title: Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in theMCEEgene.
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 theMCEEgroup. A heterozygous p.Arg47Ter (p.R47*) mutation in theMCEEgene 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.
authors.affiliation: Medical Genetics Service, Department of Pediatrics, Centre hospitalier universitaire de Sherbrooke (CHUS) and University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Waters
authors.affiliation: Medical Genetics Service, Department of Pediatrics, Centre hospitalier universitaire de Sherbrooke (CHUS) and University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Thuriot
authors.affiliation: Medical Genetics Service, Department of Pediatrics, Centre hospitalier universitaire de Sherbrooke (CHUS) and University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.affiliation: Medical Genetics Service, Department of Pediatrics, Centre hospitalier universitaire de Sherbrooke (CHUS) and University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gravel
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Medical Genetics Service, Department of Pediatrics, Centre hospitalier universitaire de Sherbrooke (CHUS) and University of Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lévesque
keywords: C3, C3, (= propionyl) carnitine; C4DC, C4dicarboxyl (= methylmalonyl + succinyl) carnitine; CSF, cerebrospinal fluid; Complementation analysis; Intronic mutation; MCE, methylmalonyl-coA epimerase; MCEE, gene encoding methylmalonyl-coA epimerase; MMA, methylmalonic acid or methylmalonate; MUT, methylmalonyl-coA mutase; Methylmalonic aciduria; Methylmalonyl-coA epimerase; Methylmalonyl-coA racemase; PCC, propionyl-coA carboxylase; Propionic aciduria; Splicing mutation