To understand why fatty acid oxidation disorders (FAODs) are so devastating, we need to first acquaint ourselves with a basic structural overview of the pathological mechanisms that drive this disease.
The mitochondria is the main site for energy production, of which the fatty acids play a significant role. Fatty acid oxidation for the purpose of generating energy is particularly important during periods of stress, such as in hypoglycemia, illness, exercise, and fasting.
Read more about long chain fatty acid oxidation disorder etiology
These fatty acids come from a number of different sources. Some come from the diet, while others are released within the cell via the hydrolysis of triglycerides and phospholipids. In addition, de novo synthesis of fatty acids can occur to meet energy demands.
Upon reaching target cells, long chain fatty acids need specific protein carriers in the plasma membrane to cross inside; among these are fatty acid translocase, fatty acid transport proteins, and fatty acid-binding proteins. In contrast, short-to-medium fatty acids can cross the plasma membrane via passive diffusion; they also cross into the mitochondria the same way.
Long chain fatty acids are converted into acyl-CoA esters upon entering the cell. Here they face the challenge of entering into the mitochondria, as the mitochondrial membrane is impermeable to acyl-CoA esters. Hence, carnitine shuttles are required for acyl-CoA esters to pass through the mitochondrial membrane. It is only after being shuttled into the mitochondrial matrix by these substances that energy production can begin.
Overview of Fatty Acid Oxidation Disorders
Collectively, FAODs represent more than 20 inborn errors of metabolisms. Each is incredibly rare. The common approach to their classification is simply by length: short/medium/long chain FAOD.
As indicated, FAODs are the result of disrupted fatty acid entry into the mitochondria or a defect in mitochondrial energy production. It is most noticeable when the body is under some stressor that causes an acute crisis in energy production. When FAODs are present under these conditions, the body becomes vulnerable to acute hypoketotic hypoglycemia, cardiomyopathy, and myopathy. These can be life-threatening.
Let’s take a closer look at each. In hypoketotic hypoglycemia, patients can experience convulsions. If left untreated, patients can fall into a coma or suffer from brain damage.
In cardiomyopathy, the left ventricular wall can thicken so as to compensate for the deficiency in energy. Pericardial effusion is sometimes present. In long chain FAODs, arrhythmias are commonly observed. Myopathy usually presents itself as muscle weakness, myalgia, or exercise intolerance. Rhabdomyolysis can also occur.
In other words, FAODs can cause sustained damage to the body on multiple fronts; it is considerably more than just an imbalance of energy needs vs supply.
“FAODs are characterized by the accumulation of [acylcarnitines] . . . The accumulation of [acylcarnitines], as well as the respective free [fatty acids], causes lipotoxicity and alters cell homeostasis,” Guerra and colleagues wrote in the International Journal of Molecular Sciences.
“The therapeutic management of FAODs aims to balance the energy deprivation and accumulation of toxic intermediates resulting from these metabolic defects,” Guerra et al wrote.
One of these methods is nutrition management. In long chain FAOD, this means 2 things: ensuring that the patient has adequate nutrients for growth and development, and limiting fat intake. Patients are also recommended to fast for only a maximum of 8 to 10 hours.
Patients should be adequately educated on “sick-day protocols,” a term we use to describe strategies put in place to ensure that the biological stress of falling ill does not cascade into manifestations of FAOD. (This term is likewise used in the management of diabetes.)
“Sick-day protocol can often be implemented at home with increased fluid and caloric intake to prevent catalysis, especially during febrile illnesses,” Vockley wrote in the American Journal of Managed Care.
Read more about long chain fatty acid oxidation disorder treatment
Triheptanoin is a drug that was developed because many patients with long chain FAODs were still symptomatic even with the use of medium chain triglyceride (MCT) oil. Through multiple studies, scientists discovered that triheptanoin can be considered to be a more physiologically balanced MCT, since 2 cycles of FAO are able to produce 2 to 3 carbon intermediates. Early studies indicate that this drug reduces hypoglycemia, cardiomyopathy, and rhabdomyolysis, resulting in fewer acute episodes and hospitalization.
Overall, the current therapeutic strategy for managing long chain FAODs is to be on triheptanoin and some form of dietary restrictions. None of the current or newly proposed treatments for FAODs will be able to eliminate the need for dietary control completely.
Today, researchers and clinicians continue to pursue greater insights into the nature of the lipidomes, enzymes, and transporters associated with this condition. The goal is always to maintain lipid homeostasis and prevent mitochondrial dysfunction. It is also imperative that patients continue to be educated and updated as our understanding of FAODs evolve.
“Patients’ access to educational, financial, and support resources are also clear needs, given the long-term implications and the need for chronic access to the healthcare system,” Vockley wrote.
Vockley J. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. Published online August 14, 2020. doi:10.37765/ajmc.2020.88480
Guerra IMS, Ferreira HB, Melo T, et al. Mitochondrial fatty acid β-oxidation disorders: from disease to lipidomic studies — a critical review. Int J Mol Sci. Published online November 11, 2022. doi:10.3390/ijms232213933