Dataset Information

Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene.

ABSTRACT: Methylmalonyl-coA epimerase (MCE) follows propionyl-coA carboxylase and precedes methylmalonyl-coA mutase in the pathway converting propionyl-coA to succinyl-coA. MCE deficiency has previously been described in six patients, one presenting with metabolic acidosis, the others with nonspecific neurological symptoms or asymptomatic. The clinical significance and biochemical characteristics of this rare condition have been incompletely defined. We now describe a patient who presented acutely at 5 years of age with vomiting, dehydration, confusion, severe metabolic acidosis and mild hyperammonemia. At presentation, organic acid profiles were dominated by increased ketones and 3-hydroxypropionate, with moderately elevated methylcitrate and propionylglycine, and acylcarnitine profiles showed marked C3 (propionylcarnitine) elevation with normal C4DC (methylmalonylcarnitine + succinylcarnitine). Propionic acidemia was initially suspected, but it was subsequently noted that methylmalonic acid was mildly but persistently elevated in urine, and clearly elevated in plasma and cerebrospinal fluid. The overall biochemical profile prompted consideration of MCE deficiency. Studies on cultured fibroblasts showed moderately decreased propionate incorporation. Complementation analysis permitted assignment to the MCEE group. A heterozygous p.Arg47Ter (p.R47*) mutation in the MCEE gene was identified by sequencing of exons, and RNA studies identified a novel intronic splicing mutation, c.379-644A > G, confirming the diagnosis of MCE deficiency. Following the initial severe presentation, development has been normal and the clinical course over the subsequent six years has remained relatively uneventful on an essentially normal diet. This report contributes to the clinical and biochemical characterisation of this rare disorder, while highlighting potential causes of under-diagnosis or of diagnostic confusion.

SUBMITTER: Waters PJ

PROVIDER: S-EPMC5037260 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the <i>MCEE</i> gene.

Waters Paula J PJ Thuriot Fanny F Clarke Joe T R JT Gravel Serge S Watkins David D Rosenblatt David S DS Lévesque Sébastien S

Molecular genetics and metabolism reports 20160924

Methylmalonyl-coA epimerase (MCE) follows propionyl-coA carboxylase and precedes methylmalonyl-coA mutase in the pathway converting propionyl-coA to succinyl-coA. MCE deficiency has previously been described in six patients, one presenting with metabolic acidosis, the others with nonspecific neurological symptoms or asymptomatic. The clinical significance and biochemical characteristics of this rare condition have been incompletely defined. We now describe a patient who presented acutely at 5 ye ...[more]

PMID: 27699154

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Project description:BackgroundPropionic acid is used primarily as a food preservative with smaller applications as a chemical building block for the production of many products including fabrics, cosmetics, drugs, and plastics. Biological production using propionibacteria would be competitive against chemical production through hydrocarboxylation of ethylene if native producers could be engineered to reach near-theoretical yield and good productivity. Unfortunately, engineering propionibacteria has proven very challenging. It has been suggested that activation of the sleeping beauty operon in Escherichia coli is sufficient to achieve propionic acid production. Optimising E. coli production should be much easier than engineering propionibacteria if tolerance issues can be addressed.ResultsPropionic acid is produced in E. coli via the sleeping beauty mutase operon under anaerobic conditions in rich medium via amino acid degradation. We observed that the sbm operon enhances amino acids degradation to propionic acid and allows E. coli to degrade isoleucine. However, we show here that the operon lacks an epimerase reaction that enables propionic acid production in minimal medium containing glucose as the sole carbon source. Production from glucose can be restored by engineering the system with a methylmalonyl-CoA epimerase from Propionibacterium acidipropionici (0.23 ± 0.02 mM). 1-Propanol production was also detected from the promiscuous activity of the native alcohol dehydrogenase (AdhE). We also show that aerobic conditions are favourable for propionic acid production. Finally, we increase titre 65 times using a combination of promoter engineering and process optimisation.ConclusionsThe native sbm operon encodes an incomplete pathway. Production of propionic acid from glucose as sole carbon source is possible when the pathway is complemented with a methylmalonyl-CoA epimerase. Although propionic acid via the restored succinate dissimilation pathway is considered a fermentative process, the engineered pathway was shown to be functional under anaerobic and aerobic conditions.

Dataset Information

Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene.

Publications

Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the <i>MCEE</i> gene.

Similar Datasets

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