INTRODUCTION — Fatty acid oxidation disorders (FAODs) (table 1) are inborn errors of metabolism resulting in failure of mitochondrial beta-oxidation or the carnitine-based transport of fatty acids into mitochondria (figure 1). FAODs lead to deficient energy production and produce widely variable clinical presentations ranging from mild hypotonia in adults to sudden death in infants .
This topic reviews the clinical features, diagnosis, and general treatment approach for FAODs. The specific disorders are reviewed in greater detail separately. (See "Specific fatty acid oxidation disorders".)
EPIDEMIOLOGY — The estimated incidence of FAODs is approximately one in every 5000 to 10,000 live births (table 1) . The most common FAOD is medium-chain acyl-CoA dehydrogenase deficiency (MCADD), with a prevalence of 1 in 20,000. Other FAODs range from 1 in 100,000 to 1 in 2,000,000. These autosomal-recessive disorders are seen in both males and females in all ethnic populations.
OVERVIEW OF FATTY ACID OXIDATION — Fatty acid beta-oxidation takes place in the mitochondria and provides a major source of energy (figure 1). There are at least 31 enzymes or carriers that participate in FAO. While short- and medium-chain fatty acids, typically <10 carbon units, can enter the mitochondria directly, longer-chain fatty acids >12 carbon units are transported by way of a carnitine shuttle cycle. Within mitochondria, the beta-oxidation cycle forms two-carbon acetyl-coenzyme A (acetyl-CoA) and generates nicotinamide adenine dinucleotide (NADH+) and flavin adenine dinucleotide (FADH2), which in turn are transferred to the respiratory chain for oxidative phosphorylation and adenosine triphosphate (ATP) generation. Acetyl-CoA is used as a substrate in the tricarboxylic acid (TCA) cycle to produce additional reducing equivalents for the electron transport chain and for ketone body and cholesterol synthesis.
PATHOPHYSIOLOGY — FAODs are autosomal-recessive disorders that are fundamentally diseases of energy deficiency. Deranged FAO leads to a triple defect in energy production. First, there is a direct decrease of reducing equivalents for oxidative phosphorylation produced directly by enzymatic reaction of FAO. Second, there is reduced production of the tricarboxylic acid (TCA) cycle substrate acetyl-coenzyme A (acetyl-CoA), leading to further reduction of reducing equivalents. Finally, there is a reduction in the production of ketone bodies, a key alternative fuel for brain, heart, muscle, kidney, and other tissues during stress.
COMMON CLINICAL PRESENTATIONS — FAODs can present at any age, with the most severe forms, such as the long-chain fatty acid oxidation disorders (LCFAODs), presenting in the first few days of life, while medium-chain acyl-CoA dehydrogenase deficiency (MCADD) usually presents in early childhood. Common presenting signs include hypoglycemia, hyperammonemia, liver disease and liver failure, cardiac and skeletal myopathy, rhabdomyolysis, and retinal degeneration (table 1) . Some patients may present with a Reye-like syndrome. Life-threatening presentations may rapidly occur with minimal fasting in infants but may require 24 to 48 hours of fasting in older individuals. In the most severe forms, death may occur prior to receipt of newborn screening (NBS) results. The accumulation of long-chain acylcarnitine species may be dysrhythmogenic and is associated with cardiac dysfunction . Patients with FAODs do not exhibit chronic central nervous system effects unless a severe episode(s) of hypoglycemia or hyperammonemia has previously caused acute, permanent damage. Disease-specific manifestations are reviewed in the topic on individual disorders. (See "Specific fatty acid oxidation disorders".)
Carriers — Carriers are typically asymptomatic, although mild biochemical abnormalities may be present. Female carriers of the defect for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are at risk of developing acute fatty liver of pregnancy or hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome when carrying an affected fetus .
LABORATORY FINDINGS — Patients with hypoketotic hypoglycemia have low serum glucose levels and low or absent serum beta-hydroxybutyrate levels and urine ketones. Electrolytes and arterial blood gas analysis show a metabolic acidosis as the patient becomes dehydrated. Patients with liver dysfunction have elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and, during a severe crisis, may also have hyperammonemia. Creatine kinase may be elevated in the long-chain fatty acid oxidation disorders (LCFAODs) with myopathy or rhabdomyolysis. Patients with long-chain acyl-CoA dehydrogenase deficiency (LCADD) can present with laboratory and clinical features compatible with a respiratory chain disorder . Accumulation of long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) in these patients disrupts energy mitochondrial homeostasis in the liver .
DIAGNOSIS — In many resource-abundant countries, most FAODs are detected through newborn screening (NBS) by tandem mass spectrometry, but the specific disorders tested can vary significantly by country, and older patients born before NBS implementation are still being identified clinically. The preferred tests to confirm a diagnosis in an infant with a positive NBS are a plasma acylcarnitine profile and total and free carnitine levels. Recommendations for follow-up diagnostic testing of an abnormal NBS result are provided in the ACT sheet and diagnostic algorithms provided by the American College of Medical Genetics and Genomics. Deoxyribonucleic acid (DNA) testing is the most common definitive test and can provide information on final diagnosis (eg, trifunctional protein deficiency [TFPD] versus isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency [LCHADD]) and predicted phenotype. When NBS is not available, early recognition of clinical symptoms is essential and should trigger appropriate testing. Clinical findings that should prompt an evaluation for FAODs include hypoketotic hypoglycemia, Reye-like syndrome (hypoglycemia with hyperammonemia), cardiomyopathy, or recurrent rhabdomyolysis.
A false-positive NBS for an FAOD can occur in infants who are carriers for one of the disorders. The positive predictive value (PPV) of NBS varies significantly among NBS laboratories; for example, the PPV for NBS for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) ranges from 8 to 78 percent . Additionally, NBS identifies many milder forms of FAOD in infants with lower but still elevated concentrations of diagnostic acylcarnitine species as compared with more severe forms of FAOD. Such infants may continue to have persistent elevations of these acylcarnitines yet remain asymptomatic. Mutation analysis may help predict the risk for clinical disease in this setting. However, long-term follow-up studies are needed to more definitively determine clinical risk and the need for monitoring for later-onset symptoms .
If variants of uncertain significance are identified on DNA sequencing, enzyme assay in leukocytes, fibroblasts, or hepatocytes may provide additional information on their functional significance. Assessment of the ability of leukocytes or skin fibroblasts to oxidize labeled fatty acids (often called an FAO probe) is available in some clinical laboratories. Urine organic acid analysis may show elevations of long-chain dicarboxylic acids in the long-chain fatty acid oxidation disorders (LCFAODs) or other organic acids in multiple acyl-CoA dehydrogenase deficiency (MADD), while quantitation of urine acylglycines may show elevated hexanoylglycine in MCADD (table 1). Urinary dicarboxylic acids and other abnormal metabolites may be present during illness but not when a patient is well. Lack of urinary ketones with fasting or illness due to a defect in ketogenesis is another suggestive, but nonspecific, sign of an FAOD.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for the FAODs reflects the various presentations:
●Hypoketotic hypoglycemia – Hyperinsulinism syndromes are the primary differential in patients who present with hypoketotic hypoglycemia. These disorders can be identified by early-onset fasting hypoglycemia that occurs only a few hours postprandial, in contrast to FAODs, which typically require longer periods of fasting (eg, at least three to four hours postprandial). Hyperinsulinism syndrome can be recognized on testing, demonstrating elevated insulin levels and low free fatty acids, and therapeutic responsiveness to diazoxide in some cases. Confirmation of diagnosis may require DNA sequencing for the known specific genetic defects (algorithm 1). (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)
●Cardiomyopathy – Other genetic and acquired cardiomyopathies (dilated or hypertrophic) are in the differential diagnosis in patients who develop cardiomyopathy. Other inborn errors of metabolisms that can cause cardiomyopathy include Pompe disease and other glycogen and lysosomal storage diseases, mitochondrial and respiratory chain disorders, organic acidemias, and congenital disorders of glycosylation . These causes of cardiomyopathy can be recognized by additional testing including elevated plasma lactate, elevated excretion of mucopolysaccharides, abnormal urine organic acids, or carbohydrate-deficient transferrin. In addition, white blood cell alpha-glucosidase is deficient in Pompe disease. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)", section on 'Differential diagnosis'.)
●Rhabdomyolysis – In patients who present with rhabdomyolysis, the differential should include glycogen storage diseases (GSDs), such as McArdle disease (GSD V), and other congenital and acquired myopathies . GSD V is recognized by a lack of fasting-induced hypoketotic hypoglycemia, the presence of lactic acidosis, and a "second wind" phenomenon. Diagnosis of an FAOD can be confirmed with plasma acylcarnitine testing. (See "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Clinical manifestations and diagnosis of rhabdomyolysis".)
●Reye syndrome – Reye syndrome is a rapidly progressing encephalopathy with hepatic dysfunction. The cause of Reye syndrome is unknown. Many cases are associated with aspirin use in children. Other associations have included FAOD and urea cycle disorders. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)
COMMON ELEMENTS OF TREATMENT — Features of treatment that are common to all FAODs are reviewed here. Unique treatments for specific disorders or groups of disorders are reviewed in each respective section.
Prevention of metabolic decompensation — Treatment of FAODs involves avoidance of prolonged fasting and maintenance of a constant energy supply during times of catabolism by simple carbohydrates by mouth or intravenously (IV) if the patient is unable to maintain anabolism though oral intake. For those who cannot tolerate oral feeding, IV administration of glucose should be initiated immediately to maintain normal glucose level. Patients are strongly advised to seek medical attention when experiencing illnesses accompanied with symptoms suggestive of metabolic decompensation. (See 'Common clinical presentations' above and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)
●Emergency protocol/letter – Patients and caregivers should be provided with an FAOD-specific emergency protocol/letter to be carried with them during times of risk for metabolic decompensation. This letter should contain information on acute recognition of risk and symptoms, initial management, and access to appropriate biochemical genetic specialists.
●Safe fasting time – A safe fasting time differs for different age groups and increases as the child ages . A neonate should fast no longer than three hours. Between 6 and 12 months, infants may fast up to four hours during the day and six to eight hours during the night. Children older than 12 months can fast four hours during the day and at least eight hours at night. If an infant is ill, especially with a fever, or is in a catabolic state due to other physiologic stresses, fasting should be limited to three to four hours with frequent monitoring for clinical symptoms. Preoperative planning for elective surgery should include limiting fasting times as above and providing IV fluids with 10 percent dextrose at 1.5 times maintenance during and after the procedure until adequate oral intake is restored.
●Use of propofol – The medication propofol, commonly used for anesthesia, has been avoided in patients with mitochondrial FAODs due to concerns that it contains long-chain fatty acids and reports of severe side effects in some critically ill patients receiving high-dose propofol infusion. However, in the examination of outcomes of eight children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) or trifunctional protein deficiency (TFPD), no adverse side effects were observed, and propofol was safely used in short-duration procedures . Further research is necessary to understand the potential risks of this drug in patients with FAODs. In the meantime, it should not be used in patients with metabolic decompensation or critical illness.
Other dietary management — Dietary fat restriction in long-chain fatty acid oxidation disorders (LCFAODs) is not strictly necessary, except to accommodate the addition of medium-chain triglyceride (MCT) oil or triheptanoin to the diet. Higher protein intake may be helpful . Carnitine supplementation is typically not necessary in medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Its use in LCFAODs is controversial due to concern about cardiotoxic effects of long-chain acylcarnitines. However, such an effect has never been demonstrated. (See "Specific fatty acid oxidation disorders", section on 'Dietary management of LCFAODs' and "Specific fatty acid oxidation disorders", section on 'L-carnitine supplementation in LCFAODs'.)
Intermediate substrate (anaplerotic) therapy — Triheptanoin is a triglyceride of three 7-carbon (C7) fatty acids approved by the US Food and Drug Administration (FDA) for use as an intermediate substrate (anaplerotic) therapy in patients with LCFAODs . It is hydrolyzed in the small intestine to three molecules of heptanoic acid that are readily absorbed. Complete beta-oxidation of this fat produces one molecule of propionyl-CoA and two of acetyl-CoA, both of which can enter the citric acid cycle. Alternatively, in the liver, pentanoyl-CoA (the product of the first cycle of FAO) can generate the 5-carbon ketone bodies beta-hydroxypentanoate and beta-ketopenanoate, which can be used as an alternative fuel by peripheral tissues . Additionally, triheptanoin may suppress lipolysis and accumulation of toxic metabolite production in LCFAODs.
Use of triheptanoin was first reported in three symptomatic patients with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) who had improvement in cardiac symptoms, muscle weakness and fatigue, hypoglycemia, and hepatomegaly, but not rhabdomyolysis, within the first month of treatment [16,17]. Subsequent studies showed similar effects in patients with LCHADD, TFPD, carnitine palmitoyltransferase 2 deficiency (CPT2D), and carnitine palmitoyltransferase 1A deficiency (CPT1D), although LCHADD-associated retinopathy was not improved with treatment . In a compassionate-use protocol of triheptanoin in patients with varies types of FAODs (11 VLCADD, 5 LCHADD, 2 TFPD, 3 CPT2D, and 1 CACTD), triheptanoin was well tolerated, and patients had reduced hospitalizations, myopathy, and hypoglycemia, although one patient had continued cardiomyopathy .
In an open-label phase-II study, 29 subjects with severe LCFAOD were treated for 78 weeks at a target dose of 25 to 35 percent total daily caloric intake, and the frequency and duration of major clinical events (hospitalizations, emergency department visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) during the treatment period were compared with the retrospective frequency and duration of events for the 78 weeks prior to the study . The mean annualized events rate decreased by 48.1 percent (from 1.69 to 0.88 events/year), and the mean annualized duration rate decreased by 50.3 percent (from 5.96 to 2.96 days/year). Hospitalizations due to rhabdomyolysis decreased by 38.7 percent. Episodes of hypoglycemia and intensive care admissions were eliminated, and cardiomyopathy events were decreased by 69.7 percent (not statistically significant due to a small number of events). Treatment-related adverse events were similar to those seem with prior treatment with MCT oil and included moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which improved with smaller, more frequent doses mixed with food. The improvement in patients was persistent in a long-term extension study .
In a second phase-II double-blind study comparing trioctanoin to triheptanoin, patients in the triheptanoin group had a 7.4 percent increase in left ventricular (LV) ejection fraction and a 20 percent decrease in LV wall mass on their resting echocardiogram . In addition, they had a lower heart rate for the same amount of work during a moderate-intensity exercise stress test compared with patients taking trioctanoin. Liver lipid deposit was also reduced with triheptanoin compared with trioctanoin treatment.
PROGNOSIS — Patient outcomes, including quality of life and survival, have improved with early detection and institution of therapy due to newborn screening (NBS) programs. However, early identification through NBS does not prevent all severe complications and death, and not all disorders are screened in all countries. In addition, available treatments do not completely eliminate disease manifestations, particularly rhabdomyolysis and cardiomyopathy. Symptoms can still be triggered by acute illness or other physiologic stress, resulting in rapid, life-threatening metabolic decompensation. Patients face a lifelong risk of recurrent symptoms and metabolic decompensation during prolonged fasting or increased metabolic stress (eg, prolonged surgery). This lifelong management has redefined the expectations and long-term planning for patients and their caregivers as the changes to daily life are significant .
FAOD patients diagnosed symptomatically at less than six years of age were reported to have over 60 percent mortality for most long-chain fatty acid oxidation disorders (LCFAODs) including very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), carnitine palmitoyltransferase 2 deficiency (CPT2D), and carnitine-acylcarnitine translocase deficiency (CACTD) despite treatment at the standard of care . Overall, the younger the age at diagnosis, the better the reported outcome. In another study, patients with VLCADD had a reported rate of sudden death of 52 percent and overall mortality of 60 percent . The risk of dying in patients identified by NBS is much lower, though not zero .
Children with inborn errors of metabolism identified through NBS versus clinical diagnosis tended to have improved outcomes, with less severe disease, fewer long-term sequelae, and higher mean intelligence quotient (IQ) . More focused studies have demonstrated reductions in severe adverse outcomes and deaths in medium-chain acyl-CoA dehydrogenase deficiency (MCADD)  and LCFAOD [28,29] with NBS. Other international long-term outcome studies are in progress.
FUTURE THERAPIES — A variety of novel therapies have been proposed or investigated for FAODs. Part of the difficulty in treating long-chain fatty acid oxidation disorders (LCFAODs) centers on a lack of complete understanding of the pathophysiologic effects of the deranged energy metabolism. The presence of rhabdomyolysis without hypoglycemia in older patients suggests an effect unrelated to energy deficit. Abnormal signaling from long-chain fatty acid metabolites, secondary carnitine deficiency, generalized mitochondrial dysfunction, and aberrant inflammatory responses are all possible mechanisms and have been demonstrated in patients with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) . Larger randomized trials, coupled with long-term clinical follow-up studies similar to those ongoing with urea cycle disorders through the Rare Disease Consortium, are needed to validate existing data and implement future therapies .
Gene transcription activation — The therapeutic strategy in development is activation of FAO enzyme gene transcription. Bezafibrate, used in the treatment of hyperlipidemia, is an agonist of peroxisome proliferator-activated receptor (PPAR) and promotes transcription of many genes encoding FAO enzymes. Reduction in episodes of rhabdomyolysis and creatine kinase levels and improvements in measures of quality of life have been reported in patients with carnitine palmitoyltransferase 2 deficiency (CPT2D) treated with bezafibrate . In studies of bezafibrate-incubated fibroblasts from VLCADD patients, all demonstrated increased VLCAD messenger ribonucleic acid (mRNA) levels, but functional changes were more variable and appeared to be mutation specific. Cells with genotypes associated with more severe, neonatal-onset disease had no significant changes in total cellular beta-oxidation flux, whereas significant improvements in flux and VLCAD protein were seen in cells from patients with milder disease . In light of these data, the proposed mechanism of action is enhanced residual activity level of the mutant enzyme rather than increased transcription of VLCAD mRNA. Patients with CPT2D or VLCADD who were treated with bezafibrate did not show improvement of clinical symptoms or FAO during exercise . Bezafibrate treatment of carnitine-acylcarnitine translocase deficiency (CACTD) led to an in vitro response in cells but failed to demonstrate any short-term clinical effect . In contrast, bezafibrate treatment was reported to provide clinical improvement in a child with multiple acyl-CoA dehydrogenase deficiency (MADD) including motor and social development .
Other gene transcription activation strategies are in the early stages of development. Studies of resveratrol and stilbenes have shown in vitro improvements in FAO flux in CPT2D and VLCADD fibroblasts [37,38].
Chaperonin therapy — Small-molecule chaperonins are chemicals that can improve folding of mutant proteins. Phenylbutyrate has been proposed as a therapy for the common medium-chain acyl-CoA dehydrogenase (MCAD) mutation . This variant protein is active when correct folding is induced by the molecular chaperonins GroEL/ES. In one study, incubation of cells with from patients with carnitine transporter deficiency (CTD) with phenylbutyrate, quinidine, and verapamil showed stimulated carnitine transport in all cells, although the effect was specific to particular solute carrier family 22 member 5 (SLC22A5) mutations . An additive effect was seen with concurrent use of phenylbutyrate and quinidine.
Gene therapy — Gene therapy strategies have been explored in VLCADD, medium-chain acyl-CoA dehydrogenase deficiency (MCADD), and short-chain acyl-CoA dehydrogenase deficiency (SCADD) [41-43]. As an example, gene therapy with a recombinant adeno-associated virus (AAV) serotype 8 vector expressing human acyl-CoA dehydrogenase, very long chain (ACADVL) in a mouse model of VLCADD resulted in expression of the human VLCAD enzyme in liver and heart with lower expression in skeletal muscle . Biochemical testing revealed improvements in long-chain acylcarnitines and fasting-induced hypoglycemia. Long-term expression up to 20 weeks, as evidenced by maintenance of euglycemia and survival by maintaining body temperature greater than 20°C following a fasting cold challenge, was seen following treatment with a recombinant pseudotyped AAV2/9-VLCAD vector . No human trials have yet been attempted.
Other therapies — Laboratory research on FAODs has identified a number of potential options for therapies. The enzymes of long-chain fatty acid oxidation (LCFAO) interact with each other and those of the mitochondrial respiratory chain to form a multiprotein complex that optimizes catalytic efficiency of the two pathways in a linked fashion . Defects in LCFAO enzymes can lead to instability of this complex and secondary reduction of oxidative phosphorylation, a decrease in adenosine triphosphate (ATP) production, and an accumulation of mitochondrial superoxides in cells from affected patients or animal models of VLCADD [46,47]. Treatment of cells with mitochondrial-targeted antioxidants decreases the superoxide levels and improves cellular oxygen consumption and FAO . These compounds are promising candidates for future clinical trials.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of metabolism".)
●Fatty acid oxidation disorders (FAODs) (table 1) are inborn errors of metabolism that result in failure of mitochondrial beta-oxidation or the carnitine-based transport of fatty acids into mitochondria (figure 1). (See 'Introduction' above and 'Overview of fatty acid oxidation' above and 'Pathophysiology' above.)
●FAODs lead to deficient energy production and produce widely variable clinical presentations ranging from mild hypotonia in adults to sudden death in infants. Common presenting signs include hypoglycemia, hyperammonemia, liver disease and liver failure, cardiac and skeletal myopathy, rhabdomyolysis, and retinal degeneration. Patients are most at risk during times of fasting or intercurrent illnesses. (See 'Common clinical presentations' above.)
●Most FAODs are detected through newborn screening (NBS) by tandem mass spectrometry in developed countries. The preferred tests to confirm a diagnosis in an infant with a positive NBS are a plasma acylcarnitine profile and total and free carnitine levels. DNA testing is the most common definitive test and can provide information on final diagnosis. Leukocyte, fibroblast, or liver enzyme assays can be used to determine functional significance of unknown variants identified on DNA sequencing. (See 'Diagnosis' above.)
●Treatment of FAODs involves avoidance of prolonged fasting and maintenance of a constant energy supply during times of catabolism. The recommended diet is often restricted in natural fat and carbohydrate or protein supplemented for most FAODs. Patients with long-chain fatty acid oxidation disorders (LCFAODs) are supplemented with medium-chain triglyceride (MCT) oil or triheptanoin to provide a substrate for beta-oxidation. Carnitine supplementation is given only if secondary carnitine deficiency is found. (See 'Common elements of treatment' above.)
●Quality of life and survival in patients with FAODs have improved with early detection and institution of therapy due to NBS programs. However, early identification through NBS does not prevent all severe complications and death, and not all disorders are screened in all countries. In addition, available treatments do not completely eliminate disease manifestations, particularly rhabdomyolysis and cardiomyopathy. Symptoms can still be triggered by acute illness or other physiologic stress, resulting in rapid, life-threatening metabolic decompensation. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J Lawrence Merritt II, MD, who contributed to an earlier version of this topic review.