Why is l carnitine a treatment for mcad

It is not clear to what extent skeletal muscle is affected in patients with medium-chain acyl—coenzyme A dehydrogenase deficiency MCADD. We investigated 1 fuel utilization during prolonged low-intensity exercise in patients with MCADD and 2 the influence of 4 weeks of oral l -carnitine supplementation on fuel utilization during exercise.

Four asymptomatic patients with MCADD and 11 untrained, healthy, age- and sex-matched control subjects were included. At rest, palmitate oxidation and total fatty acid oxidation FAO rates were similar in patients and healthy control subjects.

Palmitate oxidation and FAO rates were unchanged by the l -carnitine supplementation. Our results indicate that patients with MCADD have an impaired ability to increase FAO during exercise but less so than that observed in patients with a number of other disorders of fat oxidation, which explains the milder skeletal muscle phenotype in MCADD.

Medium-chain acyl—coenzyme A CoA dehydrogenase deficiency MCADD is the most common inborn error of fatty acid metabolism 1 , with a prevalence of 1 per 10 in Denmark and many European countries 1 , 2. The disease is autosomal recessively inherited and causes impaired mitochondrial oxidation of fatty acids of medium-chain length C6—C Typically, patients are asymptomatic until the demand for fatty acid oxidation FAO is increased, eg, during fasting or illness or after alcohol consumption.

Patients usually present in childhood with acute episodes of hypoketotic hypoglycemia and symptoms of lethargy, vomiting, encephalopathy, coma, and respiratory arrest 3 , 4. To avoid metabolic crises, patients with MCADD should avoid prolonged fasting and be cautious during illness and other stressful situations such as during anesthesia 5 , 6 , but there is no known effective therapy for MCADD.

If the preceding measures are taken, patients with MCADD may live near-normal lives, tolerate exercise 7 , 8 and up to 14 hours of fasting 6 , and have normal gluconeogenesis 9 and ketone body production during short-term fasting Most patients become symptomatic during infancy, and MCADD has been included in newborn screening programs in many countries, which has reduced the number of patients presenting with metabolic crises and neurological sequelae 1 , 3 , When treated, the disease has a benign course.

However, long-term follow-up studies have revealed more chronic complaints in terms of fatigue and frequent hospitalizations 3 , 12 , and whether MCADD is clearly a liver FAO disorder or whether skeletal muscle is involved as well has been discussed. The aim of this study was to investigate skeletal muscle fat and carbohydrate metabolism in patients with MCADD at rest and during prolonged moderate-intensity exercise, during which fat oxidation is the dominating energy source for contracting muscle Fat and carbohydrate metabolism was assessed by the stable isotope technique and indirect calorimetry.

Furthermore, we investigated the effect of 4 weeks of l -carnitine supplementation on physical performance along with fat and carbohydrate metabolism.

Four unrelated patients with MCADD and 11 healthy age- and sex-matched subjects aged 19—32 years were investigated Table 1. In all patients the classic symptoms of metabolic decompensation during periods of simple infections had been diagnosed in childhood. Since diagnosis, patients have occasionally experienced hypoglycemia, but this was managed, and severe metabolic decompensation was avoided.

The severity of symptoms did not differ among patients. All patients were asymptomatic at the time of the trial.

Three patients were homozygous for the c. They had no history of rhabdomyolysis, and 2 of the subjects exercised on a regular basis. Abbreviations: CON, healthy control subjects; F, female; Glucose max , maximal glucose concentration; Lactate max , maximal plasma lactate concentration; M, male; P, patients; W constant load , constant workload during cycling. One patient used l -carnitine for periods of 4 to 6 weeks after episodes of illness and had done so since childhood.

The other patients had only rarely taken l -carnitine in the past. None of the 4 patients had taken l -carnitine within the past year. The Regional Ethics Committee approved the study no. The trial was conducted in accordance with the Declaration of Helsinki. The subjects gave written and oral informed consent before inclusion.

After an overnight fast, the subjects performed an incremental exercise cycling test to exhaustion on a cycle ergometer E; Monark, Vansbro, Sweden to determine maximal workload capacity W max and maximal oxidative capacity V o 2max.

Pulmonary gas exchange was measured continuously with breath-by-breath indirect calorimetry Cosmed Quark b 2 ; Cosmed Srl, Milan, Italy. All subjects refrained from taking l -carnitine for 4 weeks before the tests and were instructed to eat meals rich in carbohydrate 3 times a day and avoid strenuous exercise for 3 days before testing. After an overnight fast, subjects arrived at the laboratory at hours.

One catheter was inserted in a cubital vein for isotope infusion and another one in the distal cephalic vein in the contralateral arm for drawing blood. A heating pad was wrapped around the wrist and hand to arterialize the venous blood to be sampled A resting blood sample was taken, and a resting breath sample was collected in a Vacutainer before infusion of the stable isotopes.

A single priming dose of Na 13H CO 3 0. The tracer solutions were prepared as described previously Tracers were infused continuously during the whole experimental trial. At the onset of exercise, the infusion rates of all tracer solutions were doubled. Heart rate HR and scores of perceived exhaustion Borg score were monitored every second minute during exercise.

From 20 minutes before exercise onset and during the exercise period, samples of blood and expired air were collected every 10 minutes.

Samples were taken for measurements of isotopes, various hormones, and metabolites in blood, as described below. Before, during, and after cycling, additional blood samples were drawn for analyses of acylcarnitines and free carnitine content. V o 2 and V co 2 were measured between blood sampling, using indirect calorimetry.

Compliance was assessed by counting returned bottles and measuring plasma carnitine concentrations. Blood to measure O 2 content was sampled in syringes containing heparin and measured on an ABL system Radiometer, Copenhagen, Denmark. KG, Nordhorn, Germany. Plasma palmitate and 13 CO 2 breath enrichment were analyzed by gas chromatography isotope ratio—mass spectrometry Thermo Finnigan MAT. Analyses of acylcarnitines and carnitine in plasma and muscle were performed with ultra-performance liquid chromatography—tandem mass spectrometry, using a Quattro Micro triple quadrupole mass spectrometer Waters, Milford, Massachusetts.

Carnitine and acylcarnitines were quantified using external spiked plasma calibration curves. Whole-body oxidation rates of carbohydrate and fat were calculated using a nonprotein respiratory quotient Whole-body palmitate production, rate of appearance R a , and utilization, rate of disappearance R d , were calculated using the Steele non—steady-state equation for stable isotopes 17 , Whole-body plasma palmitate oxidation R ox was calculated considering a acetate correction factor as described by van Loon et al Differences between groups were assessed by the nonparametric Mann-Whitney rank sum test.

A paired comparison, using nonparametric analysis Wilcoxon signed rank test , will never reach significance levels with only 4 observations in the patient group. The comparison between rest vs exercise and treatment vs no treatment has therefore been described qualitatively for patients. Mean value within each group is indicated by a horizontal line —. Abbreviations: FFA, free fatty acids; Palmitate R a , palmitate rate of appearance; Glucose R a , glucose rate of appearance; Glucose R d , glucose rate of dissappearance.

Exercise values are a mean of the last 10 minutes of 60 minutes of moderate-intensity cycling exercise. At rest, palmitate oxidation rates were similar in patients and healthy control subjects Figure 1 B. Guidance should be given to parents who are overfeeding because they fear fasting-induced hypoglycemia, or are underfeeding because they are over-restricting dietary fats. Some clinics instruct parents to measure blood glucose levels at the end of the longest recommended sleeping interval to determine if the infant needs to be awakened earlier for a feeding.

These measurements can also provide a baseline glucose measurement for an individuaI that can be helpful when evaluating glucose measurements during illness. Some clinics also recommend checking a glucose level when the infant or young child seems unusually sleepy, is difficult to awaken or is uninterested in eating, but without any other signs of illness.

If home glucose monitoring is desired, a glucometer sensitive to low blood glucose concentrations should be chosen. Labratory testing: After the initial confirmatory testing has been done, the only routine laboratory measurement needed is blood carntine which gives total carnitine, free carnitine and acyl carnitine. Individuals who are on supplemental carnitine should have periodic assessment of their free carnitine. There is no evidence to support the necessity of repeating either the acyl carnitine profile or the urine organic acid analysis.

Dietary assessment: Diet records should be assessed at each clinic visit. The factors to assess include: adherence to the dietary guidelines for MCADD above ; appropriate spacing of meals and snacks; and approriate nutrient intake for age and weight.

The intervention strategies for illness should be the most emphasized aspect of counseling for the MCADD individual and his caretakers. At home care: At home care for an ill MCADD individual is possible only if fasting can be avoided by providing adequate oral carbohydrate and fluid. Although rehydration fluids such as Pedialyte are extremely useful for ill infants and children without MCADD, the solution, when used exclusively, does not contain adequate glucose to maintain blood glucose levels in an ill MCADD infant or child.

Ill infants and children should be awakened during the night for feeding and assessing their condition. Carbohydrate-containing oral rehydration may allow return to regular oral intake. NOTE: Low blood glucose levels may not develop until later in an illness.

It should be emphasized that emergency care must be initiated if symptoms are present. Caregivers should not rely solely on the blood glucose levels to initiate care. Oral glucose: The use of a concentrated oral glucose source see above may be lifesaving while awaiting emergency care.

This can be rubbed, at frequent intervals, on the inside of the cheeks and under the tongue, even if the individual is non-responsive. Because not all hospitals have IV carnitine available, it may be possible to continue to give liquid carnitine orally since only small volumes are typically needed.

Many recommend doubling the oral carnitine dosage during illness. Length of stay: Discharge from the medical facility should not occur until the MCADD individual is able to consume sufficient oral intake to maintain normaglycemia. The incorporation of L-carnitine in the intracellular pool was demonstrated using stable isotopes and mass spectrometry.

Increasing doses of either i. L-carnitine or acetyl-L-carnitine did not stimulate the excretion of octanoylcarnitine in the patient with medium-chain acyl-CoA dehydrogenase deficiency, nor did it raise the plasma levels of either cis decenoate or octanoylcarnitine.

Similarly, increasing doses of either i. L-carnitine or acetyl-L-carnitine did not enhance the excretion of isovalerylcarnitine in a patient with isovaleric acidemia. The excretion of isovalerylglycine actually decreased. Because only one individual with each disorder was studied, the data are only indicative and may not necessarily be representative of all individuals with these disorders. Definite settlement of this issue will require further studies in additional subjects. You can also search for this author in PubMed Google Scholar.

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