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.

IntroductionPhenylketonuria (PKU) is an inborn error of metabolism associated with an increased risk of behavioural and mood disorders. There are currently no reliable markers for monitoring mood in PKU. The purpose of this study was to evaluate salivary serotonin as a possible non-invasive marker of long-term mood symptoms and central serotonin activity in patients with PKU.Methods20 patients were recruited from our Adult Metabolic Diseases Clinic. Age, sex, plasma phenylalanine (Phe) level, DASS (Depression Anxiety Stress Scales) depression score, DASS anxiety score, BMI, salivary serotonin, salivary cortisol, 2-year average Phe, 2-year average tyrosine (Tyr), and 2-year average Phe:Tyr ratio were collected for each patient. Spearman's ρ correlation analysis was used to determine if there was any relationship between any of the parameters.ResultsThere were positive correlations between DASS anxiety and DASS depression scores (Spearman's ρ = 0.8708, p-value < 0.0001), BMI and plasma Phe level (Spearman's ρ = 0.6228, p-value = .0034), and 2-year average Phe and BMI (Spearman's ρ = 0.5448, p-value = .0130). There was also a negative correlation between salivary cortisol and plasma Phe level (Spearman's ρ = −0.5018, p-value = .0338). All other correlations were not statistically significant.ConclusionSalivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, implying that salivary serotonin does not reflect central serotonin turnover. Additionally, this study suggests that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU.SynopsisSalivary serotonin does not correlate with peripheral phenylalanine levels, DASS depression scale scores, or DASS anxiety scale scores, suggesting that salivary serotonin is not a suitable marker for monitoring dietary control, mood, or anxiety in PKU.

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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.

Background: Diet, with an emphasis on phenylalanine restriction, is recognized as an effective treatment for phenylketonuria (PKU). A similar approach is used in pregnant PKU patients to reduce teratogenic effects of elevated circulating phenylalanine. Our objective was to assess the dietary management of pregnant PKU individuals at Vancouver General Hospital, Canada, retrospectively including dietary recommendations, phenylalanine intake, patient compliance and a comparison with protein and phenylalanine requirements determined in healthy pregnancies. Methods: We reviewed dietitian’s health records for pregnant patients monitored for PKU between 1999-2019 at the Adult Metabolic Diseases Clinic (AMDC). Data were extracted on demographics, gestational weight gain, gestational age at delivery, pregnancy outcomes, plasma analyses, reported health concerns, and dietary intake of phenylalanine, tyrosine, and protein. We present descriptive statistics of subject characteristics and clinical results. Paired sample t-test assessed for differences between prescribed phenylalanine and phenylalanine intake. Generalized additive mixed models approach was used to observe changes in phenylalanine concentration in blood spots and phenylalanine tolerance throughout the pregnancy. Results: Eleven patients aged 20-40 years, with a total of 16 pregnancies, were included for analysis. Prescribed phenylalanine intake increased from 7.2 ± 4.3 to 16.7 ± 4.8 mg·kg-1·d-1 between early (13-19wk) and late (33-39wk) gestation. Actual phenylalanine intakes increased from 7.5.2 ± 4.3 to 17.7 ± 4.9 mg·kg-1·d-1 between these stages and were not statistically different. When compared to our previously determined mean phenylalanine requirements in healthy pregnancies during ~16wk pregnancy (15 mg·kg-1·d-1) and late (~36wk) pregnancy (21 mg·kg-1·d-1), phenylalanine intake was 50% lower at 13-19wk gestation and 16 % lower at 33-39wk gestation. Mean phenylalanine concentration in blood spots decreased as pregnancy progressed, with the mean concentration being highest preconception, and a slight increase between 8 and 12 wk. Conclusions: Current management practices at AMDC are working well to achieve targeted metabolic control. Increase in phenylalanine requirements during early healthy pregnancy, combined with slight increase in blood spot phenylalanine in early PKU pregnancy is intriguing and suggests a need to directly determine phenylalanne needs. This natural history analysis provides reference values and management practices of pregnant PKU patients, contributing to the limited data available.