbeat abnormalities (cardiac arrhythmias). About 30% of affected individuals will have shortened bones in their fingers or toes, or a visibly shortened fourth toe.
The full constellation of signs and symptoms is rarely seen in a single individual; most features develop with age. Cardiac arrhythmia and heart failure are potentially life-threatening complications that develop later in life.
The primary treatment for ARD is to restrict or avoid foods that contain phytanic acid, including dairy products, beef, lamb and fatty fish such as tuna, cod and haddock. Some individuals may also require plasma exchange (plasmapheresis) in which blood is drawn, filtered and re-infused to control the buildup of phytanic acid. ARD is treatable because phytanic acid is not produced by the body – it is only found in food. With treatment, muscle weakness, numbness and dry or scaly skin generally disappear. Vision and hearing problems may persist, however, and the patient’s sense of smell may not return. Untreated, ARD can lead to sudden death caused by heartbeat abnormalities.