Studies on the oxidation of phytanic acid and pristanic acid in human fibroblasts by acylcarnitine analysis.

[neonatal adrenoleukodystrophy]

The alpha-oxidation of phytanic acid and the beta -oxidation of pristanitc acid were investigated in cultured fibroblasts from controls and patients affected with different peroxisomal disorders using deuterated substrates . Formation of [omega-2 H 6 ]4 ,8 -dimethylnonanoylcarnitine ([omega-2 H 6 ]C 11 -carnitine ) from [omega-2 H 6 ]phytanic acid and [omega-2 H 6 ]pristanic acid was used as marker for these processes . Analysis was performed by tandem mass spectrometry . In normal cells , formation of [omega-2 H 6 ]C 11 -carnitine from both [omega-2 H 6 ]phytanic acid and [omega-2 H 6 ]pristanic acid was observed . When peroxisome-deficient fibroblasts were incubated with these substrates , [omega-2 H 6 ]C 11 -carnitine was not detectable or , in two cases , very low , which results from deficiencies in both peroxisomal alpha- and beta -oxidation . In cells with an isolated beta -oxidation defect at the level of the peroxisomal bifunctional protein , formation of [omega-2 H 6 ]C 11 -carnitine could also not be detected . Cells with an isolated defect in the alpha-oxidation of phytanic acid , obtained from patients affected with Refsum disease (McKusick 266500 ) or rhizomelic chondrodysplasia punctata (McKusick 215100 ), did not form [omega-2 H 6 ]C 11 -carnitine from [omega-2 H 6 ]phytanic acid . The observed formation of [omega-2 H 6 ]C 11 -carnitine from [omega-2 H 6 ]pristanic acid in these cells is in accordance with a normal peroxisomal beta -oxidation in these disorders . This study shows that separate incubation of fibroblasts with [omega-2 H 6 ]phytanic acid and [omega-2 H 6 ]pristanic acid , followed by acylcarnitine analysis in the medium by tandem mass spectrometry , can be used for screening cell lines for deficiencies in the peroxisomal alpha- and beta -oxidation pathways . Phytanic acid (3 ,7 ,11 ,15 -tetramethylhexadecanoic acid ) and pristanic acid (2 ,6 ,10 ,14 -tetramethylpentadecanoic acid ) are branched-chain fatty acids that are constituents of the human diet . As phytanic acid possesses a beta -methyl group , it can not be degraded by beta -oxidation . Instead , phytanic acid is first degraded by alpha-oxidation , yielding pristanic acid , which is subsequently degraded by beta -oxidation (Figure 1 ). Phytanic acid alpha-oxidation is thought to occur partly , and pristanic acid beta -oxidation exclusively , in peroxisomes (see Wanders et al 1995 for review ). Accumulation of phytanic acid and pristanic acid is found in blood and tissues of patients affected with generalized peroxisomal disorders . In this type of disorder , no morphologically distinguishable peroxisomes are present in tissues , resulting in accumulation of metabolites that are normally metabolized in these organelles (see Wanders et al 1995 for review ). The group of generalized peroxisomal disorders consists of three diseases , differing in clinical presentation . Patients suffering from the most severe disease , Zellweger syndrome (McKusick 214100 ), have symptoms from birth on and usually do not live beyond their first year of life . Neonatal adrenoleukodystrophy (N-ALD , McKusick 2023 70 ) has a milder presentation , whereas infantile Refsum disease (IRD , McKusick 266510 ) is the mildest form among the generalized peroxisomal disorders . Not only in these generalized peroxisomal disorders , but also in some isolated peroxisomal beta -oxidation defects , elevated levels of phytanic acid and pristanic acid are found (ten Brink et al 1992 a ). The elevated phytanic acid levels are considered to be caused by product inhibition of alpha-oxidation by accumulating pristanic acid . This is reflected in a highly elevated pristanic acid to phytanic acid ratio in plasma from patients suffering from bifunctional protein deficiency or peroxisomal thiolase deficiency (ten Brink et al 1992 a ). Elevated phytanic acid concentrations are also found in plasma from patients affected with classical Refsum disease and rhizomelic chondrodysplasia punctata (RCDP ). As pristanic acid beta -oxidation is not disturbed in these disorders , pristanic acid levels are normal (ten Brink et al 1992

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neonatal adrenoleukodystrophy

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