Plasma Carnitine Concentrations Research Articles

Evaluation of taurine and carnitine concentrations in whole blood, plasma, skeletal muscle and cardiac muscle in dogs.

Little is known about how plasma and whole blood taurine and plasma carnitine correlate to concentrations in skeletal and cardiac muscle and the effects of diet in dogs. The purpose of this study was to evaluate the correlation among plasma, skeletal and cardiac muscle carnitine and taurine and whole blood taurine and determine the effect of diet. The study protocol was approved by the Pet Food Solutions Institutional Animal Care and Use Committee. Thirty-three mixed-breed hounds and 32 beagles were evaluated at Day 0 then removed from their baseline diet and randomized to a test diet: high animal protein, grain-inclusive (HA-GI), low animal protein, grain-free (LA-GF), low animal protein, grain-inclusive (LA-GI), or high animal protein, grain-free (HA-GF). Blood was drawn every 30 days and endomyocardial (mixed breeds only) and skeletal muscle biopsies were collected at Days 0 and 180. The correlations between plasma and whole blood taurine, or plasma carnitine and skeletal and cardiac muscle concentrations were weak (p < 0.01-0.05). Mixed-breed hounds had increased (p = 0.029) whole blood taurine compared to beagles. Plasma taurine was lower with diet HA-GF, (p = 0.009) however, all diets had increased taurine from Day 0 and were, on average within the laboratory reference range. Dogs fed the HA-GI diet had increased cardiac muscle carnitine esters (p = 0.014). Increased carnitine esters were also appreciated in cardiac muscle in all diets from Day 0 to 180 (p = 0.0001). On Day 180 mixed-breed hounds had increased skeletal total carnitine (p < 0.001) compared to all time points and breeds. This study observed no correlation between plasma, whole blood, skeletal and cardiac muscle taurine concentrations but noted some effects between time, breed and diet.

Impact of haemodialysis on plasma carnitine concentrations in haemodialysis patients.

To evaluate the impact of haemodialysis on plasma carnitine levels. The cross-sectional study was conducted from April 20, 2020 to May 10, 2022, at the dialysis unit of the nephrology ward of Jinnah Postgraduate Medical Centre, Karachi, and the Pakistan Navy Ship Shifa Hospital, Karachi, in collaboration with the Department of Biochemistry, University of Karachi, and comprised patients of either gender aged >18 years. They were divided into chronic kidney disease group A and end-stage renal disease group B. Control group C included subjects from the general population. Free carnitine and total carnitine values were detected using enzyme-linked immunosorbent assay. Acyl carnitine was estimated by applying the standard formula, and the ratio between acyl carnitine and free carnitine was calculated for accurate assessment of the carnitine status. Data was analysed using SPSS 23. Of the 203 subjects, 143(70.44%) were cases and 60(29.55%) were controls. Among the cases, 120(84%) were recruited from Jinnah Postgraduate Medical Centre and 23(16%) from Pakistan Navy Ship Shifa Hospital. There were 60(29.55%) patients in group A, 83(40.88%) in group B and 60(29.55%) in group C. The mean age in group A was 47.90 5.±65 years, it was 44.10 ±8.92 years in group B and 40.90 ± 6.73 years in group C. There was a significant difference related to free carnitine, total carnitine, acyl carnitine values and the ratio between acyl carnitine and free carnitine values in groups A and B compared to control group C (p<0.05). Patients on maintenance haemodialysis developed were found to have developed carnitine deficiency.

Carnitine affects Octanoate Oxidation to Carbon Dioxide and Dicarboxylic Acids in Colostrum-Deprived Piglets: In Vivo Analysis of Mechanisms Involved Based on CoA- and Carnitine-Ester Profiles

Newborn, colostrum-deprived piglets (n = 21) were used to study the effects of L-carnitine supplementation on the in vivo oxidation of [1-14C]octanoate to CO2 and dicarboxylic acids. Pigs were fitted with arterial and bladder catheters and were infused with octanoate (supplying 35–100% of piglets' energy expenditure) and with or without valproate for a period of 24 h. After achieving steady-state octanoate oxidation, carnitine was coinfused [50 µmol/kg0.75 prime plus 20 µmol/(h·kg0.75)], and deviations in the octanoate oxidation rate, dicarboxylic acid excretion rate, and carnitine metabolism were monitored. At the end of the 24-h infusion, samples of liver and muscle were analyzed for carnitine- and CoA-esters by HPLC. Carnitine stimulated octanoate oxidation by 7% (P < 0.05) and decreased dicarboxylic acid excretion by 45% (P < 0.05). Carnitine supplementation increased (P < 0.05) concentrations of carnitine and acetyl carnitine in hepatic tissue (three- and 55-fold, respectively) and plasma (seven- and 11-fold); whereas, muscle-carnitine concentration doubled upon carnitine supplementation, but acetyl carnitine concentration remained unaltered. Urinary excretion of acetyl and free carnitine also increased with carnitine supplementation, but accounted for <10% of carnitine infused. Hepatic total CoA and CoA esters increased with carnitine supplementation, whereas muscle acetyl-CoA decreased. Valproate had only marginal effects on octanoate metabolism. These data confirm the hypothesis that carnitine affects the in vivo oxidation of octanoate in colostrum-deprived piglets and suggest that the effects may be mediated by aiding the export of excess acetyl groups from muscle or by enhancing uptake of octanoate into liver mitochondria.

Carnitine Supplementation Ameliorates the Steatosis and Ketosis Induced by Pivalate in Rats

These studies examined the effect in rats of carnitine supplementation on variables of fat metabolism altered by administration of sodium pivalate, a compound which induces a carnitine deficiency. Weanling male rats received 20 mmol/L sodium pivalate or 20 mmol/L sodium bicarbonate in their drinking water for 2 wk. They were food-deprived for 24 h, and to maximize fatty acid oxidation, were cold-stressed for 4 h. In Experiment 1, group 1 received the bicarbonate, group 2 received the pivalate, group 3 received the pivalate and 0.46 mmol L-carnitine in the diet/d, while group 4 received the pivalate and 0.95 mmol L-carnitine in the diet/d. In Experiment 2, group 1 received unsupplemented drinking water, group 2 received the bicarbonate, group 3 received the pivalate, and group 4 received the pivalate and 0.95 mmol L-carnitine in the diet/d. Pivalate-treated rats given the low carnitine diet had plasma and liver triglyceride levels (Experiment 1), plasma β-hydroxybutyrate concentrations (Experiments 1 and 2) and urinary dicarboxylic acid excretion (Experiment 2) significantly greater than those of controls (P < 0.05). The reduced tissue carnitine concentrations, starvation ketosis and lipid accumulation in the liver are findings also reported for human secondary carnitine deficiency due to organic acidurias. Supplementing the diet with L-carnitine at the level of 0.95 mmol/d significantly raised plasma and tissue carnitine concentrations and reduced the plasma β-hydroxybutyrate and liver triglyceride concentrations to levels not significantly different than control values. Carnitine supplementation ameliorates the degree of liver lipid accumulation and exaggerated starvation ketosis induced by pivalate.

Features of carnitine metabolism in young athletes

Objective: to study the indicators of carnitine metabolism in young athletes of various specializations.Materials and methods: This study involved 46 people with different levels of physical activity aged 15 to 18 years. The first group consisted of 18 girls professionally involved in field hockey (mean age, 16.17 ± 0.31 years). The second group included 21 swimmers (10 girls and 11 boys, mean age 17.00 ± 0.26 years). The control group included 7 young men with a standard mode of motor activity, not involved in sports (the age of the subjects was 16 years). In the course of the study, the method of liquid tandem chromatography-mass spectrometry with ionization in an electrospray was used. The material for research is capillary blood. As a result of the analysis of the material, the concentrations of bound carnitine (acylcarnitines) and free carnitine were determined in µmol/l.Results: Comparative blood analysis between the three groups showed differences in free carnitine levels. It was shown that the concentration of free carnitine in the blood plasma of field hockey athletes was significantly lower than in the groups of swimmers and non-athletes (p &lt; 0.001). At the same time, the values of indicators of bound carnitine did not differ significantly between all subjects. We also studied that the values of the carnitine coefficient were significantly higher in the group of hockey players compared to other groups (p &lt; 0.001).Conclusion: The decrease in free carnitine levels in the group of hockey players is probably the result of long-term adaptation of the body to conditions in which glucose is the main energy substrate for working muscles. Further studies are needed to clarify the exact mechanisms of development of this phenomenon.

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis.

Golden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane‐like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.

Limited Impact of Pivalate-Induced Secondary Carnitine Deficiency on Hepatic Transcriptome and Hepatic and Plasma Metabolome in Nursery Pigs.

Administration of pivalate has been demonstrated to be suitable for the induction of secondary carnitine deficiency (CD) in pigs, as model objects for humans. In order to comprehensively characterize the metabolic effects of secondary CD in the liver of pigs, the present study aimed to carry out comparative analysis of the hepatic transcriptome and hepatic and plasma metabolome of a total of 12 male 5-week-old pigs administered either pivalate (group PIV, n = 6) or vehicle (group CON, n = 6) for 28 days. Pigs of group PIV had approximately 40–60% lower concentrations of free carnitine and acetylcarnitine in plasma, liver and different skeletal muscles than pigs of group CON (p < 0.05). Transcript profiling of the liver revealed 140 differentially expressed genes (DEGs) between group PIV and group CON (fold change > 1.2 or <−1.2, p-value < 0.05). Biological process terms dealing with the innate immune response were found to be enriched with the DEGs (p < 0.05). Using a targeted metabolomics approach for the simultaneous quantification of 630 metabolites, 9 liver metabolites and 18 plasma metabolites were identified to be different between group PIV and group CON (p < 0.05). Considering the limited alterations of the hepatic transcriptome and of the liver and plasma metabolome, it can be concluded that pivalate-induced secondary CD is not associated with significant hepatic metabolism changes in pigs.

抗てんかん薬および栄養法が重症心身障害児（者）の血中カルニチン濃度に及ぼす影響

抗てんかん薬および栄養法が重症心身障害児（者）の血中カルニチン濃度に及ぼす影響

Metabolic changes induced by oral glucose tests in horses and their diagnostic use.

BackgroundLittle is known about the implications of hyperinsulinemia on energy metabolism, and such knowledge might help understand the pathophysiology of insulin dysregulation.ObjectivesDescribe differences in the metabolic response to an oral glucose test, depending on the magnitude of the insulin response.AnimalsTwelve Icelandic horses in various metabolic states.MethodsHorses were subjected to 3 oral glucose tests (OGT; 0.5 g/kg body weight glucose). Basal, 120 and 180 minutes samples were analyzed using a combined liquid chromatography tandem mass spectrometry and flow injection analysis tandem mass spectrometry metabolomic assay. Insulin concentrations were measured using an ELISA. Analysis was performed using linear models and partial least‐squares regression.ResultsThe kynurenine : tryptophan ratio increased over time during the OGT (adjusted P‐value = .001). A high insulin response was associated with lower arginine (adjusted P‐value = .02) and carnitine (adjusted P‐value = .03) concentrations. A predictive model using only baseline samples performed well with as few as 7 distinct metabolites (sensitivity, 86%; 95% confidence interval [CI], 81%‐90%; specificity, 88%; 95% CI, 84%‐92%).Conclusions and Clinical ImportanceOur results suggest induction of low‐grade inflammation during the OGT. Plasma arginine and carnitine concentrations were lower in horses with high insulin response and could constitute potential therapeutic targets. Development of screening tools to identify insulin‐dysregulated horses using only baseline blood sample appears promising.

Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades

Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.

Changes in the concentrations of trimethylamine N-oxide (TMAO) and its precursors in patients with amyotrophic lateral sclerosis

To compare the plasma concentrations of trimethylamine N-oxide (TMAO) and its precursors in amyotrophic lateral sclerosis (ALS) patients, their spouses and healthy controls and to find associations between gut microbiota metabolites and ALS. ALS patients were recruited at Peking University Third Hospital from January 2015 to December 2018. Information was collected from their spouses at the same time. Age and gender matched healthy controls were recruited from individuals who visited the physical examination center for health checkups. Blood samples were collected after at least 4 h of fasting. Concentrations of the metabolites were quantified using stable isotope dilution liquid chromatography–tandem mass spectrometry. Group differences were analyzed using parametric and nonparametric tests, as appropriate. In this study, 160 patients with ALS were recruited. In these patients, 63 were compared with their spouses, 148 were compared with age and gender matched controls, and 60 were compared with both their spouses and heathy controls in the same time. The carnitine concentration was significantly higher in patients than in their spouses, while there were no significant differences in the concentrations of other metabolites. The carnitine and betaine concentrations were higher, while the choline, TMAO and butyrobetaine concentrations were lower in ALS than in healthy controls. The concentrations of the metabolites in the spouses were more similar to the ALS patients rather than to the healthy controls. In the ALS group, the plasma concentrations of carnitine, betaine, choline and TMAO were inversely related to the severity of upper motor neuron impairment. The TMAO metabolic pathway of the gut microbiota is disturbed in both ALS patients and their spouses, which might suggest that the changes in the gut microbiota occurred before disease onset. The negative correlations between the involvement of UMNs and the concentrations of the metabolites might suggest that the inhibition of this metabolic pathway might lead to a better prognosis in ALS patients.

Reduced 24-h Sodium Excretion Is Associated With a Disturbed Plasma Acylcarnitine Profile in Vasovagal Syncope Children: A Pilot Study.

Objective: To investigate if the low sodium intake is associated with the plasma carnitine and acylcarnitine profile in children with vasovagal syncope (VVS).Materials and Methods: Twenty-six children suffering from VVS were recruited in the present study and divided into a group of low urinary sodium excretion or a group of normal urinary sodium excretion according to the excretion of 24-h urinary sodium <3 or 3–6 g, respectively. The excretion of 24-h urinary sodium was detected with ion-selective electrode approach. Plasma carnitine and acylcarnitine concentrations were measured with tandem mass spectrometry. Each participant completed the head-up tilt test. The demographics, clinical characteristics, hemodynamic parameters and plasma carnitine and acylcarnitine concentrations were compared between the two groups. A bivariate correlation between plasma acylcarnitine profiles and the excretion of 24-h urinary sodium was conducted with Spearman's correlation coefficients.Results: Of the enrolled VVS patients, 14 patients were assigned to the group of low urinary sodium excretion and the remaining 12 patients were assigned to the group of normal urinary sodium excretion. Symptoms of fatigue were more prevalent in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion (p = 0.009). Aside from fatigue, no other differences in the demographics, clinical characteristics or hemodynamic parameters during the head-up tilt test were found between the two groups (p > 0.05). Concentrations of plasma tiglylcarnitine (C5:1), hydroxyhexadecanoylcarnitine (C16OH), hydroxyoctadecanoylcarnitine (C18OH), and carnitine C22 were significantly higher in the group of low urinary sodium excretion than in the group of normal urinary sodium excretion (all p-values = 0.048); moreover, they were all negatively correlated with 24-h urinary sodium levels (all p-values = 0.016). There were no differences between the two groups in other acylcarnitines or free carnitine.Conclusions: Reduced excretion of 24-h urinary sodium is associated with a disturbed plasma acylcarnitine profile in children with VVS. The findings suggest that restricted sodium intake-induced disturbance of plasma acylcarnitines and related cellular energy metabolism might be involved in the pathogenesis of VVS in children.

Polymorphisms in CPT1B and CPT2 have no significant effect on plasma carnitine levels in Japanese cancer patients.

ABSTRACTTreatment of cancer patients undergoing chemotherapy with L-carnitine (LC) supplementation is becoming increasingly popular in the clinic. The present study aimed to examine the possible effects of polymorphisms in CPT1B and CPT2 (CPT1B G320D, S427C, c.282-18 C>T, and p.E531K, and CPT2 V368I) on the plasma concentration of carnitine in humans. The subjects were the 218 participants of the Iga Cohort Study. Differences in plasma-free carnitine levels by genotype were examined. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The plasma carnitine levels were significantly higher in males (P<0.001; Student’s t-test), and there was no significant difference in plasma carnitine levels between the age groups (P=0.202; ANOVA). One-way ANOVA revealed the plasma levels of carnitine were neither significantly different by CPT1B G320D, S427C, c.282-18 C>T, or p.E531K, nor by CPT2 V368I genotypes (P=0.133, P=0.538, P=0.636, P=0.509, and P=0.398, respectively). When analysis of covariance (ANCOVA) adjusted for age and sex was applied, the plasma levels of carnitine were not statistically significantly different according to these genotypes (P=0.299, P=0.715, P=0.980, P=0.851, and P=0.674, respectively). The present study did not identify any statistically significant differences in plasma carnitine levels between subjects with different CPT1 and CPT2 genotypes, suggesting that there may be no need to tailor treatments to patients’ genotypes when determining the dose/amount of LC to be administered to cancer patients undergoing palliative care.

Effect of lifelong carnitine supplementation on plasma and tissue carnitine status, hepatic lipid metabolism and stress signalling pathways and skeletal muscle transcriptome in mice at advanced age

While strong evidence from clinical studies suggests beneficial effects of carnitine supplementation on metabolic health, serious safety concerns associated with carnitine supplementation have been raised from studies in mice. Considering that the carnitine doses in these mice studies were up to 100 times higher than those used in clinical studies, the present study aimed to address possible safety concerns associated with long-term supplementation of a carnitine dose used in clinical trials. Two groups of NMRI mice were fed either a control or a carnitine-supplemented diet (1 g/kg diet) from weaning to 19 months of age, and parameters of hepatic lipid metabolism and stress signalling and skeletal muscle gene expression were analysed in the mice at 19 months of age. Concentrations of free carnitine and acetylcarnitine in plasma and tissues were higher in the carnitine than in the control group (P&lt;0·05). Plasma concentrations of free carnitine and acetylcarnitine were higher in mice at adult age (10 and 15 months) than at advanced age (19 months) (P&lt;0·05). Hepatic mRNA and protein levels of genes involved in lipid metabolism and stress signalling and hepatic and plasma lipid concentrations did not differ between the carnitine and the control group. Skeletal muscle transcriptome analysis in 19-month-old mice revealed only a moderate regulation between carnitine and control group. Lifelong carnitine supplementation prevents an age-dependent impairment of plasma carnitine status, but safety concerns associated with long-term supplementation of carnitine at doses used in clinical trials can be considered as unfounded.

Effects of l-carnitine administration on health-related quality of life during cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma

ObjectivesCancer-related fatigue impairs daily functioning and negatively impacts health-related quality of life (HRQoL). Our previous study revealed that cisplatin-based chemoradiotherapy (CRT) impairs the carnitine system and carnitine deficiency leads to poor physical functioning. This open label, randomized, controlled prospective study investigated the effects of l-carnitine administration on plasma carnitine concentration, CRT-induced fatigue, and decline in HRQoL in patients with head and neck squamous cell carcinoma (HNSCC). MethodsPatients were divided into experimental group (received 1000mg of oral liquid l-carnitine once daily for 8 weeks) and control group. The primary and secondary endpoints were the change in HRQoL scores and the change in carnitine levels, respectively, from baseline (pre-CRT) to after CRT. ResultsThe mean total plasma carnitine concentration in the control group decreased significantly, 2 weeks after the end of chemotherapy, while no significant differences were seen in the l-carnitine group. l-carnitine administration, therefore, kept the physical functioning score unchanged. ConclusionOur study shows that patients who receive CRT experience chemotherapy-induced damage of carnitine homeostasis leading to deficiency of carnitine and impairment of HRQoL. l-carnitine administration is beneficial in improving the HRQoL in patients with HNSCC.

L-Carnitine Supplementation in Older Women. A Pilot Study on Aging Skeletal Muscle Mass and Function.

Skeletal muscle wasting, associated with aging, may be regulated by the inflammatory cytokines as well as by insulin-like growth factor 1 (IGF-1). l-carnitine possesses anti-inflammatory properties and increases plasma IGF-1 concentration, leading to the regulation of the genes responsible for protein catabolism and anabolism. The purpose of the present study was to evaluate the effect of a 24-week l-carnitine supplementation on serum inflammatory markers, IGF-1, body composition and skeletal muscle strength in healthy human subjects over 65 years of age. Women between 65 and 70 years of age were supplemented for 24 weeks with either 1500 mg l-carnitine-l-tartrate or an isonitrogenous placebo per day in a double-blind fashion. Before and after the supplementation protocol, body mass and composition, as well as knee extensor and flexor muscle strength were determined. In the blood samples, free carnitine, interleukin-6, tumor necrosis factor-α, C-reactive protein and IGF-1 were determined. A marked increase in free plasma carnitine concentration was observed due to l-carnitine supplementation. No substantial changes in other parameters were noted. In the current study, supplementation for 24 weeks affected neither the skeletal muscle strength nor circulating markers in healthy women over 65 years of age. Positive and negative aspects of l-carnitine supplementation need to be clarified.

Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria

Individuals with phenylketonuria (PKU) have a risk of cognitive impairment and inflammation. Many follow a low-phenylalanine (low-Phe) diet devoid of animal protein in combination with medical foods (MFs). To assess lipid metabolism in participants with PKU consuming amino acid MFs (AA-MFs) or glycomacropeptide MFs (GMP-MFs), we conducted fatty acid and metabolomics analyses. We used subsets of fasting plasma and urine samples from our randomized crossover trial in which participants with early-treated classical and variant (milder) PKU consumed a low-Phe diet combined with AA-MFs or GMP-MFs for 3 wk each. Fatty acid profiles of red blood cell (RBC) membranes were determined for 25 adults (aged 18-49 y) with PKU and 143 control participants. Metabolomics analyses of plasma and urine samples were conducted by Metabolon for 9-10 adolescent and adult participants with PKU and for 15 control participants. RBC fatty acid profiles were not significantly different with AA-MFs or GMP-MFs. PKU participants showed higher total n-6:n-3 (ω-6:ω-3) fatty acids (mean ± SD percentages of total fatty acids: AA-MF = 5.45% ± 1.07%; controls = 4.33%; P < 0.001) and lower docosahexaenoic acid (DHA; AA-MF = 3.21% ± 0.98%; controls = 3.70% ± 1.01%; P = 0.02) and eicosapentaenoic acid (AA-MF = 0.33% ± 0.12%; controls = 0.60% ± 0.43%; P < 0.001) in RBCs than did control participants. Despite higher carnitine intake from AA-MFs than GMP-MFs (mean ± SE intake: AA-MFs = 58.6 ± 5.3 mg/d; GMP-MFs = 0.3 ± 0.01 mg/d; P < 0.001), plasma concentrations of carnitine were similar and not different from those in the control group (AA-MF compared with GMP-MF, P = 0.73). AA-MFs resulted in higher urinary excretion of trimethylamine N-oxide (TMAO), which is synthesized by bacteria from carnitine, compared with GMP-MFs (mean ± SE scaled intensity-TMAO: AA-MFs = 1.2 ± 0.1, GMP-MFs = 0.9 ± 0.1; P = 0.005). Plasma deoxycarnitine was lower in PKU participants than in control participants, suggesting reduced carnitine biosynthesis in PKU (AA-MF = 0.9 ± 0.1; GMP-MF = 1.0 ± 0.1; controls = 1.3 ± 0.1; AA-MF compared with controls, P = 0.01; GMP-MF compared with controls, P = 0.04). Supplementation with DHA is needed in PKU. Carnitine supplementation of AA-MFs shows reduced bioavailability due, in part, to bacterial degradation to TMAO, whereas the bioavailability of carnitine is greater with prebiotic GMP-MFs. This trial was registered at www.clinicaltrials.gov as NCT01428258.

Carnitine deficiency induces a short QT syndrome

Short QT syndrome is associated with an increased risk of cardiac arrhythmias and unexpected sudden death. Until now, only mutations in genes encoding the cardiac potassium and calcium channels have been implicated in early T-wave repolarization. The purpose of this study was to confirm a relationship between a short QT syndrome and carnitine deficiency. We report 3 patients affected by primary systemic carnitine deficiency and an associated short QT syndrome. Ventricular fibrillation during early adulthood was the initial symptom in 1 case. To confirm the relationship between carnitine, short QT syndrome, and arrhythmias, we used a mouse model of carnitine deficiency induced by long-term subcutaneous perfusion of MET88. MET88-treated mice developed cardiac hypertrophy associated with a remodeling of the mitochondrial network. The continuous monitoring of electrocardiograms confirmed a shortening of the QT interval, which was negatively correlated with the plasma carnitine concentration. As in humans, such alterations coincided with the genesis of ventricular premature beats and ventricular tachycardia and fibrillation. Altogether, these results suggest that long-chain fatty acid metabolism influence the morphology and the electrical function of the heart.

Effect of L-carnitine supplementation on the body carnitine pool, skeletal muscle energy metabolism and physical performance in male vegetarians.

More than 95% of the body carnitine is located in skeletal muscle, where it is essential for energy metabolism. Vegetarians ingest less carnitine and carnitine precursors and have lower plasma carnitine concentrations than omnivores. Principle aims of the current study were to assess the plasma and skeletal muscle carnitine content and physical performance of male vegetarians and matched omnivores under basal conditions and after L-carnitine supplementation. Sixteen vegetarians and eight omnivores participated in this interventional study with oral supplementation of 2 g L-carnitine for 12 weeks. Before carnitine supplementation, vegetarians had a 10% lower plasma carnitine concentration, but maintained skeletal muscle carnitine stores compared to omnivores. Skeletal muscle phosphocreatine, ATP, glycogen and lactate contents were also not different from omnivores. Maximal oxygen uptake (VO2max) and workload (P max) per bodyweight (bicycle spiroergometry) were not significantly different between vegetarians and omnivores. Sub-maximal exercise (75% VO2max for 1 h) revealed no significant differences between vegetarians and omnivores (respiratory exchange ratio, blood lactate and muscle metabolites). Supplementation with L-carnitine significantly increased the total plasma carnitine concentration (24% in omnivores, 31% in vegetarians) and the muscle carnitine content in vegetarians (13%). Despite this increase, P max and VO2max as well as muscle phosphocreatine, lactate and glycogen were not significantly affected by carnitine administration. Vegetarians have lower plasma carnitine concentrations, but maintained muscle carnitine stores compared to omnivores. Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.

Carnitine deficiency: Risk factors and incidence in children with epilepsy.

Carnitine deficiency is relatively common in epilepsy; risk factors reportedly include combination antiepileptic drug (AED) therapy with valproic acid (VPA), young age, intellectual disability, diet and enteral or parenteral feeding. Few studies have examined the correlation between each risk factor and carnitine deficiency in children with epilepsy. We examined the influence of these risk factors on carnitine deficiency, and identified a formula to estimate plasma free carnitine concentration in children with epilepsy. Sixty-five children with epilepsy and 26 age-matched controls were enrolled. Plasma carnitine concentrations were measured using an enzyme cycling assay, and correlations were sought with patients' other clinical characteristics. Carnitine deficiency was found in approximately 17% of patients with epilepsy and was significantly associated with carnitine-free enteral formula only by tube feeding, number of AEDs taken (independent of VPA use), body weight (BW), body height and Gross Motor Function Classification System (GMFCS) score. Stepwise multiple linear regression analysis indicated that carnitine concentration (in μmol/L) could be accurately estimated from a formula that does not require blood testing: 42.44+0.14×(BW in kg)-18.16×(feeding)-3.19×(number of AEDs), where feeding was allocated a score of 1 for carnitine-free enteral formula only by tube feeding and 0 for taking food orally (R(2)=0.504, P<0.001). Carnitine-free enteral formula only by tube feeding, multiple AED treatment and low BW are risk factors for carnitine deficiency in children with epilepsy. l-carnitine should be administered to children at risk of deficiency to avoid complications. Treatment decisions can be informed using an estimation formula that does not require blood tests.