Refsum disease (ORPHA:773)
A metabolic disease characterized by anosmia, cataract, early-onset retinitis pigmentosa and possible neurological manifestations, including peripheral neuropathy and cerebellar ataxia. Other features can be deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia. It is characterized biochemically by accumulation of phytanic acid in plasma and tissues.
Epidemiology
About 60 cases of Refsum disease (RD) 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.
Clinical description
Age of onset ranges is childhood 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 may develop subsequently. Mixed motor 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 birth are found in about 1/3 of cases. Cardiac arrhythmia and cardiomyopathy causing heart failure are also reported.
Etiology
RD is caused by mutations in the PHYH gene (10p13) in more than 90% of cases, and mutations in the PEX7 gene (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.
Diagnostic methods
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 fibroblast analysis and molecular genetic testing of the causative genes are required to confirm the diagnosis.
Differential 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-Larsson syndrome). Refsum disease should not be confused with infantile Refsum disease a misnomer that belongs to the Zellweger syndrome spectrum.
Antenatal diagnosis
Prenatal diagnosis can be performed if a disease-causing mutation is known in the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
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. Rapid weight loss should be prevented (e.g. during hospital admission) because that can cause rapid increase in plasma phytanic acid levels.
Prognosis
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: 
                            June 2019


                            - Expert reviewer(s): 
                            Dr M. [Marc] ENGELEN  - Pr C.E.M. [Carla] HOLLAK  - Dr M. [Mirjam] LANGEVELD