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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


MCEE mutations in the affected patient. The three coding exons are numbered and an additional 96 bp putative untranslated exon is shown between exons 2 and 3. (A) Normal splicing is shown (in blue). Aberrant splicing (shown in red) is caused by a mutation located 4 bp preceding the 3′ end of the untranslated exon, which creates a strong consensus splice site resulting in a 92 bp fragment inserted between exons 2 and 3. The positions of the two mutations identified in the patients are localised by arrows. (B) Gene products: two abnormal transcripts identified in the patient. The predicted translation of each is also shown. (C) The mutation p.Arg47Ter was validated by Sanger sequencing. It causes a premature stop codon. (D) The mutation c.379–644 A > G was validated by Sanger sequencing. It causes an aberrant splicing.
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f0010: MCEE mutations in the affected patient. The three coding exons are numbered and an additional 96 bp putative untranslated exon is shown between exons 2 and 3. (A) Normal splicing is shown (in blue). Aberrant splicing (shown in red) is caused by a mutation located 4 bp preceding the 3′ end of the untranslated exon, which creates a strong consensus splice site resulting in a 92 bp fragment inserted between exons 2 and 3. The positions of the two mutations identified in the patients are localised by arrows. (B) Gene products: two abnormal transcripts identified in the patient. The predicted translation of each is also shown. (C) The mutation p.Arg47Ter was validated by Sanger sequencing. It causes a premature stop codon. (D) The mutation c.379–644 A > G was validated by Sanger sequencing. It causes an aberrant splicing.

Mentions: Extracted DNA from blood was sequenced to screen for mutations in the three coding exons and splice site junctions of MCEE, by the Sanger method using a 3730XL DNA analyzer (Applied Biosystems), at the McGill University and Genome Quebec Innovation Center. A heterozygous variant (c.139C > T, p.Arg47Ter, Refseq NM_032601.3) was found in exon 2 (Fig. 2). This mutation was previously reported in the homozygous state in several unrelated patients with MCE deficiency, as described above in the Introduction. Deletion/duplication analysis by exon array (MitoMet V3.0 oligonucleotide microarray, performed by BCM Medical Genetics Laboratories) yielded normal results.


Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene
MCEE mutations in the affected patient. The three coding exons are numbered and an additional 96 bp putative untranslated exon is shown between exons 2 and 3. (A) Normal splicing is shown (in blue). Aberrant splicing (shown in red) is caused by a mutation located 4 bp preceding the 3′ end of the untranslated exon, which creates a strong consensus splice site resulting in a 92 bp fragment inserted between exons 2 and 3. The positions of the two mutations identified in the patients are localised by arrows. (B) Gene products: two abnormal transcripts identified in the patient. The predicted translation of each is also shown. (C) The mutation p.Arg47Ter was validated by Sanger sequencing. It causes a premature stop codon. (D) The mutation c.379–644 A > G was validated by Sanger sequencing. It causes an aberrant splicing.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037260&req=5

f0010: MCEE mutations in the affected patient. The three coding exons are numbered and an additional 96 bp putative untranslated exon is shown between exons 2 and 3. (A) Normal splicing is shown (in blue). Aberrant splicing (shown in red) is caused by a mutation located 4 bp preceding the 3′ end of the untranslated exon, which creates a strong consensus splice site resulting in a 92 bp fragment inserted between exons 2 and 3. The positions of the two mutations identified in the patients are localised by arrows. (B) Gene products: two abnormal transcripts identified in the patient. The predicted translation of each is also shown. (C) The mutation p.Arg47Ter was validated by Sanger sequencing. It causes a premature stop codon. (D) The mutation c.379–644 A > G was validated by Sanger sequencing. It causes an aberrant splicing.
Mentions: Extracted DNA from blood was sequenced to screen for mutations in the three coding exons and splice site junctions of MCEE, by the Sanger method using a 3730XL DNA analyzer (Applied Biosystems), at the McGill University and Genome Quebec Innovation Center. A heterozygous variant (c.139C > T, p.Arg47Ter, Refseq NM_032601.3) was found in exon 2 (Fig. 2). This mutation was previously reported in the homozygous state in several unrelated patients with MCE deficiency, as described above in the Introduction. Deletion/duplication analysis by exon array (MitoMet V3.0 oligonucleotide microarray, performed by BCM Medical Genetics Laboratories) yielded normal results.

View Article: PubMed Central - PubMed

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.

No MeSH data available.