Disease group Keratinization Disorder
Synonymous Phytanic acid oxidase deficiency, Heredopathia atactica polyneuritiformis, Hereditary motor and sensory neuropathy IV
Estimated prevalence <1>
OMIM 266500
Inheritance Autosomal recessive
Gene s) PHYH (602026), PEX7 (601757)


Classic Refsum disease (RD) is a peroxisomal disease first described in 1940s by Sigvald Refsum. It is caused by the accumulation of phytanic acid in plasma and tissues. Two genes have been implicated: mutations in the gene encoding the phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation, and defects in the gene encoding the peroxin 7 receptor, involved in the import of phytanic acid into peroxisomes. In both cases, phytanic acid is not degraded and accumulates in tissues. The infantile form of RD (MIM 266510) is genetically distinct from classic RD and shows no ichthyosis.

Clinical Description

RD is a multisystemic disorder, which classically associates retinitis pigmentosa, cerebellar ataxia, and peripheral polyneuropathy. The onset of clinical signs is in late childhood or early adulthood. The first clinical signs are ocular abnormalities: decreased night vision is the earliest clinical sign and retinitis pigmentosa is the most frequent ocular finding. Neurological deterioration is progressive, starting with weakness or an unsteady gait, with usually no mental retardation. Other frequently associated manifestations include anosmia, sensorineural deafness, skeletal abnormalities (which may be more frequent in PEX7 defects), renal dysfunction and cardiomyopathy with cardiac arrhythmias. Ichthyosis is a tardive and inconstant feature. It may not be apparent until early adulthood and resembles ichthyosis vulgaris with diffuse small white scales.


Classical RD results from tissue accumulation of phytanic acid which causes retinal, brain and periperal nervous system lesions. In approximately 45% of cases, the disease is caused by mutations in the PHYH gene (or PAXH, localied on 10pter-p11.2) which encodes the peroxisomal enzyme, phytanoyl-CoA hydroxylase (PhyH). PhyH allows the alpha-oxydation of phytanic acid during the first step of its degradation. Mutations in the PEX7 gene, localised on 6q22-24, can also cause classical RD. PEX7 encodes peroxin 7, a receptor which allows the import of phytanic acid as well as enzymes such as those included in plasmalogen synthesis and fatty acid-alpha-oxidation into peroxisomes.


The diagnosis of RD is often delayed due to late onset and the progressive course of the disease. Patients with retinitis pigmentosa, isolated or associated with peripheral neuropathy and/or cerebellar ataxia, should be tested for RD. The diagnosis of classical RD relies on elevated plasma phytanic acid levels, which are increased up to 100-fold (normal levels are below 33 microM). Decreased phytanic acid oxidase acitivity can be observed in fibroblast culture. Urine levels of phytanic acid are also increased. In patients with disease due to mutations in PEX7, erythrocyte plasmalogen levels and dihydroxyacetone phosphate acyltransferase (DHAP) activity in platelets and fibroblasts are reduced. Skin biopsy shows lipid vacuoles in the basal layer and suprabasal epidermal cells.


Phytanic acid is a branched-chain fatty acid, derived exclusively from dietary sources of chlorophyll. Therefore, the basis of treatment in classic RD is dietary restriction of phytanic acid. Phytanic acid is mainly found in dairy products, fish, some meets such as mutton and ruminant fats. Dietary intervention may improve ocular, neurological and dermatological complications, but does not affect skeletal abnormalities. Acute increases in plasma phytanic acid levels should be treated by plasmapheresis to rapidly decrease phytanic acid levels, preventing potentially fatal complications such as cardiac arrythmias.