Refsum disease (RD) is a very rare, clinically variable, multisystemic metabolic disease, characterized by anosmia,early-onset retinitis pigmentosa (see this term) and possible neurological manifestations, including neuropathy, and cerebellar ataxia, deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia. It is characterized biochemically by accumulation of phytanic acid in plasma and tissues.
About 60 cases have been reported worldwide. Prevalence rates are not known but the disorder may be underdiagnosed. Prevalence has been estimated to be 1/1,000,000 in the United Kingdom. Males and females are affected equally.
Age of onset ranges from early infancy to over 50 years of age but may be difficult to determine. Retinitis pigmentosa is often the first sign and is found in almost all patients. Onset of night blindness in childhood is common. Cataract and nystagmus may be found later on. Anosmia is a universal clinical manifestation. Symmetric mild-to-profound sensorineural hearing loss, ataxia of late onset causing an unsteady gait, and more rarely mild generalized ichthyosis (see this term) may develop subsequently. Mixedmotor and sensory neuropathy may also be found, causing muscular atrophy, weakness, and peripheral sensory disturbances. Autism spectrum disorder and attention deficit-hyperactivity disorder (AD-HD) are also reported. Short metacarpals and metatarsals at birthare found in about 1/3 of cases.Cardiac arrhythmia and cardiomyopathycausing heart failure are also reported.
RF is caused by mutations in the PHYHgene(10p13) in more than 90% of cases, and mutations in the PEX7gene(6q21-q22.2) in less than 10%. These genes are involved in lipid metabolism and protein transport. The pathogenic mechanism is related to the accumulation of phytanic acid, which is predominantly (>90%) degraded by alpha-oxidation in peroxisomes.
The diagnosis is based on clinical manifestations including retinitis pigmentosa and variable combinations of the other features. The interval between initial signs and diagnosis may exceed 10 years. All classic disease manifestations are rarely found in a single affected person. Analysis of phytanic acid concentrations in plasma or serum shows abnormal levels generally above 200 micromol/L. Enzymatic fibroblastanalysis and molecular genetic testing of the causative genesare required to confirm the diagnosis.
Other causes of retinitis pigmentosa and sensorineural hearing loss should be considered in the differential diagnosis (Usher syndromes, types 1, 2, and 3; Alström syndrome; Kearns-Sayre syndrome; Sjögren-Larssonsyndrome; see these terms). Refsum disease should not be confused with infantile Refsum disease (see this term) a misnomer that belongs the Zellweger syndrome spectrum (see this term).
Prenatal diagnosis can be performed if a disease-causing mutation is known in the family.
RD is inherited in an autosomal recessive manner. Genetic counseling should be provided to affected families.
Phytanic acid is obtained from the diet, particularly from meat and dairy products. Dietary restriction helps to control sensory neuropathy, myopathy, ataxia and ichthyosis. In acute presentations (arrhythmia, weakness), plasmapheresis or lipapheresis may be useful. Supportive treatment includes hydrating creams, anti-arrhythmics, and cardiac medication. Bilateral cochlear implantation may be considered for severe hearing loss. Cardiac and ophthalmological monitoring is required.
Prognosis in the absence of treatment is generally poor. Severe cases or late diagnosis may be life-threatening. The main cause of death is arrhythmia and heart failure.
Last update: July 2015
- Pr B.T. [Bwee Tien] POLL-THE
- Pr R.J.A. [Ronald] WANDERS