Contributed by by Ahmed Bedeir, MD, Jing Yu, MD, PhD, David Finegold, MD and Mohamed Virji, MD
This female in her 20s with no significant past medical history that presented with presumed anorexia nervosa. She was admitted to the hospital and subsequently required total parenteral nutrition. Physical examination was significant for retinitis pigmentosa on ophthalmoscopic exam as well as shortening of the fourth toe. Her hospital stay was complicated by progressive impairment of vision and hearing loss. Her lab values showed elevated levels of phytanic acid.
Refsum's disease is a rare autosomal recessive condition first characterized by Sigvald Refsum in 1945 (1). It 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 food supply including dairy products, some meats and fish (2). 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 (3). This results in accumulation of phytanic acid, with elevated levels in blood and other tissues including fat and neurons. 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. The 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 (4).
The onset of symptoms is typically in late childhood or adolescence, but may be as late as the fifth decade. The disease usually follows a progressive course, but acute and sub-acute presentations have been described. The cardinal neurological manifestations of the disease include a demyelinating neuropathy, pes cavus, cerebellar ataxia, sensorineural deafness, anosmia and cranial nerve involvement (5).There may be marked nerve hypertrophy. Nyctalopia and visual failure secondary to retinitis pigmentosa often precede the neurological symptoms. Most patients have gross constriction of the visual fields by the time they present (6). Cataracts and photophobia caused by impaired pupillary light responses are also described. Miosis may occur because of high lipid levels in the iris or as a consequence of a generalized dysautonomia. Cardiac involvement (conduction abnormalities and a cardiomyopathy) has resulted in premature death. Aminoaciduria secondary to reversible renal involvement is usually associated with extremely high phytanic acid levels. The skin is also affected, with rough scaly thickening over the extremities (7). Epiphyseal dysplasia results in syndactyly and a characteristic shortening of the fourth toe, which is diagnostically useful (8).
Nerve conduction studies are abnormal, with slowing of conduction velocities. CSF protein levels are usually elevated. The electroretinogram may be grossly abnormal. Nerve biopsies from affected patients have shown 'onion bulb' formation, and targetoid inclusions have been described in Schwann cells which have a similar appearance on electron microscopy to those seen in cultured fibroblasts. Plasma levels of phytanic acid measured by gas chromatography-mass spectroscopy are consistently elevated (normal range <19 mmol/l). Phytanic acid levels >800 mmol/l are not uncommon at presentation (8).
Phytanic acid is almost exclusively of exogenous origin, and dietary restriction reduces plasma and tissue levels Fish, beef, lamb and dairy products should be avoided (9). The average daily intake of phytanic acid is 50-100 mg/day, and ideally this should be reduced to 10-20 mg/day.The neurological, cardiac and dermatological sequelae can be reversed by reduction of phytanic acid levels, but the visual and hearing impairments are less responsive to treatment.Dietary treatment should be lifelong (8).
Rapid weight loss, fever and pregnancy have been associated with acute and sub-acute presentations that mimic Gullain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Lowering the plasma phytanic acid level by plasma exchange usually produces a rapid clinical improvement. Plasma exchange should also be considered where dietary control is inadequate. Dialysis is ineffective, as plasma phytanic acid is bound to lipoproteins (10).