Long chain fatty acid oxidation disorder (LCFAOD) is a rare and life-threatening disease that is inherited in an autosomal recessive manner. It impairs the body’s production of energy, which leads to chronic energy insufficiency and injury to the organs that depend on it.
Although LCFAOD is screened for in newborns, current management strategies still too frequently lead to acute crises that require hospital stays. The current approach to LCFAOD is to avoid fasting and take supplements of medium-chain triglyceride (MCT) oil. The race is on for the discovery of more effective treatments that can give patients a relatively normal life with predictable disease outcomes, such as in the case of diabetes.
Read more about LCFAOD etiology
A study published in The American Journal of Managed Care reviewed the current scientific literature around LCFAOD. This article is a summary of some of its findings in terms of current LCFAOD management strategies.
The Impact of Energy Deficiency
LCFAOD impairs energy production in the body because fatty acids are a massive source of energy for the body. A lack of fatty acids impairs ketone synthesis, thus depriving the body of an alternative source of energy when glucose is unavailable. Glucose reserves tend to be used up during times of physiological stress or fasting. Without an alternative source of energy, organs such as the brain, kidney, and heart experience injury.
“Fatty acid oxidation disorders (FAODs) are a group of more than 20 life-threatening, inborn errors of metabolism caused by either disruption of entry of fatty acid substrates into mitochondria or a defect in their β-oxidation in the mitochondrial matrix,” wrote the author of this study. It is associated with significant morbidity and mortality, driven mainly by acute episodes of energy deficiency.
Read more about LCFAOD epidemiology
This disease has an incidence of about 1 in every 9300 individuals globally. Newborn screening of this disease has led to significantly better patient outcomes; before newborn screening was available, mortality was approximately 60% to 90%. Although that figure has been reduced, LCFAOD still overwhelmingly impacts patients’ quality of life in a negative way.
LCFAOD is commonly associated with:
- Hypoketotic hypoglycemia
- Skeletal myopathy
Current Management Strategies
Treatments for LCFAOD have been centered on nutritional and symptomatic management. With regards to nutritional management, the goal is to “limit long-chain fat as a substrate for energy production, both by preventing β-oxidation and catabolism and by restricting the amount of dietary long-chain fat while still providing adequate nutrients for normal growth and development,” wrote study author Jerry Vockley, MD, PhD.
As part of this strategy, breastfeeding in infants may need to be halted because breast milk is known to be high in fat. Where possible, mothers should consider supplementing pumped breast milk with a metabolic formula containing medium-chain triglycerides (MCT), or alternate breastfeeding with metabolic formula. These formulas are usually prescribed by physicians for infants with LCFAOD.
For children and adults, the nutritional strategy should be to limit calories from fat to 30% to 35% of total energy consumed. Patients with severe LCFAOD may need to further limit their long-chain fat intake to just 10% of total energy and use MCT for their remaining energy requirements. Needless to say, severe dietary restrictions such as this can be difficult to maintain, and leeway to 20% is often allowed.
MCT that is prescribed usually comes in the form of pure trioctanoylglycerol. Although MCT oil is generally well-tolerated, older adults may experience side effects, such as diarrhea, flatulence, and abdominal bloating. In the cases of gastrointestinal intolerance, patients are recommended to not exceed 4-7 tablespoons per day (60-100 ml/day).
The proper way to take MCT is to divide the daily dosage equally between meals. MCT can also be mixed into and consumed with food and beverages. MCT supplementation must never be considered the patient’s only source of fat for more than 3 weeks. After 3 weeks, high essential fatty acid (EFA) oil should be incorporated into the diet. This is to reduce the risk of EFA deficiency, which may lead to its own set of health problems.
Trihepatanoin (Dojolvi®) is a drug consisting of synthetic, medium-chain triglycerides. When it is ingested, it is digested into heptanoate, which can enter the mitochondria and be metabolized by medium-chain–specific enzymes of FAO. This process bypasses the carnitine cycle, the long-chain transport, and long-chain–specific enzymes. Through a series of metabolic processes, it eventually restores ATP production needed for gluconeogenesis, thus replenishing the body’s energy reserve.
Multiple studies have been conducted looking into the efficacy of triheptanoin in managing LCFAOD. Two retrospective studies show that it reduces acute episodes and hospital stays caused by rhabdomyolysis, cardiomyopathy, and hypoglycemia. Studies have also shown that triheptanoin is cardioprotective, with patients receiving the medication experiencing increased left ventricular fraction, decreased left ventricular mass on their resting echograms, and reduced heart rate during moderate-intensity exercise. The most common side effects reported were diarrhea, vomiting, and nausea.
The twin traditional treatment strategies of nutritional and symptomatic management do improve outcomes; however, they still leave patients vulnerable to acute crises that require hospital stays. The FDA approval of triheptanoin in 2020 “represents a substantial breakthrough that will greatly improve the treatment and management of LCFAODs,” Dr. Vockley opines. Certainly, a greater focus on developing drugs that directly tackle energy deficiencies caused by LCFAOD is the way forward.
Vockley J. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. Published online August 15, 2020. doi:10.37765/ajmc.2020.88480
Park B. FDA approves first treatment for long-chain fatty acid oxidation disorders. MPR. July 1, 2020. Accessed July 30, 2021.