Refsum disease

Paul A Watkins MD PhD (Dr. Watkins of Johns Hopkins University has no relevant financial relationships to disclose.)
Raphael Schiffmann MD, editor. (Dr. Schiffmann, Director of the Institute of Metabolic Disease at Baylor Research Institute, received research grants from Amicus Therapeutics, Protalix Biotherapeutics, and Shire.)
Originally released January 2, 1996; last updated July 14, 2016; expires July 14, 2019

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.

Overview

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. In this article, the author highlights current data on pathogenetic mechanisms and studies aimed at developing new therapeutic approaches.

Key points

 

• 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.

 

• 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.

 

• Most Refsum disease patients have a mutation in Phyh, the gene encoding the peroxisomal alpha-oxidation enzyme, phytanoyl-CoA alpha-hydroxylase.

 

• 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.

 

• 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 (Refsum 1946). 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 (Scotto et al 1982). 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 (Lazarow and Moser 1995). 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 (Lazarow and Moser 1995). The term "infantile Refsum disease" is now generally used to describe the longest surviving subset of this group.

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