What are fatty oxidative disorders?

Fatty Acid Oxidation Disorders (FAODs)

Definition and Pathophysiology

Fatty acid oxidation disorders are inherited metabolic diseases caused by defects in enzymes or proteins that transport and metabolize fatty acids in the mitochondria, preventing the body from converting long-chain fatty acids into energy during fasting, illness, or prolonged exercise. 1

• FAODs disrupt the key metabolic pathway that maintains energy homeostasis for high-energy organs such as the heart, skeletal muscle, and liver, which rely on fatty acid oxidation as their main energy source during prolonged fasting 1, 2
• These disorders result in decreased production of acetyl-coenzyme A and adenosine triphosphate, leading to energy deficiency in multiple organ systems 2
• All FAODs are inherited as autosomal recessive traits, meaning both parents must carry the defective gene 1

Clinical Presentations

Life-Threatening Acute Manifestations

• Hypoketotic hypoglycemia is the hallmark presentation, occurring because patients cannot generate ketones from fatty acids during fasting 1, 2
• Cardiomyopathy develops due to the heart's inability to utilize fatty acids as its primary fuel source 1, 2, 3
• Rhabdomyolysis presents with muscle breakdown, particularly triggered by prolonged aerobic exercise, fasting, or physiologic stress 1, 2, 3
• Acute liver dysfunction manifests as hepatomegaly, elevated transaminases, and Reye-like syndrome, typically in infancy but can extend into childhood and adolescence 1, 3
• Encephalopathy and acute metabolic acidosis can occur during metabolic crises 1

Triggering Events

• Febrile illnesses, vomiting, and fasting are common precipitants that lead to severe metabolic decompensation 1
• Prolonged aerobic exercise or sustained physical activity can trigger acute episodes, particularly in adolescents and adults 2, 3, 4
• Physiologic stress from any source increases metabolic demand and can precipitate crisis 2, 5

Age-Specific Presentations

• Neonatal period: Severe cardiomyopathy is the predominant initial presentation 3
• Infancy and childhood: Liver dysfunction with hypoketotic hypoglycemia dominates the clinical picture 3
• Adolescence and adulthood: Episodic rhabdomyolysis becomes the most frequent initial presentation, though symptoms can develop at any age 3, 4

Maternal-Fetal Connections

• Infants born to mothers who develop acute fatty liver of pregnancy or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) are at high risk for having FAODs 1
• This connection exists because the fetus with FAOD cannot properly oxidize fatty acids, leading to accumulation that affects maternal liver function 1

Specific FAOD Subtypes

The following disorders are detectable by acylcarnitine profile analysis 1:

• Carnitine uptake defect
• Carnitine palmitoyltransferase I (CPTI) deficiency
• Carnitine-acylcarnitine translocase (CACT) deficiency
• Carnitine palmitoyltransferase II (CPTII) deficiency
• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
• Long-chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
• Trifunctional protein (TFP) deficiency
• Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
• Short-chain acyl-CoA dehydrogenase (SCAD) deficiency
• Multiple-CoA dehydrogenase (MAD) deficiency (Glutaric acidemia type II)

Diagnostic Approach

Laboratory Evaluation

• Acylcarnitine profile analysis is the key diagnostic test, showing characteristic patterns of elevated specific acylcarnitines depending on the enzyme defect 1
• Plasma amino acids, urine organic acids, and plasma carnitine (free and total) complete the comprehensive metabolic evaluation 1
• During acute episodes, check serum glucose (typically low), lactate, liver enzymes, creatine kinase, and ammonia 1
• The diagnosis is almost exclusively a laboratory process, as clinical features alone cannot distinguish between different FAODs 1

Genetic Testing

• Genetic testing confirms the specific FAOD subtype and guides management 3
• Newborn screening programs detect many FAODs through acylcarnitine analysis on dried blood spots 3, 5

Management Principles

First-Line Therapy

Management of FAODs with diet and intravenous glucose should be the first-line therapy. 1

• Avoidance of fasting is the cornerstone of management for all FAODs 1, 3
• Dietary recommendations address fat and carbohydrate content and specify maximal fasting periods based on age and specific disorder 1
• During acute crises, administer intravenous glucose at least 10 mg/kg/min to maintain serum glucose above 100 mg/dL 1

Long-Chain FAOD-Specific Management

• Long-chain FAODs require a fat-restricted diet with supplementation of medium-chain triglyceride (MCT) oil 3, 5
• Supplementation with docosahexaenoic acid (DHA) prevents deficiency of this essential fatty acid crucial for brain, visual, and immune function 3
• Monitor for fat-soluble vitamin deficiencies and supplement as needed 3

Carnitine Supplementation

• Carnitine supplementation may be necessary, as carnitine facilitates excretion of toxic acylCoA compounds by forming acylcarnitine, which is quickly excreted 6
• Carnitine clears accumulated acylCoA compounds that disrupt intermediary metabolism and cause life-threatening acidosis 6

Liver Transplantation Considerations

• Patients with FAODs should be considered for liver transplant evaluation if they experience recurrent episodes of pediatric acute liver failure (PALF) or have failed medical therapy 1
• Prompt dietary intervention may reverse symptoms, including those associated with PALF, and preclude the need for transplantation 1
• Liver transplantation is an acceptable therapeutic option for patients presenting with fulminant liver failure who fail medical and dietary intervention 1

Prognosis and Ongoing Challenges

• Despite newborn screening and early management, symptom onset can be sudden and serious, even resulting in death 2
• Current standard therapy leaves many patients continuing to experience major clinical events, with elevated mortality rates 5
• Patients with long-chain FAODs continue to experience recurring hospitalizations and high morbidity despite medium-chain triglyceride supplementation 5
• The phenotypic diversity in FAODs results from complex interactions of genetic, epigenetic, and environmental factors beyond simple monogenic inheritance 4

Critical Clinical Pitfalls

• Never delay treatment waiting for confirmatory genetic testing—begin dietary management and glucose support immediately based on clinical suspicion and initial metabolic screening 1, 2
• Recognize that FAODs can present as recurrent episodes throughout life, not just in infancy 1
• During illness or stress, aggressive treatment with intravenous glucose is essential even if the patient appears stable 1, 3
• Abnormalities in fatty acid oxidation predispose to worse outcomes in acute liver failure, requiring heightened vigilance 1