2 General management of FAOD
Management of FAOD generally includes dietary restrictions to minimize reliance on long-chain fatty acid catabolism and, ultimately, prevent crises, although nutritional guidelines for FAOD vary depending on subtype and symptomatic or asymptomatic status.
Treatment recommendations for patients with more challenging subtypes, such as LCHADD/TFPD, suggest dietary protein and carbohydrate intake meet age-appropriate guidelines, whereas 20% of daily caloric intake should be derived from medium-chain triglyceride (MCT) [
32,
33]. Dietary long-chain fats are significantly reduced while ensuring that levels of essential fatty acids, such as alpha-linoleic acid and linoleic fatty acids, are sufficient [
32,
33]. Carnitine supplementation is also recommended to replace carnitine deficiency, although supplementation should be based on circulating plasma levels and excess carnitine should be avoided. When studied in the short-term, a higher-protein diet increased energy expenditure and decreased energy intake in patients with LCHADD/TFPD, suggesting that higher-protein diets may have benefit over higher-carbohydrate diets [
34]. Nutrition recommendations for those with MCADD are to consume a generally heart-healthy diet. Dietary fat restriction is not indicated in patients with MCADD or LC-FAOD deficiencies with no or few symptoms; however, in highly symptomatic cases of LC-FAOD, long-chain fatty acids should be substituted by MCTs [
35]. No specific dietary guidelines are currently published for CPT-IID, although treatment has followed similar recommendations as other LC-FAOD. Dietary management is typically based on an overall clinical assessment based on factors, including age of onset of symptoms, diagnosis, and presenting and ongoing symptoms. For example, patients with LC-FAOD manifesting symptoms in infancy may require highly restrictive dietary interventions, whereas those manifesting symptoms later in life may only require MCT supplementation with exercise.
Medium-chain triglyceride supplementation acts by bypassing any LC-FAOD defects, thereby allowing the body to process fatty acids normally. However, this can lead to an imbalance in the enzymes associated with the tricarboxylic acid cycle, warranting further supplementation. Notably, MCT is contraindicated in patients with MCADD. Timing of MCT supplementation throughout the day is essential for appropriate energy utilization. For example, specifically timing MCT supplementation prior to periods of exercise may improve energy availability and performance [
36]. However, one alternative treatment under investigation is triheptanoin, an odd-carbon MCT comprising three 7-carbon fatty acids on a glycerol backbone. Unlike MCT, as well as acetyl-CoA, when metabolized, triheptanoin provides an additional energy source in the form of the 3-carbon propionyl-CoA, as well as 4- and 5-carbon ketone bodies [
22]. Through an anaplerotic effect, this additional supplementation prevents depletion of key substrates, restoring energy production for gluconeogenesis [
37]. Triheptanoin thus preserves tricarboxylic acid cycle function while bypassing the deficient enzymes.
Patients managing VLCADD with dietary long-chain fatty acid restrictions are at risk of deficiencies in both essential fatty acids and fat-soluble micronutrients [
38]. These patients may require supplementation with docosahexaenoic acid or oils high in essential fatty acids, including linoleic acid and α-linoleic acid, to meet necessary nutritional needs [
38]. Fasting depletes glycogen stores and forces the body to use fatty acids for energy; therefore, avoidance of fasting is key in the prevention of metabolic crises associated with FAOD. In neonates, additional precautions must be taken when weaning infants from breastfeeding or from an overnight feeding schedule [
38].
Furthermore, Genetic Metabolic Dieticians International has recommended guidelines for younger patients with VLCADD. These guidelines note in asymptomatic patients, fasting should be limited to no more than 4 h in patients aged <4 months (with approximately one additional hour for each additional month of life), whereas symptomatic patients should have their maximum fasting period reduced by ~2 h from that recommended for asymptomatic patients. Similarly, according to Genetic Metabolic Dieticians International, healthy infants with MCADD should be fed at the same interval as those without MCADD (age < 4 months, maximum fasting of 4 h; age 5–12 months, maximum fasting of 4 h + 1 h per additional month of age) [
39]. Moreover, treatment guidelines recommend a bedtime snack high in complex carbohydrates to prevent a metabolic decompensation overnight [
38]. It is important patients prevent over-nutrition and excess weight gain because weight loss attempts can result in metabolic crisis.
Finally, patients often use personal lifestyle strategies, such as avoidance of physical activities, to minimize glucose depletion and prevent crises. Beyond the standard preventative management recommended for patients with FAOD, most treatments address specific symptom manifestations that arise during periods of decompensation. Parents of children with FAOD have reported that one of the most difficult aspects of being a caregiver is minimizing fasting by feeding their child every 3 h, as well as frequent trips to the grocery store to accommodate these altered meal plans [
27]. This management strategy is challenging for both patients and their caregivers because strict dietary changes require constant vigilance and foresight. Some parents of children with FAOD have had to leave their jobs to adapt their lifestyles to better accommodate the complex treatment and management of FAOD. Particular challenges arise during holidays, vacations, or special events, when caregivers and patients must adapt their care routine to a new schedule or environment or when they have limited access to physicians or dietitians.
4 Family planning and pregnancy
Although the outcomes of FAOD can be serious, it is also important to consider the potential effects of these disorders on women who are pregnant. It has been noted that the human placenta expresses six of the enzymes of the β-oxidation pathway at levels similar to those of skeletal muscle. It is acknowledged that certain disorders affecting fatty acid oxidation can have adverse effects on women during pregnancy [
78]. For example, some mothers of children born with LCHADD or TFPD develop acute fatty liver of pregnancy or maternal hemolysis, elevated liver enzymes, and low platelets syndrome [
78,
79].
Mothers heterozygous for FAOD and pregnant with an affected fetus can develop preeclampsia, acute fatty liver of pregnancy, maternal hemolysis, elevated liver enzymes, and low platelets syndrome and can deliver a premature, intrauterine growth–restricted child. In pregnancies of fetuses with LCHADD or general TFPD, maternal liver disease occurs 20–70% of the time [
79]. Furthermore, 62% of mothers developed acute fatty liver of pregnancy or maternal hemolysis, elevated liver enzymes, and low platelets syndrome in pregnancies of fetuses with LCHADD [
79]. Among women pregnant with a fetus with a FAOD, neither the fetus nor the placenta are able to fully oxidize fatty acids, resulting in transfer of metabolic intermediates to the maternal circulation [
79]. It is believed that these intermediates are what leads to preeclampsia, maternal hemolysis, elevated liver enzymes, low platelets syndrome, and acute fatty liver of pregnancy.
5 Key conclusions
FAOD are a group of rare, potentially life-threatening autosomal-recessive disorders that affect a wide range of organ systems and can be unpredictable in the timing and severity of their onset. Moreover, identifying a genotype-phenotype link is not always clear, making it difficult to predict outcomes (Table
2) [
22]. However, it does appear that certain genetic variants, namely LC-FAOD, are associated with a greater propensity for decompensation events in affected individuals [
14].
Currently, there are only limited management options for this array of disorders aside from strict adherence to nutritional plans to minimize crises [
11]. Without proper identification based on NBS or symptoms, patients cannot be instructed to follow the recommended nutritional plan, leading to dysfunction that can be chronic, progressive, and fatal. Importantly, although NBS may be effective in reducing certain events in patients with FAOD (e.g., hypoglycemic events in patients with residual enzyme activity), serious clinical symptoms (e.g., cardiac symptoms) are known to manifest rapidly and unpredictably, and death can occur despite appropriate management [
14,
31]. Recognition of clinical manifestations is crucial in the timely identification and management of crises stemming from FAOD.
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