Low Plasma Carnitine Concentrations Research Articles

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.

Determining and Surveying the Role of Carnitine and Folic Acid to Decrease Fatigue in β-Thalassemia Minor Subjects

Beta-thalassemia minor (BTM) patients usually experience fatigue, bone pain complaint, and muscle weakness. Carnitine is an essential protein for transportation of long-chain fatty acids to the matrix for beta-oxidation. BTM patients have abnormally low plasma carnitine concentrations, which results in deficient ATP production. Carnitine and folic acid together may have a role in preventing bone pain complaint and fatigue in these patients. The aim of this study is to determine the effect of carnitine and folic acid supplementation in subjects with BTM. Seventy three BTM (mean age 11.06 ± 5.46 years) and 23 healthy controls (mean age 8.48 ± 3.78 years) were enrolled in the study. Fasting blood was drawn to determine baseline free and total carnitine levels, red blood cell folate concentration, and hemoglobin level. BTM were divided into three groups and received different types of supplementation for 3 months: Group 1, 50 mg/kg/day carnitine; Group 2, 50 mg/kg/day carnitine plus 1 mg/day folic acid; and Group 3, 1 mg/day folic acid. Controls did not receive supplementation. Laboratory parameters were again evaluated after 3 months’ supplementation. A detailed quality of life questionnaire was designed to investigate muscle symptoms before and after supplementation. Free and total plasma carnitine concentration and hemoglobin levels in BTM subjects increased significantly after carnitine supplementation (P < .0001). Bone pain complaint and muscle weakness decreased with carnitine. Red blood cell folate level increased after folic acid supplementation. Carnitine and folic acid supplementation resulted in a decrease in bone pain complaint and muscle weakness in cases with β-thalassemia minor.

Low availability of carnitine precursors as a possible reason for the diminished plasma carnitine concentrations in pregnant women

BackgroundIt has been shown that plasma carnitine concentrations decrease markedly during gestation. A recent study performed with a low number of subjects suggested that this effect could be due to a low iron status which leads to an impairment of carnitine synthesis. The present study aimed to confirm this finding in a greater number of subjects. It was moreover intended to find out whether low carnitine concentrations during pregnancy could be due to a reduced availability of precursors of carnitine synthesis, namely trimethyllysine (TML) and γ-butyrobetaine (BB).MethodsBlood samples of 79 healthy pregnant women collected at delivery were used for this study.ResultsThere was only a weak, non-significant (P > 0.05), correlation between plasma concentration of ferritin and those of free and total carnitine. There was no correlation between other parameters of iron status (plasma iron concentration, hemoglobin, MCV, MCH) and plasma concentration of free and total carnitine. There were, however, significant (P < 0.05) positive correlations between concentrations of TML and BB and those of free and total carnitine in plasma.ConclusionsThe results of this study suggest that an insufficient iron status is not the reason for low plasma carnitine concentrations observed in pregnant women. It is rather indicated that low plasma carnitine concentrations are caused by a low availability of precursors for carnitine synthesis during gestation.

Pivalate-generating prodrugs and carnitine homeostasis in man.

Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.

Plasma and liver carnitine status of children with chronic liver disease and cirrhosis.

Carnitine is an essential cofactor in the transfer of long-chain fatty acids across the inner mitochondrial membrane for oxidation. As its synthesis is performed in the liver, alterations in carnitine metabolism is expected in liver diseases, especially in cirrhosis. In this study, we investigated plasma and liver carnitine concentrations of 68 children with chronic liver disease, 36 of whom had cirrhosis as well. Carnitine level was determined by enzymatic method. Plasma and liver carnitine concentrations were not correlated. Mean plasma carnitine level of cirrhotic children was significantly lower than that of the control group (P<0. 0001). While there was no difference between liver carnitine concentrations of children with chronic liver disease and cirrhosis (P>0.05), mean plasma level of cirrhotics were lower (P<0.05). Plasma carnitine was correlated with albumin, triglyceride and gamma glutamyl transpeptidase (GGT) in patients with chronic liver disease (P<0.05). Liver carnitine was correlated with GGT in cirrhotic patients (P<0.005). Children with malnutrition had higher plasma and liver carnitine levels (P<0.05). The highest plasma and liver carnitine levels were detected in children with biliary atresia and criptogenic cirrhosis, respectively. Both the lowest plasma and liver carnitine levels were detected in Wilson's disease. Children with cirrhosis have low plasma carnitine concentrations. This finding is prominent in children with Wilson's disease. As carnitine is an essential factor in lipid metabolism, the carnitine supplementation for patients with cirrhosis in childhood, especially with Wilson's disease, seems to be mandatory.

L-carnitine: effect of intravenous administration on fuel homeostasis in normal subjects and home-parenteral-nutrition patients with low plasma carnitine concentrations

We studied the effects of intravenous L-carnitine on the metabolism of fatty acids, ketone bodies, glucose, and branched-chain amino acids in four normal volunteers and four patients on long-term home parenteral nutrition (HPN) with low plasma carnitine concentrations. Substrate kinetics were determined by use of [1-14C]palmitate, [3,4-13C2]-acetoacetate, [6,6-2H2]glucose, and [5,5,5-2H3]leucine before and during a 3-h intravenous infusion of L-carnitine. HPN patients were restudied after 1 mo of nightly intravenous carnitine administration. HPN patients tolerated the short-term fast well, exhibiting neither hypoglycemia nor hypoketonemia. Intravenous carnitine had no effect on rates of fatty acid oxidation, ketone body production, glucose production, or leucine kinetics in either group. Routine addition of carnitine to the HPN regimen does not appear to be necessary. The failure of L-carnitine administration to have discernable effects on intermediary metabolism in normal volunteers casts doubt on its role in the treatment of a variety of medical conditions.

Renal conservation of carnitine by infants and adults: no evidence of developmental regulation

To determine the efficiency of renal conservation of carnitine in infants, urinary carnitine excretion was measured at intervals in 10 infants while plasma carnitine concentration was manipulated by supplementing carnitine-free formula with 0 μM, 140 μM and 280 μM l-carnitine. As carnitine supplementation increased from 0 μM to 280 μM, fractional excretion of free carnitine increased tenfold from 0.6% to 6.0%; fractional excretion of acylcarnitine esters increased to a lesser degree (10.5–15.6%). At all supplementation levels fractional excretion of acylcarnitine esters was significantly greater than fractional excretion of free carnitine. We conclude that free and esterified carnitine are handled differently in the infant kidney. Results in infants were compared to previously reported data for adults. Mean fractional excretions of total, free and esterified carnitine by infants (7.2%, 5.4% and 12.7%, respectively) were similar to those by adults (6.5%, 5.0% and 15.0%). Thus, renal losses of carnitine apparently do not account for the low plasma carnitine concentrations observed in infants fed carnitine-free formulas.

L-Carnitine therapy in home parenteral nutrition patients with abnormal liver tests and low plasma carnitine concentrations

Persistent abnormalities of liver function tests occur in ~15% of home parenteral nutrition (HPN) patients and are associated with steatosis, steatohepatitis, and, rarely, fibrosis or cirrhosis. Approximately one-third of patients with gut failure on long-term HPN have low total and free plasma carnitine concentrations, and it has been suggested that a deficiency of l-carnitine may be responsible for the steatosis and steatohepatitis in HPN patients. To determine whether administration of l-carnitine is capable of reversing steatosis in HPN patients, 4 adult women on HPN for a mean of 53 mo (range 21–80 mo) were studied before and after 1 mo of intravenous l-carnitine supplementation (1 g/day). All patients had abnormalities in standard liver function tests and low total and free plasma carnitine values. The mean total and free plasma carnitine concentrations and the mean total hepatic carnitine concentration were reduced before supplementation and rose to normal values after treatment (27.4 ± 2.3 to 35.5 ± 3.1 nmol/ml, 19.4 ± 2.8 to 25.7 ± 2.5 nmol/ml, and 3.5 ± 0.65 to 6.5 ± 1.2 nmol/mg of noncollagen protein, respectively). However, there were no significant changes in mean serum aspartate aminotransferase and alkaline phosphatase levels (65 ± 21 vs. 54 ± 12 IU and 429 ± 220 vs. 472 ± 224 IU, respectively), plasma free fatty acids, plasma triglycerides, hepatic free fatty acid and triglyceride concentrations, or the grade of hepatic steatosis on light microscopy. These results suggest that carnitine deficiency is not a major cause of steatosis and steatohepatitis in patients receiving HPN.

Plasma carnitine and renal-carnitine clearance during pregnancy

This study assessed the time course of decrease in plasma carnitine during pregnancy and compared the renal clearance of carnitine during late pregnancy with nonpregnant women. As early as the 8th wk of pregnancy, the mean (±SD) value of total plasma-carnitine concentration in 19 women was significantly decreased from 39.0 ± 6.3 to 32.8 ± 4.6 µmol/l and the values continued to fall to 17.3 µmol/1 by the 36th wk. The pattern was due to a fall in free-carnitine level; acylcarnitine remained unchanged. In 12 other women examined during late pregnancy, the renal clearance of acylcarnitine was significantly higher than in nonpregnant women, 53.9 ± 29.4 versus 13.3 ± 3.0 ml/min, in contrast to free carnitine, 3.5 ± 2.8 versus 2.8 ± 1.9 ml/min. Urinary excretion of carnitine (expressed per mol creatinine) did not differ between the two groups. Pregnant women showed sustained excretion of carnitine in the presence of low plasma-carnitine concentrations.