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Disclaimer: This article is for informational purposes only and is not intended for diagnostic use. LifeDNA does not provide diagnostic reports on any traits discussed. Genetics is just one piece of the puzzle; please consult a healthcare professional for comprehensive guidance on any health condition.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD deficiency) is a rare genetic disorder that affects the body’s ability to break down medium-chain fatty acids into energy. This condition primarily impacts energy production, especially during prolonged fasting or periods of increased energy demand, such as illness or physical exertion.Â
Medium-chain fatty acids (MCFAs) are a type of saturated fatty acid that contain 6 to 12 carbon atoms. They are found in various food sources and play a critical role in energy production and metabolism. Unlike long-chain fatty acids (LCFAs), MCFAs are more easily digested, absorbed, and utilized by the body for quick energy.
MCFAs are unique compared to short-chain (less than 6 carbons) and long-chain (more than 12 carbons) fatty acids due to their rapid absorption and metabolism. Some key characteristics include:
MCFAs are naturally present in various food sources, including:
The most common MCFAs include:
MCFAs are metabolized through a process called mitochondrial beta-oxidation. In this process fats that enter the body from the diet are converted into usable energy.Â
MCFA metabolism is considered to be more efficient compared to that of LCFAs. This is because MCFAs bypass the lymphatic system and enter the liver quickly through the portal vein. In the liver, they enter the mitochondria without requiring carnitine transport. Inside the mitochondria, MCFAs undergo beta-oxidation. During beta-oxidation MCFAs are sequentially cleaved into acetyl-CoA molecules. Acetyl CoA enters the Krebs cycle and generates ATP, the body’s main energy currency. Additionally, excess acetyl-CoA from MCFAs can be converted into ketones, an alternative fuel source for the brain and muscles, especially during fasting or low-carbohydrate intake.
Understand the Genetics of Saturated Fat Metabolism in more detail
The ACADM gene provides instructions for producing the enzyme medium-chain acyl-CoA dehydrogenase (MCAD). This enzyme plays a crucial role in beta-oxidizing MCFAs in the mitochondria.
When mutations occur in the ACADM gene, the production or function of MCAD enzyme is impaired, preventing the efficient breakdown of medium-chain fatty acids. As a result, individuals with MCAD deficiency experience an accumulation of fatty acid metabolites in the body, leading to metabolic crisis, hypoglycemia (low blood sugar), and potential organ damage if left untreated.
The p.K304E mutation accounts for ~80% of MCADD cases in Northern European populations who are homozygous for it. MCAD enzyme needs a molecule called FAD (flavin adenine dinucleotide) to function properly. Normally, MCAD enzymes group together into four-unit structures (tetramers) to work efficiently. A 2023 study examined 12 different MCAD mutations, including p.K304E and 11 otherrare ones. It found that half of these variants had trouble holding onto FAD, with levels dropping below 65% of normal.
MCAD deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two mutated copies of the ACADM gene, one from each parent, to develop the disorder. Individuals with only one mutated copy are carriers and do not typically show symptoms, but they can pass the mutation to their offspring.
More than 100 mutations in the ACADM gene have been identified, with the most common mutation being the c.985A>G (K304E). Although MCAD deficiency is found only in 1 in 15,000 to 1 in 20,000 births in the whole USA, this specific genetic variant accounts for up to 80% of the cases in individuals of Northern European descent. Other mutations, including frameshift and missense mutations, contribute to the variability in disease severity observed among affected individuals.
Read about another autosomal recessive condition: Cystic Fibrosis
Genetic testing for MCAD deficiency is commonly performed through newborn screening programs in many countries. Screening involves detecting elevated levels of medium-chain fatty acids, particularly octanoylcarnitine (C8), in dried blood spots. Confirmatory diagnosis is done via:
Early diagnosis is crucial in preventing life-threatening metabolic crises, which can occur in infancy or early childhood. Benefits of early diagnosis of MCADD was reinforced by this large 2022 study in ~200,000 new borns in China between 2016 and 2022. Genetic analysis identified four known and four novel ACADM variants. Five children remained asymptomatic with proper dietary management, while one died due to a vaccination-triggered metabolic crisis leading to hypoglycemia and elevated acylcarnitines. The study highlights that genetic screening is essential for early detection, prevention, and improved prognosis of the disorder.
Identifying specific ACADM mutations can help predict disease severity and guide personalized medical management. Some individuals with milder mutations may experience fewer metabolic episodes, while others with severe mutations may have a higher risk of metabolic decompensation.
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A case study published in 2010 follows the clinical history of a female patient. Her metabolic tests showed low urinary hexanoylglycine and suberylglycine, failure to produce ketones after 12 hours of fasting, and low blood carnitine level. This suggested a mitochondrial β-oxidation defect. Enzyme activity analysis confirmed mild MCADD, with octanoyl-CoA dehydrogenase activity reduced to 25% of normal. Other mitochondrial enzymes remained functional. Genetic testing revealed compound heterozygosity with the common c.985A>G (p.K304E) mutation and a novel c.145C>G (p.Q24E) mutation in the ACADM gene, marking the first report of this variant. This case shows that mild MCADD phenotypes, despite retaining some enzyme activity and showing low glycine conjugate excretion, can still lead to metabolic crises, reinforcing the need for early diagnosis and management.Â
Carrier screening for at-risk populations, especially among those of Northern European descent, can help prospective parents make informed reproductive decisions. Genetic counseling is recommended for families with a history of MCAD deficiency.
MCAD deficiency is a genetic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid metabolism. Understanding its genetic basis has improved early detection, newborn screening, and personalized treatment strategies. With proper management, individuals with MCAD deficiency can lead healthy lives by following dietary recommendations and avoiding prolonged fasting. Advances in genetic research continue to enhance our knowledge of this condition, offering hope for improved interventions in the future.
