Why is L-carnitine used for Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency?

From the Guidelines

Carnitine is used in Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency to help transport fatty acids into mitochondria for energy production. This is because carnitine plays a crucial role in fatty acid metabolism, acting as a carrier molecule that transports long-chain fatty acids from the cytosol across the outer and inner membranes of the mitochondrial matrix for β-oxidation, i.e., for energy generation 1. In MCAD deficiency, the body cannot properly break down medium-chain fatty acids, leading to energy shortages and potentially dangerous metabolic crises.

• Supplemental L-carnitine helps prevent carnitine deficiency that can occur in this condition and assists with removing toxic metabolites that build up during metabolic stress.
• The primary role of carnitine in fatty acid metabolism makes it an essential component of the treatment approach for MCAD deficiency, as it supports overall metabolic function and helps prevent complications, especially during illness or fasting when the body needs to rely more on fat metabolism 1.
• While carnitine doesn't fix the underlying enzyme defect, its supplementation is usually part of a comprehensive treatment approach that also includes avoiding fasting, following a specific diet, and having an emergency protocol for illness.
• Regular monitoring of carnitine levels in the blood helps ensure appropriate dosing, which is typically 100-200 mg/kg/day divided into 2-3 doses.
• It is worth noting that healthy individuals, including strict vegetarians, synthesize enough L-carnitine in vivo not to require supplementation 1, but in the case of MCAD deficiency, supplemental carnitine is necessary to support metabolic function.

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. Conditions for which this effect has been demonstrated are: ... medium chain fatty acylCoA dehydrogenase deficiency. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted

Carnitine is used for Medium Chain Acyl-CoA Dehydrogenase (MCAD) deficiency because it helps to:

• Facilitate the entry of long-chain fatty acids into cellular mitochondria for energy production
• Clear acylCoA compounds by forming acylcarnitine, which is then quickly excreted, thereby alleviating the accumulation of toxic organic acids and preventing acidosis 2

From the Research

Carnitine Use in MCAD Deficiency

• Carnitine is used in the treatment of Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, a disorder of fatty acid beta-oxidation, due to its potential to prevent the accumulation of toxic medium-chain fatty acid metabolites 3.
• MCAD deficiency is characterized by episodes of coma and hypoketotic hypoglycemia in response to prolonged fasting, and secondary carnitine deficiency has been documented in these patients 3.
• The use of L-carnitine supplementation in MCAD deficiency is controversial, with some studies suggesting it may promote clearance of accumulating acylcarnitines during exercise 4, while others have found no apparent beneficial effect on clinical and biochemical parameters 4, 5.

Mechanism of Action

• L-carnitine supplementation may help to remove accumulating acyl moieties, improving intramitochondrial homeostasis and potentially improving exercise tolerance in MCAD-deficient patients 6.
• However, some studies have found that MCAD patients are able to increase carnitine biosynthesis during exercise to compensate for carnitine losses, suggesting that L-carnitine supplementation may not be necessary 4.

Clinical Evidence

• A study of 93 persons with MCAD deficiency found that secondary carnitine deficiency was unrelated to the frequency and duration of acute unscheduled preventive hospital visits, and that carnitine supplementation did not reduce the risk of fatigue, muscle ache, or exercise intolerance 5.
• Another study found that serum free carnitine concentrations decreased during acute attacks of Reye-like illness in a patient with MCAD deficiency, and took up to 25 days to normalize after treatment 7.