Refsum Disease
DISEASE CARD
| Disease group | Keratinization Disorder |
|---|---|
| DISEASE NAME | REFSUM DISEASE |
| 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) |
Definition
Classic Refsum disease (RD) is a peroxisomal disease first described in 1940s by Sigvald Refsum. It is caused by accumulation of phytanic acid (an unusual branched-chain fatty acid) in plasma and tissues. Pathogenic variants in the genes PHYH and PEX7 are causative, both mutations impair degredation of phytanic acid, which then accumulates in tissues.
The infantile form of RD (OMIM 266510) is genetically distinct from classic RD and shows no ichthyosis.
Clinical Description
RD is a multisystemic disorder, which is associated with retinitis pigmentosa, cerebellar ataxia and peripheral polyneuropathy. The disease commonly manifests in late childhood or early adulthood.
The first clinical signs are ocular abnormalities, i.e. progressive decrease of night vision and retinitis pigmentosa, as well as miosis, cataracts and reduced visual fields arising after several years.1 A progressive neurological deterioration occurs, starting with muscle weakness at the distal lower extremities or an unsteady gait (mixed asymmetric polyneuropathy) that may become more widespread with involvement of the trunk. Usually, no mental retardation occurs, but motor and sensory nerves are involved. Electron microscopic changes of peripheral nerve fibres include an onion bulb formation and targetoid, paracrystalline inclusions in Schwann cells.2 Other frequently associated manifestations include anosmia (loss of sense of smell), progressive bilateral sensorineural deafness, skeletal abnormalities (which may be more frequent in PEX7 defects), renal dysfunction and cardiomyopathy with cardiac arrhythmias.3, 4 Ichthyosis is a tardive and inconstant feature. It may not be apparent until early adulthood and resembles ichthyosis vulgaris with diffuse distribution of small white scales.5-7
The life-expectancy of individuals with RD is up to the 4th, 5th decade of life. Arrhythmias are the most frequent causes of death.
Pathogenesis
Classical RD results from tissue accumulation of phytanic acid, which causes retinal, brain and periperal nervous system disorders. In approximately 90% of cases, the disease is caused by mutations in the PHYH gene (or PAXH, localized on 10pter-p11.2) which encodes the peroxisomal enzyme, phytanoyl-CoA hydroxylase (PhyH). PhyH enables 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.6
Diagnosis
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 evaluated for RD. The diagnosis of classical RD relies on elevated plasma phytanic acid levels, which are increased up to 200-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 as well as a moderate hyperkeratosis and acanthosis with thinned granular layer.2
Treatment
Evaluation should include ophthalmological examination including visual fields, anosmia testing, neurological examination, audiology testing and a radiologic assessment for skeletal abnormalities as well as cardiac evaluation.
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 to less than 10mg and avoiding rapid weight loss or fastings (whereby lipolysis is stimulated and phytanic acid rapidly mobilized from hepatic lipid and body adipose stores). 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. 8
Ibuprofen, amiodarone and further medications that might increase levels of thyroxine should be avoided as they may increase phytanic acid levels.
Pregnant patients must be closely monitored as especially in the third trimester the enhanced catabolism might increase levels of phytanic acid.
Hypercaloric parenteral infusions may be necessary during periods of severe illness or postoperatively.
Acute increases in plasma phytanic acid levels should be treated by plasmapheresis (once or serially over weeks) to rapidly decrease phytanic acid levels (50-70%), preventing potentially fatal complications such as cardiac arrythmias. However, neurologic abnormalities are usually not reversible via plasmapheresis.6, 9