Refsum Disease Health Article

Definition

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.

Description

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.

Genetic profile

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.

Demographics

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.