Abstract
Refsum's disease (hereditary motor and sensory neuropathy type IV) is a rare autosomal recessive condition first characterized by Sigvald Refsum in 1945. He initially chose the name heredoataxia hemeralopica polyneuritiformis,1 subsequently amending this to heredopathia atactica polyneuritiformis.2 Thankfully, the eponymous version now predominates in the literature, and these earlier terms have been largely abandoned. Refsum's disease is caused by defective alpha oxidation of phytanic acid (3,7,11,15 tetramethylhexadecanoic acid), a branched‐chain fatty acid present in a wide range of foodstuffs including dairy products, some meats and fish.3 The defective enzyme is phytanoyl‐coenzyme A hydroxylase, which normally catalyses the second step in the breakdown of phytanic to pristanic acid using the CoA derivative as a substrate (the first step in alpha oxidation is the conversion of phytanic acid to phytanoyl CoA by Phytanoyl CoA ligase).4 This results in accumulation of phytanic acid, with elevated levels in blood and other tissues including fat and neurons (Figure 1). Phytanic acid can also be catabolized from the non‐carboxyl end by omega oxidation, but the capacity of this pathway is severely limited to ∼10 mg of phytanic acid per day.5 The average diet contains ∼50 mg/day, and this factor, in combination with limited excretory mechanisms (via the kidneys and skin), leads to phytanic acid accumulation. The mechanism of phytanic acid toxicity is unclear, but it may be incorporated into tissue lipids and result in impaired myelin function. An alternative hypothesis is that excess levels affect the metabolism of fat‐soluble vitamins. Levy has suggested that high phytanic acid levels interfere with vitamin A esterification in the retinal pigment epithelium leading to the production of a toxic substance and progressive visual failure.6 The physiological role of phytanic acid is unknown. Figure 1. The biochemistry of Refsum's disease. The onset of symptoms is typically in late childhood or …
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