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  • Updated 08.10.2022
  • Released 01.02.1996
  • Expires For CME 08.10.2025

Adult Refsum disease



Adult Refsum disease (ARD) is a rare, autosomal recessive disorder that most frequently manifests in young adults as a variable combination of early-onset retinitis pigmentosa, anosmia, peripheral polyneuropathy, cerebellar ataxia, sensorineural hearing loss, and ichthyosis. Adult Refsum disease is caused by a defect in the catabolism of phytanic acid, a dietary branched chain fatty acid (BCFA), which leads to its toxic overaccumulation in the body. Although its neurologic phenotypes are often irreversible by the time of diagnosis, appropriate dietary interventions can result in clinically relevant neurologic improvements in some people with adult Refsum disease.

Key points

• Adult Refsum disease (ARD) is a rare, autosomal recessive disorder caused by an impaired ability to breakdown the branched chain fatty acid phytanic acid that can accumulate to toxic levels in tissues.

• Adult Refsum disease typically presents in early adulthood as a variable combination of retinitis pigmentosa, anosmia, peripheral polyneuropathy, cerebellar ataxia, sensorineural hearing loss, and ichthyosis.

• Adult Refsum disease patient typically have loss-of-function variants in the PHYH gene encoding phytanoyl-CoA alpha-hydroxylase, an enzyme involved in phytanic acid catabolism.

• In humans, phytanic acid is solely acquired from dietary sources, primarily ruminant meats and fats, dairy products, and certain fish.

• Adult Refsum disease is managed by life-long dietary avoidance of phytanic acid and dietary management is supplemented by lipid apheresis when acute lowering of phytanic acid levels is indicated.

Historical note and terminology

Adult Refsum disease (ARD), originally referred to as “heredoataxia hemeralopica polyneuritiformis” (99) and then "heredopathia atactica polyneuritiformis” (100), is a neurologic syndrome first described by Norwegian neurologist Sigvald Refsum (21).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 (100). Although Jan Cammermeyer suggested that its pathology might results from a disturbance in lipid metabolism (100; 15; 16), the nature of the pathogenesis and pathophysiology was unknown until 1963 (118). At that time, 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 it was a lipidosis (59). 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). The discovery that a phytanoyl CoA hydroxylase enzyme is involved in phytanic acid alpha-oxidation was followed by the discovery that adult Refsum disease is caused by a phytanoyl-coenzyme A hydroxylase deficiency (55). The phytanoyl-coenzyme A hydroxylase gene (now known as PHYH) was cloned in 1997 (53; 84).

Adult Refsum disease is frequently referred to as “Refsum disease” and should not be confused with the peroxisome biogenesis 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 adult Refsum disease (113). Other biochemical defects not found in typical adult Refsum disease patients were present in these cases, including elevated plasma levels of very long-chain fatty acids and pipecolic acid, decreased plasmalogen synthesis, and abnormal subcellular catalase distribution (72). 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 peroxisome biogenesis disorder. Zellweger spectrum disorder is the modern term encompassing Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate), and infantile Refsum disease (milder), which are all caused by inherited biallelic defects in PEX genes responsible peroxisome assembly, structure, and downstream functions (09).

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