Refsum's Disease: Nature of the Enzyme Defect

Abstract

Two siblings with Refsum's disease, an inherited disorder of lipid metabolism, oxidized intravenously injected uniformly labeled phytanic acid-C(14) at rates less than 5 percent of those found in normal subjects. The defect in oxidation of phytanic acid persisted in cultures of fibroblasts from the patients' skin. The rate of oxidation of the phytanic acid-C(14) was less than 1 percent of that found in cultures of fibroblasts from normal skin. However, pristanic acid, previously shown to be the first product of phytanic acid degradation, was oxidized at a normal rate in the patients' cultures. These results indicate that the enzymatic defect in Refsum's disease is in the first step of the pathway for degradation of phytanic acid, that is, in the unusual alpha-oxidative process that leads to a shortening of phytanic acid by one carbon atom.

Scavenger Receptor Class B Type I Is Expressed in Cultured Keratinocytes and Epidermis

“…Third, the epidermis lacks ⌬5 and ⌬6 desaturase activity (40,41), and therefore the epidermis presumably must obtain arachidonic acid from other sites. Lastly, plant-derived fatty acids accumulate in the epidermis in certain disease states, such as Refsum's disease (42,43). Taken together, these observations indicate that extraepidermal sources can contribute to the epidermal lipid pool.…”

Localization of the oxidative defect in phytanic acid degradation in patients with refsum's disease

“…This is evident, first, from the fact that they apparently reach a more or less steadystate level of plasma and tissue phytanate despite continued ingestion of phytanic acid and phytol in their regular diets over many years. Their plasma and tissue levels fall when the dietary load is reduced (20 present studies with intravenously administered phytanic acid-U-m'C, in previous studies with orally administered phytol-U-14C (7,9), and in experiments with fibroblast cultures (13,14), a very low but still measurable amount of 'CO2 was produced; in all these studies, however, less than 5% of the administered substrate was converted to 14COi. Some of this "CO2 could possibly have arisen from radioimpurities that were not separated from methyl phytanate during the TLC and GLC purification.…”

“…Nevertheless, the fractional oxidation of phytanate was not depressed. Finally, tissue culture studies provide an independent demonstration that oxidation is drastically impaired in fibroblasts derived from skin biopsies of the three HAP cases reported here even though in culture they contain no abnormal stores of phytanic acid (13,14).…”

“…In the current studies, patients with HAP have been studied to compare their oxidative capacity for phytanic acid, a-OH-phytanic acid, and pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) with that of controls. Preliminary reports of some of these results have appeared elsewhere (14)(15)(16).…”

Identification of phytanoyl‐CoA ligase as a distinct acyl‐CoA ligase in peroxisomes from cultured human skin fibroblasts

“…The defect in the a-oxidation of phytanic acid is at the level of the conversion of phytanic acid to a-hydroxyphytanic acid [1, 4,5]. Because of the presence of a methyl group at the /%carbon, phytanic acid does not undergo B-oxidation but is first a-oxidized to pristanic acid .…”