What is the enzyme deficiency characterized by the inability to utilize fatty acids for energy?

From the Guidelines

The enzyme deficiency that causes an inability to utilize fatty acids for energy is most commonly medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, as identified in the acylcarnitine profile analysis study published in Genetics in Medicine 1. This disorder prevents the body from converting fat to energy during periods of fasting or increased energy demands, leading to potentially life-threatening complications. Management strategies include:

• Avoiding prolonged fasting by eating every 3-4 hours during the day and not going more than 10-12 hours overnight without food
• Following a low-fat, high-carbohydrate diet to reduce the reliance on fatty acid oxidation for energy
• Taking L-carnitine supplements, typically 50-100 mg/kg/day divided into 2-3 doses, to help transport fatty acids into the mitochondria for oxidation During illness or periods of low food intake, patients require an emergency protocol involving glucose-containing fluids or IV dextrose to prevent metabolic crisis. These disorders are caused by genetic mutations affecting enzymes in the mitochondrial beta-oxidation pathway, which normally breaks down fatty acids to produce energy, as outlined in the study 1. Without proper enzyme function, toxic intermediates accumulate while the body becomes energy-deficient, potentially leading to hypoglycemia, lethargy, seizures, and even coma if untreated. Early diagnosis through newborn screening and strict adherence to dietary management are essential for preventing life-threatening complications. Other fatty acid oxidation disorders, such as very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, and trifunctional protein (TFP) deficiency, also require similar management strategies to prevent energy deficiency and toxic intermediate accumulation, as discussed in the study 1.

From the FDA Drug Label

It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 μmol/L at one week post term and may be associated with low tissue and/or urine concentrations.

Enzyme deficiency and the inability to utilize fatty acids for energy can be related to carnitine deficiency, as it is required for the transport of fatty acids into the mitochondria for energy production.

• Carnitine deficiency can be caused by inborn errors of metabolism that result in the accumulation of toxic organic acids.
• Levocarnitine may alleviate the metabolic abnormalities of patients with inborn errors that result in the accumulation of toxic organic acids.
• Conditions that have been demonstrated to be affected by levocarnitine include glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency 2.

From the Research

Enzyme Deficiency and Inability to Utilize Fatty Acids for Energy

• Enzyme deficiencies, such as very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, can lead to an inability to utilize fatty acids for energy 3, 4.
• This can result in hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death, particularly during prolonged fasting, infection, or exercise 3.
• Medium-chain acyl-CoA dehydrogenase deficiency is another example of an enzyme deficiency that can cause episodes of coma and hypoketotic hypoglycemia in response to prolonged fasting 5.

Diagnosis and Treatment

• Diagnosis of these enzyme deficiencies can be made through newborn screening, and treatment may involve dietary management, restriction of exercise, and supplementation with L-carnitine 3, 6.
• However, the effectiveness of L-carnitine supplementation can vary depending on the specific enzyme deficiency and the individual patient 5, 7.
• Other treatments, such as triheptanoin and bezafibrate, have shown promise in improving cardiac function and quality of life in patients with fatty acid oxidation disorders 3.

Biochemical Characteristics

• Patients with VLCAD deficiency can be characterized by the accumulation of longer-chain length acylcarnitines, such as hexadecanoylcarnitine and tetradecanoylcarnitine, in their cells 4.
• The plasma level of acyl-carnitine esters, primarily acetyl-carnitine, can increase during diabetic ketoacidosis, fasting, and physical activity, while the plasma concentration of free L-carnitine decreases simultaneously 7.