malonyl-coenzyme-a and propionylcarnitine

Methyl malonic academia (MMA) is characterized by abnormal accumulation of methyl malonic acid in body fluids. Patients usually have a variety of clinical symptoms including recurrent vomiting, metabolic acidosis, developmental delay, seizure, or death. However, a few cases where the patients have no symptom are also reported. Here, we conducted clinical, biochemical, and molecular analysis of eight Chinese patients identified through newborn screening between 2003 and 2013. All the patients had significantly higher blood propionylcarnitine (C3) concentrations, ratio of propionylcarnitine/acetylcarnitine (C3/C2); and their urine methyl malonic acid and methylcitric acid (MCA) excretions were remarkably higher than normal at diagnosis and during follow-ups. In addition, five different known mutations were identified in seven of the eight patients in either MUT or MMACHC. All these mutations were expected to produce defective proteins that would result in decreased or even total loss of methyl malonyl-CoA mutase activity. However, normal outcomes were found in all patients in physical growth, intellectual performance and cerebral MRI analysis at diagnosis (range, 14-53 days) and during follow-ups (range, 1.8-10 years). Our study is the first report of Chinese MMA patients with increased secretion of methyl malonic acid and molecular defects in MUT or MMACHC yet remain asymptomatic.

Topics: Acetylcarnitine; Acidosis; Asian People; Asymptomatic Diseases; Carboxy-Lyases; Carnitine; Carrier Proteins; Child; Citrates; Female; Gene Expression; Humans; Infant; Infant, Newborn; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mutation; Neonatal Screening; Oxidoreductases

Although propionyl L-carnitine improves contractile function of hypertrophied rat hearts, the mechanism(s) by which it does this are not known. One postulated mechanism is that propionyl L-carnitine reverses the alterations in energy metabolism that occur secondary to the carnitine deficiency seen in hypertrophied myocardium. This study determined the effects of chronic propionyl L-carnitine administration on myocardial carnitine content and energy metabolism in hypertrophic hearts from male Wistar Kyoto rats. Pressure-overload hypertrophy was produced by constriction of the abdominal aorta in juvenile rats. Propionyl L-carnitine was administered to the rats via the drinking water for an 8 week period (60 mg.kg(-1).day-1). Myocardial function and metabolic analysis was determined in isolated working hearts obtained from aortic-banded and sham-operated (control) animals at the end of the 8 week study period. Carnitine content was significantly decreased in hypertrophied hearts compared to control hearts, but was normalized by propionyl L-carnitine treatment. Propionyl L-carnitine treatment also prevented the decrease in cardiac work that occurred in hypertrophied hearts compared to control hearts. The primary change in energy substrate use in hypertrophied hearts was a decrease in fatty acid oxidation rates. Glucose and lactate oxidation were similar in control and hypertrophied hearts. While glycolytic rates were slightly higher at moderate workloads, this was not seen at high workloads. Surprisingly, propionyl L-carnitine treatment did not reverse the depression of fatty acid oxidation seen in hypertrophied rat hearts. In fact, a further significant decrease in fatty acid oxidation occurred, such that the contribution of fatty acid oxidation to ATP production decreased from 35 to 26%. Since propionyl L-carnitine treatment increased cardiac work in hypertrophied hearts despite an overall decrease in ATP production rates, an increase in cardiac efficiency was seen. In treated vs. untreated hypertrophied hearts efficiency (cardiac work/ATP produced) increased from 0.23 to 0.40 ml.mm Hg.mumol ATP-1.g dry weight at high workloads. These data suggest that the beneficial effect of propionyl L-carnitine on mechanical function in the hypertrophied heart does not result from a normalization of fatty acid oxidation, but rather from an increase in the efficiency of translating ATP production into cardiac work.

Topics: Acetyl Coenzyme A; Acyl Coenzyme A; Adenosine Triphosphate; Animals; Cardiomegaly; Cardiotonic Agents; Carnitine; Heart; In Vitro Techniques; Male; Malonyl Coenzyme A; Myocardium; Rats; Rats, Inbred WKY