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  • Heredopathia atactica polyneuritiformis was first delineated as a distinct disease entity on a clinical basis by Sigvald Refsum in 1946. According to Refsum, the cardinal manifestations of the disease include retinitis pigmentosa, cerebellar ataxia, chronic polyneuropathy, and an elevated protein level in cerebrospinal fluid with a normal cell count. Less constant features are sensorineural hearing loss, anosmia, ichthyosis, skeletal malformations, and cardiac abnormalities. The clinical picture of Refsum disease is often that of a slowly developing, progressive peripheral neuropathy manifested by severe motor weakness and muscular wasting, especially of the lower extremities.

  • As first shown by Klenk and Kahlke in 1963, Refsum disease (MIM # 266500) is associated with the accumulation of an unusual 20-carbon, branched-chain fatty acid called phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) in blood and tissues. These findings identified Refsum disease as an inborn error of lipid metabolism inherited as an autosomal recessive trait.

  • Accumulation of phytanic acid reliably distinguishes Refsum disease from the large number of neurologic disorders with which Refsum disease shares some features. The availability of a biochemical marker has clearly established that the classical tetrad of abnormalities is not seen in all patients. Indeed, several patients have been described lacking cerebellar ataxia.

  • Accumulation of phytanic acid is not unique to Refsum disease. Phytanic acid also accumulates in a number of other disorders with a clinical course very different from that of Refsum disease. This includes patients affected by a disorder of peroxisome biogenesis (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease) and rhizomelic chondrodysplasia punctata, type 1. To clearly distinguish between Refsum disease and infantile Refsum disease, in which phytanic acid oxidation is deficient due to the absence of peroxisomes, the term “classical Refsum disease” is used to designate those patients in which phytanic acid is elevated due to a selective defect in phytanic acid α-oxidation with all other peroxisomal functions being normal.

  • Phytanic acid is a 3-methyl fatty acid that cannot be β-oxidized directly. The major mechanism by which phytanic acid is degraded, involves an initial α-oxidation to generate the 19-carbon (n-1) homologue, pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) plus CO2. Pristanic acid is a 2-methyl fatty acid that can be degraded by β-oxidation.

  • The precise mechanism by which phytanic acid is α-oxidized remained obscure until the recent discovery of the enzyme phytanoyl-CoA hydroxylase (PhyH), that catalyzes the hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA, a reaction requiring 2-oxoglutarate, Fe2+ and ascorbate (vitamin C). The subsequent steps in the α-oxidation pathway have also been identified and include the enzyme 2-hydroxyphytanoyl-CoA lyase producing pristanal plus formyl-CoA and an aldehyde dehydrogenase catalyzing the formation of pristanic acid from pristanal. Finally, pristanic acid is activated to its CoA-ester, which can now undergo β-oxidation.

  • In vivo and in vitro studies have shown that α-oxidation of phytanic acid is grossly deficient in patients with Refsum disease. Recent studies show that in all classical Refsum patients studied so far, the defective enzyme is phytanoyl-CoA hydroxylase due to mutations in the structural gene coding ...

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