Impaired synthesis of DHA in patients with X-linked retinitis pigmentosa

Many patients with X-linked retinitis pigmentosa (XLRP) have lower than nor mal blood levels of the long-chain polyunsaturated omega3 fatty acid docosa hexaenoic acid (DHA; 22:6 omega3). This clinical trial was designed to test whether downregulation of DHA biosynthesis might be responsible for these reduced DHA levels. DHA biosynthesis was assessed in five severely affected patients with XLRP and in five age-matched controls by quantifying convers ion of [U-C-13]alpha -linolenic acid (alpha -LNA) to [C-13]DHA. Following o ral administration of [U-C-13]alpha -LNA, blood samples were collected at d esignated intervals for 21 days and isotopic enrichment of all omega3 fatty acids was determined by gas chromatography/mass spectroscopy. Activity of each metabolic step in the conversion of alpha -LNA to DHA was determined b y comparison of the ratios of the integrated concentration of C-13-product to C-13-precursor in plasma total lipid fractions. The ratio of [C-13]DHA t o [C-13]18:3 omega3 (the entire pathway) and that of [C-13]20:5 omega3 to [ C-13]20:4 omega3 (Delta (5)-desaturase) were significantly lower in patient s versus controls (P = 0.03 and 0.05, respectively). The estimated biosynth etic rates of [C-13]20:5 omega3, [C-13]22:5 omega3, [C-13]24:5 omega3, [C-1 3]24:6C omega3, and [C-13]22:6 omega3 were significantly lower in XLRP pati ents (42%, 43%, 31%, 18%, and 32% of control values, respectively; P < 0.04 ), supporting down-regulation of <Delta>(5)-desaturase in XLRP. The disappe arance of C-13-labeled fatty acids from plasma was not greater in XLRP pati ents compared with controls, suggesting that XLRP was not associated with i ncreased rates of fatty acid oxidation or other routes of catabolism. Thus, despite individual variation among both patients and controls, the data ar e consistent with a lower rate of Delta (5)-desaturation, suggesting that d ecreased biosynthesis of DHA may contribute to lower blood levels of DHA in patients with XLRP.