In Vivo Study of Phytanic Acid α-Oxidation in Classic Refsum's Disease and Chondrodysplasia Punctata

Abstract

ABSTRACT. A series of in vivo experiments is described in which [l-'3C]phytanic acid was given as an oral substrate to a healthy subject and two patients showing an impairment in phytanic acid degradation, one with Refsum's disease and one with chondrodysplasia punctata. After intake of the substrate by the control in a dose of 20 mg/ kg body weight, the production of I3CO2 was measured in exhaled breath air and the concomitant formation of labeled 2-hydroxyphytanic acid and of pristanic acid was demonstrated by plasma analysis. After application of a substrate dose of 1 mg/kg body weight to the control, no substantial amounts of 13COz were measured, whereas time-dependent analysis of labeled 2-hydroxyphytanic acid in plasma yielded a concentration curve superimposed upon the baseline value (0.2 pmollL) of the unlabeled substance. Phytanic acid accumulated in plasma from the Refsum's disease patient 1649 pmol/L, controls > 1 y (n = 100): c 10 pmol/L], whereas the pristanic acid concentration was within the control range 11.4 pmol/L, controls > 1 y (n = 100): c 3 pmol/L]. Low amounts of 2-hydroxyphytanic acid were found normally present 10.04 pmol/L, controls > 1 y (n = 11): < 0.2 pmol/L], and formation of labeled 2-hydroxyphytanic acid could not be demonstrated after ingestion of [1-13C]phytanic acid in a dose of 1 mg/kg body weight. In addition to phytanic acid accumulation (232 pmol/L), the chondrodysplasia punctata patient showed an elevated 2-hydroxyphytanic acid plasma concentration (0.4 pmol/L), whereas the plasma pristanic acid level was in the control range (0.7 pmol/L). Oral administration of [l-I3C]phytanic acid (1 mg/kg body weight) to this patient resulted in a plasma concentration/time profile of labeled 2-hydroxyphytanic acid similar to that of the control. These findings demonstrate that a-hydroxylation of phytanic acid is a physiologic process and indicate that Refsum's disease and chondrodysplasia punctata patients have a different ability to convert phytanic acid into 2-hydroxyphytanic acid. (Pediatu Res 32: 566-570, 1992) Abbreviations CDP, chondrodysplasia punctata PFB, pentafluorobenzyl RCDP, rhizomelic chondrodysplasia punctata RD, Refsum's disease TMS, trimethylsilyl

Involvement of microsomal fatty aldehyde dehydrogenase in the α‐oxidation of phytanic acid

“…The concentrations of phytanic acid and pristanic acid in plasma samples from controls and patients affected with SLS were determined by stable isotope dilution gas chromatography mass spectrometry as previously described [16].…”

“…In RCDP, an import defect of proteins containing a peroxisomal targeting sequence 2 results in mistargeting and thus severe deficiency of phytanoyl‐CoA hydroxylase [13–15]. Patients affected with classical Refsum disease, generalized peroxisomal disorders and RCDP accumulate phytanic acid in blood and tissues [16].…”

CYP4 Isoform Specificity in the ω-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease

“…In the absence of ␣-oxidation, phytanic acid cannot be degraded by conventional ␤-oxidation and accumulates in nerve tissue, causing the pathology of the disease. Comparison of the metabolism of [ 13 C]phytanic acid by control and Refsum's disease individuals showed that the plasma phytanic acid concentration rose to 649 M in the Refsum's patients in contrast to a level of 1.4 M in the control individual (ten Brink et al, 1992). The progress of the disease can be retarded by dietary management and, if necessary, plasmapheresis (Refsum, 1981).…”