Abstract
BackgroundPropionic acidemia is an inborn error of metabolism caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase that converts the propionyl CoA to methyl malonyl CoA. This leads to profound changes in distinct metabolic pathways, including the urea cycle, with consequences in ammonia detoxification. The implication of the tricarboxylic acid cycle is less well known, but its repercussions could explain both some of the acute and long-term symptoms of this disease.Materials and methodsThe present observational study investigates the amino acid profiles of patients with propionic acidemia being monitored at the Hospital Ramón y Cajal (Madrid, Spain), between January 2015 and September 2017, comparing periods of metabolic stability with those of decompensation with ketosis and/or hyperammonemia.ResultsThe concentrations of 19 amino acids were determined in 188 samples provided by 10 patients. We identified 40 metabolic decompensation episodes (22 only with ketosis and 18 with hyperammonemia). Plasma glutamine and alanine levels were reduced during these metabolic crises, probably indicating deficiency of anaplerosis (p < 0.001 for both alanine and glutamine). Hypocitrulllinemia and hypoprolinemia were also detected during hyperammonemia (p < 0.001 and 0.03, respectively).ConclusionsThe amino acid profile detected during decompensation episodes suggests deficient anaplerosis from propionyl-CoA and its precursors, with implications in other metabolic pathways like synthesis of urea cycle amino acids and ammonia detoxification.
Highlights
Propionic acidemia (PA; MIM #606054) is an inherited autosomic recessive metabolic disease caused by a deficiency in the propionyl-CoA carboxylase, a mitochondrial enzyme that transforms propionyl-CoA into methyl malonyl-CoA which later enters the tricarboxylic acid (TCA) cycle after its conversion to succinyl-CoA by the methyl malonyl-CoA mutase
It has been proposed that the main factor is that the accumulation of propionyl-CoA inhibits the enzyme N-acetylglutamate synthetase (NAGS) which catalyzes the formation of N-acetyl glutamate (NAG) needed to activate carbamoyl phosphate synthetase 1 (CPS1), a key mitochondrial enzyme in starting the urea cycle (Dercksen et al 2014)
Samples corresponded to 148 periods of metabolic stability, and 40 decompensation episodes (22 with only ketosis and 18 had hyperammonemia)
Summary
Propionic acidemia (PA; MIM #606054) is an inherited autosomic recessive metabolic disease caused by a deficiency in the propionyl-CoA carboxylase, a mitochondrial enzyme that transforms propionyl-CoA into methyl malonyl-CoA which later enters the tricarboxylic acid (TCA) cycle after its conversion to succinyl-CoA by the methyl malonyl-CoA mutase. Propionic acidemia is an inborn error of metabolism caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase that converts the propionyl CoA to methyl malonyl CoA. This leads to profound changes in distinct metabolic pathways, including the urea cycle, with consequences in ammonia detoxification. Materials and methods The present observational study investigates the amino acid profiles of patients with propionic acidemia being monitored at the Hospital Ramón y Cajal (Madrid, Spain), between January 2015 and September 2017, comparing periods of metabolic stability with those of decompensation with ketosis and/or hyperammonemia. Conclusions The amino acid profile detected during decompensation episodes suggests deficient anaplerosis from propionylCoA and its precursors, with implications in other metabolic pathways like synthesis of urea cycle amino acids and ammonia detoxification
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