Infantile refsum disease
Infantile refsum disease (IRD) is an inherited disorder characterized by the reduction or absence of cellular peroxisomes and by the accumulation of various unmetabolized substances in the blood and bodily tissues. The disorder arises in infancy and results in visual and hearing impairments, decreased muscle tone, poor growth, mental retardation, decreased coordination, liver damage, and abnormal development of facial structures. There is no cure for the disorder, and treatment is limited to the relief of symptoms.
Living bodies are built up of millions of individual cells specifically adapted to carry out particular functions. Within cells are even smaller structures, called organelles, which perform different jobs and enable the cell to serve its ultimate purpose. One type of organelle is the peroxisome, whose function is to break down waste materials or to process materials that, if allowed to accumulate, would prove toxic to the cells.
Peroxisomes break down various materials through the use of enzymes (proteins that assist in biochemical reactions), and 80 different peroxisomal enzymes have been identified. These enzymes are made by the cell and transported into the peroxisome by a complex process, requiring at least 15 other proteins. In some cases, an absence or deficiency of these proteins results in a failure to transport enzymes into peroxisomes, leaving the cell unable to metabolize various substances. These substances build up in the blood stream and deposit in various tissues, causing damage.
Infantile refsum disease (IRD) results from an abnormality in the transport of enzymes into the peroxisome, manifesting as absent or reduced functioning peroxisomes. As a consequence of peroxisome deficiency, various substances accumulate in the bloodstream, including phytanic acid, pipecolic acid, hydroxycholestanoic acids, glyoxylate, and substances called very-long-chain fatty acids (VLCFA). Mutations in at least two different genes that encode proteins that participate in the transport of enzymes to the peroxisome have been identified in IRD.
IRD is thought to be the mildest form of leukodystrophy, a group of genetic disorders including Zellweger syndrome and neonatal adrenoleukodystrophy, that damage the fatty sheaths surrounding nerves. In the past, IRD was thought to be a variant of adult refsum disease (also called classical refsum disease) because
IRD is a genetic condition and is inherited or passed on in a family. The genetic abnormality for the disorder is inherited as an autosomal recessive trait, meaning that two mutant genes are needed to display the disease. A person who carries one mutant gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to their children. A child must inherit the same abnormal gene from each parent to display the disease.
IRD is caused by an abnormality in proteins that assist in the transport of enzymes into the peroxisome. Mutations in the genes for at least two different peroxisomal transport proteins have been identified. The first gene is designated PEX1 (mapped to human chromosome 7, locus 7q21-q22) and encodes for a protein called peroxisome biogenesis factor-1. The second gene is designated PEX2 (mapped to human chromosome 8, locus 8q21.1) and encodes for a protein called peroxisomal membrane protein-3.
The combined incidence of all leukodystrophy disorders is estimated to be between 1 in 25,000 and 1 in 50,000. It is unclear whether these disorders are distributed equally among different geographical areas and ethnic groups. Because of some overlap with other leukodystrophy disorders, the incidence and prevalence of IRD in the general population is not clear.
Signs and symptoms
Symptoms associated with IRD arise at birth or very early infancy and affect many different organ systems and tissues, resulting in severe disease. Babies with IRD show decreased muscle tone and a failure to grow at appropriate rates. Characteristic facial features are often present, including prominent forehead and folds at the inner aspect of the eye, flat face and bridge of the nose, and low-set ears. While affected children are able to walk, the gait may be irregular due to abnormalities in muscle coordination.
High levels of unmetabolized substances can deposit in the fatty sheaths surrounding nerves, causing damage and resulting in peripheral neuropathy. 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 ears can be affected, resulting in hearing loss or deafness. IRD also results in cerebellar ataxia, an abnormality in a specific part of the brain (the cerebellum), resulting in loss of coordination and unsteadiness. In contrast to adult refsum disease, people with IRD have extensive impairments in cognitive function resulting in severe mental retardation.
IRD often affects the eyes, causing retinitis pigmentosa, a degeneration of the retina resulting in poor nighttime vision, followed by loss of peripheral vision and eventually loss of central vision late in the course of the disease. Nystagmus (uncontrollable movements of the eye) may also be present due to related nervous system damage. Other manifestations of IRD include enlargement of the liver, poor digestion, and abnormally low blood cholesterol. Early osteoporosis (decalcifications of the bone) may also develop, leading to bone fractures or compression of the spinal bones.
IRD is diagnosed though a combination of consistent medical history, physical exam findings, and laboratory and genetic testing. Typically, parents bring newborns to their physicians because of the signs of low muscle tone. Other times, the characteristic facial abnormalities or a failure to grow at appropriate rates is noted. These findings raise suspicion for a genetic syndrome or metabolic disorder, and further tests are conducted.
Laboratory tests reveal several abnormalities. Blood samples from patients with IRD show accumulation of various substances including phytanic acid, pipecolic acid, hydroxycholestanoic acids, glyoxylate, and VLCFA. Other measurements demonstrate low levels of plasmalogen, a substance normally produced by action of the peroxisomal enzymes. Immunoblot tests that measure levels of specific proteins will show deficiencies in many peroxisomal enzymes. Additional studies will reveal abnormal electrical responses from the retina and various nerve groups.
Finally, genetic testing can be preformed. When a diagnosis of IRD is made in a child, genetic testing of the PEX1 and PEX2 genes 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 IRD 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 by chorionic villus sampling (CVS) where cells are obtained from the chorionic villi (a part of the placenta) at 10-12 weeks of pregnancy.
Treatment and management
There is no cure or standard course of treatment for IRD. Currently, treatment of patients has generally involved only supportive care and symptomatic therapy. Several studies suggest that a diet that is free of phytanic acid can limit symptoms of IRD, but this is not nearly effective as in adult refsum disease. A useful adjunct to dietary treatment is plasmapheresis. Plasmapheresis is a procedure by which determined amounts of plasma (the fluid component of blood that contains the unmetabolized substances) is removed from the blood and replaced with fluids or plasma that are free of accumulated substances. While treatment strategies may mitigate some of the symptoms experienced by the patient with IRD, they do not slow the progression of the disorder.
Experimental studies are underway to investigate whether several different agents can be of additional use. Patients with IRD have reduced levels of docosahexaenoic acid and arachidonic acid that can be corrected with the administration of oral supplements. There are some reports of improvement in symptoms with these therapies, and trials to formally investigate these claims are now in progress. Other scientific laboratories are investigating the usefulness of agents that stabilize peroxisomes in the treatment of IRD, but the experiments are still in their early stages.
Patients with IRD 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. Genetic counseling can help people with IRD, those who are carriers of the abnormal gene, or those who have a relative with the disorder, learn more about the disease, inheritance, testing, and options available to them so they can make informed decisions appropriate to their families.
For patients with IRD, some success has been achieved with multidisciplinary early intervention, including physical and occupational therapy, hearing aids, alternative communication, nutrition, and support for the parents. Although most patients continue to function in the profoundly or severely retarded range, some make significant gains in self-help skills, and a small percentage may reach stable condition in their teens. Despite these few successes, the prognosis for individuals with IRD is poor; death generally occurs in the second decade of life.
"Peroxisomal Disorders" In Nelson Textbook of Pediatrics. Edited by R. E. Behrman. Philadelphia: W.B. Saunders, 2000, pp. 318-384.
Bader, P. I., et al. "Infantile refsum disease in four Amish sibs." American Journal of Medical Genetics 90 (January 2000): 110-114.
Naidu, S., and H. Moser. "Infantile refsum disease." American Journal of Neuroradiology. 12 (November 1991): 1161-1163.
Torvik A., et al. "Infantile Refsum's disease: a generalized peroxisomal disorder." Journal of Neurological Science 85 (May 1988): 39-53.
Infantile Refsum disease support and information. 6004 NE 108th Avenue, Vancouver, WA, 98662. (360) 891-5878. <http://home.pacifier.com/~mstephe/>.
Infantile Refsum's Disease Webring. <http://www.angelfire.com/nc/homefireplace/IRDring.html>.
National Center for Biotechnology Information. OMIM—Online Mendelian Inheritance in Man. <http://www3.ncbi.nlm.nih.gov/htbinpost/Omim>.
NINDS Infantile Refsum Disease Information Page. <http://www.ninds.nih.gov/health_and_medical/disorders/refsum_infantile_doc.htm>.
Oren Traub, MD, PhD