Refsum disease is a genetically determined disorder of the oxidation of phytanic acid with its accumulation in the tissues of the body, leading to neurological disorders, deterioration of vision, hearing, smell, ichthyous skin changes, heart disorders. It is diagnosed by the level of phytanic acid in the blood and urine, significantly exceeding the norm. Additionally, a study of the nervous system, visual function, hearing and smell, and cardiac activity is carried out. The basis of treatment is a diet with a restriction of nutrients containing phytanic acid. In severe condition, plasmapheresis is indicated for patients.
G60.1 Refsum disease
Refsum disease is a rare disease caused by genetically determined dysmetabolism of phytanic acid with its accumulation in various tissues: in the brain and spinal cord, peripheral nerve trunks, heart, liver and kidneys. Refsum disease is named after a Norwegian neurologist who first described the pathology in 1946. In neurology, it is also known as hereditary polyneuropathic ataxia, Refsum syndrome. Since lipid dysmetabolism is the main substrate in the pathogenesis of the disease, Refsum disease can be attributed to hereditary lipidoses, which also includes Niemann-Pick disease, Tay-Sachs disease, Gaucher disease, etc.
The age of manifestation of symptoms varies from 1 to 50 years. Due to such a wide range of debut, an adult form of the disease is distinguished with the onset after the age of 10 and infantile – in children 1-10 years old. The prevalence has not been established. People of both sexes get sick.
Refsum disease is characterized by an autosomal recessive inheritance pathway. To date, 2 gene mutations have been identified that cause the disease: a defect in the phytanoyl-CoA hydroxylase gene (10th chromosome, locus 10pter-p11.2) and a defect in the peroxin 7 gene (6th chromosome, locus 6q22-q24). Genetic disorders determine the defective oxidation of phytanic acid and its accumulation in the body. As a result, phytanic acid replaces other essential fatty acids.
First of all, the nervous system is affected. Degenerative changes affect peripheral nerve trunks, anterior horns and spinal cord roots, cerebellar tracts, visual, oculomotor, olfactory and auditory nerves. The retina of the eyes is affected with the development of retinopathy pigmentosa. The accumulation of phytanic acid in the myocardium leads to the formation of cardiomyopathy. Degenerative changes in the nerves of the conduction system of the heart cause the occurrence of arrhythmia. Replacement of linoleic and arachidonic acids of the dermis with phytanic acid leads to ichthyosis.
Multiple lesions of peripheral nerve trunks are manifested by symptoms of polyneuropathy: numbness of the hands and feet, paresthesia, decreased pain perception and deep (proprioceptive, vibrational) sensitivity. Polyneuropathy is sensorimotor in nature. Motor disorders begin mainly with paresis of the extensor muscles of the feet, later sluggish paresis spreads to the distal parts of the legs and arms, accompanied by hypotrophy of the muscles of the feet, shins, hands and forearms. Cerebellar ataxia is characterized by unsteadiness of walking, hypermetry, and handwriting changes. From the side of vision, there is a decrease in its acuity, hemeralopia, narrowing of the visual fields, in some cases — cataract. Sometimes there is photophobia.
Refsum disease is often accompanied by hearing loss, loss of olfactory acuity (anosmia), drooping of the upper eyelid, oculomotor disorders. There is dry skin and peeling. The degree of manifestation of ichthyotic changes is very variable: from mild hyperkeratosis of the feet and palms with the formation of small white crusts to severe lamellar ichthyosis. Some patients have concomitant skeletal dysplasia: curvature of the spine (scoliosis), deformities of the feet (hollow foot, curvature and shortening of the toes).
The diagnosis can be confirmed by a blood and urine test with a study of the concentration of phytanic acid. With Refsum disease, this indicator reaches 800 mmol / l, while normally it does not exceed 19 mmol / l. All patients are consulted by an ophthalmologist. Checking visual acuity reveals its decrease, perimetry establishes a concentric narrowing of the visual fields, ophthalmoscopy reveals signs of optic nerve atrophy, polymorphic degenerative changes in the retina.
Electroneuromyography makes it possible to determine the polyneuropathic nature of the lesion of the peripheral nervous system, to identify the pathology of the motor neurons of the anterior horns. When examining the cerebrospinal fluid, an elevated level of albumins is diagnosed. Olfactory disorder is detected by olfactometry. In case of hearing disorders, a consultation with a surdologist and audiometry is indicated.
The presence of bone deformities is a reason for the appointment of spine x-ray, CT or radiography of the feet with subsequent consultation of an orthopedist. To assess the condition of the heart, an ECG is performed, patients are advised by a cardiologist. In order to determine the type of inheritance of pathology, a genealogical study is carried out. The final diagnosis can be confirmed by DNA analysis.
During diagnosis, Refsum disease is differentiated from Charcot-Marie-Tutt amyotrophy, polyneuropathies of other genesis (Dejerin-Sott syndrome, diabetic neuropathy, Russi-Levy syndrome, neuropathy with paraneoplastic syndrome, etc.), Friedreich’s ataxia.
Phytanic acid is not formed in the body, so limiting its exogenous intake is an effective way of treatment. The diet consists in limiting the intake of phytanic acid to 5 mg per day. It is this amount of phytanic acid that the patient’s body is able to metabolize, thanks to the available alternative mechanisms of its oxidation. It is recommended to exclude the use of green vegetables, greens and animal fats from the diet. In order to avoid rapid weight loss, the diet should include a large amount of carbohydrates. Strict adherence to the diet quickly leads to an improvement in the clinical status of patients. The severity of polyneuropathy and paresis decreases, coordination is normalized, the skin condition improves. Patients must constantly adhere to a diet for life.
In severe cases, plasmapheresis is used to cleanse the body of excessive amounts of phytanic acid. In order to reduce neurological symptoms, anticholinesterase pharmaceuticals (galantamine, neostigmine), B vitamins, physical therapy, massage are prescribed. In case of deformation of the feet and / or paresis of the extensor muscles, it is recommended to wear orthopedic shoes. Pronounced bilateral hearing loss is an indication for cochlear implantation.
The prognosis with proper treatment is favorable. In the absence of therapy, the disease continues to progress slowly, leading to severe paresis and ataxia, a significant drop in vision and hearing, and cardiac disorders. The latter can cause sudden death of the patient.