This article includes discussion of Refsum disease, heredopathia atactica polyneuritiformis, and phytanic acid storage disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Refsum disease is a rare, autosomal recessive disorder characterized clinically by retinitis pigmentosa, peripheral polyneuropathy, and cerebellar ataxia and biochemically by accumulation in tissues of the dietary branched-chain fatty acid, phytanic acid. Neurologic deficits are often irreversible by the time a diagnosis is established. In this article, the author notes that aggressive therapy can result in neurologic improvement in some cases.
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• Refsum disease is a rare, autosomal recessive disorder characterized by retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and a high cerebrospinal fluid protein concentration without pleocytosis.
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• Symptoms typically present in early adulthood and are caused by toxic levels of the branched-chain fatty acid, phytanic acid, which accumulates in tissue lipids secondary to deficient activity of the peroxisomal fatty acid alpha-oxidation pathway.
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• Most Refsum disease patients have a mutation in Phyh, the gene encoding the peroxisomal alpha-oxidation enzyme, phytanoyl-CoA alpha-hydroxylase.
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• Phytanic acid in humans comes solely from dietary sources, including ruminant meats and fats, dairy products, and certain fish, but not from consumption of chlorophyll-containing vegetables.
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• Refsum disease is managed mainly by life-long dietary avoidance of foods containing phytanic acid and is supplemented by lipid apheresis when acute lowering of phytanic acid levels is indicated.
Historical note and terminology
Refsum disease, originally termed "heredopathia atactica polyneuritiformis," is a familial neurologic syndrome first described by Sigvald Refsum in 1946 (73). The 4 Norwegian cases originally reported by Refsum had what is now considered to be a diagnostic tetrad of clinical findings that include retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and a high cerebrospinal fluid protein concentration without pleocytosis.
Until 1963 the pathogenesis and pathophysiology of Refsum disease was not known. Postmortem studies of liver and kidney tissue from a patient diagnosed with this disorder revealed fatty infiltrates composed mainly of neutral lipids, providing the first evidence that Refsum disease was a lipidosis. More than half of the total fatty acids isolated from liver lipids were a single, unusual species not previously reported in human tissues and subsequently identified as phytanic acid (3,7,11,15-tetramethylhexadecanoic acid).
Refsum disease must not be confused with the peroxisomal disorder "infantile Refsum disease." Scotto and colleagues found elevated levels of phytanic acid in 3 infants and suggested that this "infantile phytanic acid storage disease" was a variant of Refsum disease (85). Other biochemical defects not found in typical Refsum disease patients were present in these cases, including elevated plasma levels of long-chain fatty acids and pipecolic acid, decreased plasmalogen synthesis, and abnormal subcellular catalase distribution (51). As a result of these additional findings, it is now recognized that phytanic acid accumulation in these children is not the primary defect but is secondary to a disorder of peroxisome biogenesis. This group of patients also includes the Zellweger syndrome and neonatal adrenoleukodystrophy phenotypes (51). The term "infantile Refsum disease" is now generally used to describe the longest surviving subset of this group.