Marked elevation in plasma trimethylamine-N-oxide (TMAO) in patients with mitochondrial disorders treated with oral l-carnitine.

Oral supplementation with l-carnitine is a common therapeutic modality for mitochondrial disorders despite limited evidence of efficacy. Recently, a number of studies have demonstrated that a gut microbiota-dependent metabolite of l-carnitine, trimethylamine oxide (TMAO), is an independent and dose-dependent risk factor for cardiovascular disease (CVD). Given the limited data demonstrating efficacy with oral l-carnitine therapy and the newly raised questions of potential harm, we assessed plasma TMAO levels in patients with mitochondrial disease with and without oral l-carnitine supplementation. Nine subjects were recruited and completed the study. Eight out of 9 subjects at baseline had plasma TMAO concentrations <97.5th percentile (<15.5 µM). One subject with stage 3 renal disease, had marked elevation in plasma TMAO (pre 33.98 µm versus post 101.6 µm). Following at least 3 months of l-carnitine supplementation (1000 mg per day), plasma TMAO levels were markedly increased in 7out of 9 subjects; overall, plasma TMAO significantly increased 11.8-fold (p < 0.001) from a baseline median level of 3.54 µm (interquartile range (IQR) 2.55-8.72) to 43.26 (IQR 23.99-56.04) post supplementation. The results of this study demonstrate that chronic oral l-carnitine supplementation markedly increases plasma TMAO levels in subjects with mitochondrial disorders. Further studies to evaluate both the efficacy and long term safety of oral l-carnitine supplementation for the treatment of mitochondrial disorders are warranted.

Diet History Is a Reliable Predictor of Suboptimal Docosahexaenoic Acid Levels in Adult Patients with Phenylketonuria.

BACKGROUND: Omega-3 long-chain polyunsaturated fatty acids (n3LCPUFA) levels are reduced in phenylketonuria (PKU). Recent care guidelines recommend essential fatty acid status is monitored in patients with PKU but access to such testing is limited. We hypothesized that information obtained on diet history would identify PKU adults with suboptimal levels of n3LCPUFA. METHODS: A 12-month single site prospective study was completed including 35 adults (age 18-46) attending a clinic for adults with inborn errors of metabolism. Levels of n3LCPUFA were correlated with estimated intake using a published food frequency questionnaire. n3LCPUFA levels were tested at a commercial laboratory and values > one SD below the laboratory mean value were considered suboptimal. RESULTS: Mean levels of docosahexaenoic acid (DHA) were lower and levels of eicosapentaenoic acid (EPA) and alpha-linoleic acid (ALA) higher in subjects with PKU than in laboratory controls. n3LCPUFA levels correlated with estimated intake (p <0.002). Diet history had a positive predictive value of 93% and negative predictive value of 90% to identify subjects with suboptimal n3LCPUFA levels. CONCLUSIONS: Diet history is sufficient to predict adult subjects who may have low DHA levels and can be used to target testing or supplementation to those at risk. DHA levels are low despite high levels of ALA suggesting that supplementation, if indicated, should be with preformed DHA rather than with its precursors.