Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common autosomal recessive disorder of mitochondrial fatty acid beta-oxidation that manifests with rapidly progressive metabolic crises.

Beta-oxidation of fatty acids is a metabolic process that provides energy when liver glycogen stores are depleted during prolonged fasting.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) belongs to the group of inborn errors of mitochondrial oxidation and is the most common recessive disorder of fatty acid beta-oxidation. The disease manifests with the onset of rapidly progressive and potentially life-threatening metabolic crises.

MCADD is caused by pathogenic variants in the ACADM gene that affect the medium-chain acyl-CoA dehydrogenase enzyme. This enzyme is essential in beta-oxidation and if altered can lead to toxic accumulation of medium-chain acylcarnitine esters.

MCADD is now included in neonatal screening programs. The prevalence of MCADD in the general population is approximately 5 per 100,000 births and may vary according to the population, being especially prevalent in people from Northern Europe.

Symptoms

Elevated C8-acylcarnitine (octanoylcarnitine) levels in body fluids with slightly increased C6-, and C10-acylcarnitine values.

Metabolic crises present with hypoketotic hypoglycemia, lethargy, vomiting, convulsions and coma, and can be fatal in the absence of urgent medical intervention.

Disease management

The intervention usually performed when a metabolic crisis occurs consists of oral administration of simple carbohydrates to reverse the catabolic process of beta-oxidation and activate anabolism.

To minimize the occurrence of metabolic crises, it is recommended to avoid fasting and to monitor glucose levels in the diet. Frequent meals high in complex carbohydrates, a low-fat diet and avoidance of foods containing oil with a high content of medium chain triglycerides, such as coconut oil, are usually recommended.

Genes analyzed

ACADM

Bibliography

Maier EM, Gersting SW, Kemter KF, et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet. 2009 May 1;18(9):1612-23.

Merritt JL 2nd, Chang IJ. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. 2000 Apr 20 [updated 2019 Jun 27]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.

Sturm M, Herebian D, Mueller M, et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7(9):e45110.