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  • Updated 01.22.2024
  • Released 01.02.1996
  • Expires For CME 01.22.2027

Adult Refsum disease



Adult Refsum disease 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 with shortened metacarpals and metatarsals at birth. It 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 affected individuals.

Key points

• Adult Refsum disease (ARD) is an ultra-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 with shortened metacarpals and metatarsals at birth.

• Affected individuals typically have biallelic 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 reduction 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 is a multisystemic neurologic syndrome first described by Sigvald Refsum (94; 95; 18). The original reported cases had what is now considered to be a diagnostic tetrad of clinical findings that include retinitis pigmentosa, peripheral polyneuropathy, and cerebellar ataxia as well as a high cerebrospinal fluid protein concentration without pleocytosis (95). Postmortem studies of liver and kidney tissue from a person diagnosed with adult Refsum disease revealed fatty infiltrates composed mainly of neutral lipids, providing the first evidence that it was a lipidosis (57). More than half of the total fatty acids isolated from liver lipids were a single, unusual species subsequently identified as phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) (57). Adult Refsum disease is caused by a deficiency in the catabolism of the phytanic acid, which results in its toxic overaccumulation (124). This is primarily caused by an inherited deficiency in the activity of the phytanoyl-coenzyme A hydroxylase enzyme, which is required for phytanic acid catabolism via alpha-oxidation (53), encoded by the PHYH gene (52; 79).

Adult Refsum disease is frequently referred to as “Refsum disease” and should not be confused with the peroxisome biogenesis disorder, formerly called “infantile Refsum disease.” Zellweger spectrum disorder is the modern term encompassing a group of peroxisome biogenesis disorders (Zellweger syndrome [severe], neonatal adrenoleukodystrophy [moderate], and infantile Refsum disease [milder]) caused by inherited biallelic loss-of-function variants in any of 13 PEX genes (PEX1, 2, 3, 5, 6, 10, 11B, 12, 13, 14, 16, 19, and 26), excluding PEX7 (07). These genes are required for the assembly, structure, and replication of peroxisomes, metabolic membrane-bound organelles involved in cell signaling (120). In addition to their distinct etiologies, adult Refsum disease and Zellweger spectrum disorder most often have distinct clinical presentations and biochemical abnormalities.

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