MCEE – Methylmalonic Acidemia due to Methylmalonyl-CoA Epimerase Deficiency

Methylmalonyl-CoA epimerase (MCEE) deficiency is an autosomal recessive metabolic disorder characterized by mild to intermittent methylmalonic acidemia with episodic metabolic acidosis and normal homocysteine levels. Newborn screening (NBS) may reveal elevated propionylcarnitine (C3) and 2-methylcitric acid (MCA) with normal methylmalonic acid (MMA) and homocysteine, prompting targeted enzymatic and genetic testing. A first reported NBS case identified a homozygous nonsense variant c.139C>T (p.Arg47Ter) in exon 2 of MCEE, confirming methylmalonyl-CoA epimerase deficiency in a neonate with C3 and MCA elevations (PMID:39051409).

Subsequent single-patient descriptions include a 5-year-old with severe metabolic acidosis, hyperammonemia, and fibroblast studies showing decreased propionate incorporation; genetic analysis revealed compound heterozygosity for p.Arg47Ter and an intronic splice mutation c.379-644A>G (PMID:27699154). An additional case presenting with acute acidosis mimicking propionic acidemia harbored homozygous c.139C>T (p.Arg47Ter) with intermittent MMA excretion (PMID:29104221).

A multi-patient cohort of 150 individuals with unexplained methylmalonic aciduria identified ten new patients harboring MCEE variants: nine homozygous for the common nonsense allele c.139C>T (p.Arg47Ter) and one with a novel missense change c.158T>G (p.Ile53Arg) (PMID:30682498). In total, eleven unrelated probands have been described across four studies, establishing a consistent autosomal recessive inheritance and variant spectrum.

The variant spectrum includes nonsense (c.139C>T (p.Arg47Ter)), frameshift (c.102_105dup (p.Asp36fs)), missense (c.158T>G (p.Ile53Arg)), and intronic splice variants (c.379-644A>G). The recurrent founder variant p.Arg47Ter accounts for the majority of alleles, suggesting population-specific enrichment. No large structural or deep-intronic variants have been reported to date.

Functional assessments in patient fibroblasts demonstrated moderately reduced propionate incorporation, while recombinant expression of p.Ile53Arg yielded virtually undetectable soluble protein and absent enzymatic activity. Structural mapping of p.Ile53Arg and p.Arg143Cys onto a 1.8 Å human MCEE model revealed disrupted dimer interfaces and active-site conformations, consistent with protein misfolding and loss of function ([PMID:30682498]).

Collectively, biallelic loss-of-function variants in MCEE cause methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency via a recessive mechanism. Elevated C3 and MCA on NBS with normal initial MMA should prompt consideration of MCEE deficiency, confirmed by genetic testing. Key take-home: MCEE deficiency is a clinically actionable autosomal recessive disorder with a well-defined variant and functional profile, supporting reliable diagnosis and management.

References

• International journal of neonatal screening • 2024 • Biochemical Pattern of Methylmalonyl-CoA Epimerase Deficiency Identified in Newborn Screening: A Case Report. PMID:39051409
• Molecular genetics and metabolism reports • 2016 • Methylmalonyl-coA epimerase deficiency: A new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene. PMID:27699154
• International journal of molecular sciences • 2017 • Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria. PMID:29104221
• Biochimica et biophysica acta. Molecular basis of disease • 2019 • Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. PMID:30682498

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