Medium-chain Acyl-COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment

Abstract

Introduction: Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is the most common inherited metabolic disorder of β-oxidation. Patients with MCADD present with hypoketotic hypoglycemia, which may quickly progress to lethargy, coma, and death. Prognosis for MCADD patients is highly promising once a diagnosis has been established, though management strategies may vary depending on the severity of illness and the presence of comorbidities.

Methods and results: Given the rapid developments in the world of gene therapy and implementation of newborn screening for inherited metabolic disorders, the provision of concise and contemporary knowledge of MCADD is essential for clinicians to effectively manage patients. Thus, this review aims to consolidate current information for physicians on the pathogenesis, diagnostic tools, and treatment options for MCADD patients.

Conclusion: MCADD is a commonly inherited metabolic disease with serious implications for health outcomes, particularly in children, that may be successfully managed with proper intervention.

Keywords: dietary management; fatty acids; medium-chain Acyl-CoA dehydrogenase; metabolic myopathy; β-Oxidation.

FIGURE 1

Beta‐Oxidation & its relation to MCADD. The metabolic pathway of MCFA oxidation is depicted including absorption, carnitine transport into the mitochondrial matrix, and ß‐oxidation. The normal activity of MCAD is bolded, and impact of MCAD deficiency indicated with a red box.

FIGURE 2

Signs and Symptoms of MCADD. The clinical presentation of MCAD deficiency is described along with the organ system most heavily impacted by each observed symptom.

FIGURE 3

Mechanism of MCADD‐related patient decomposition. Physiological impact of MCADD on patient metabolism is indicated. Direct impacts of MCAD deficiency are indicated with red arrows.

FIGURE 4

Genetic mutations of ACADM gene resulting in MCAD Protein Misfolding. (A) Normal protein structure of MCADD. The location of the ACADM gene is indicated on Chromosome 1 with a red line. The MCAD protein is depicted in blue, in complex with the electron transport chain (ETC). (B) Location, protein misfolding, and inheritance of K329E mutation. The structure of the MCAD protein harbouring the K329E mutation is depicted. The autosomal recessive inheritance pattern of the mutation is depicted in a pedigree chart on the right.