Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, inherited metabolic conditions. They affect how the body processes long-chain fatty acids to produce energy. These disorders disrupt the body’s ability to break down fats, leading to various health problems. Understanding these conditions highlights the intricate processes involved in human energy production.
Understanding Long Chain Fatty Acid Oxidation Disorders
The human body primarily uses sugars for immediate energy. When sugar stores run low, such as during fasting, illness, or exercise, the body switches to burning fat for fuel. This process, known as fatty acid oxidation, occurs within the mitochondria. Long-chain fatty acids are transported into the mitochondria via the carnitine shuttle.
Once inside the mitochondria, long-chain fatty acids undergo beta-oxidation, broken into smaller units. These units form acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle to generate adenosine triphosphate (ATP). In individuals with LC-FAODs, one or more enzymes in this pathway are missing or not functioning correctly.
This enzyme deficiency prevents the body from breaking down long-chain fatty acids for energy. The body’s energy supply is compromised, especially during increased energy demand. Unprocessed long-chain fatty acids and their intermediates can accumulate in organs like the heart, liver, and muscles, causing damage. Different types of LC-FAODs exist, such as very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, and trifunctional protein (TFP) deficiency.
Recognizing the Signs and Symptoms
Signs and symptoms of LC-FAODs vary significantly depending on the specific type and severity. They often become apparent during metabolic stress, such as fasting, fever, illness, or strenuous exercise. Symptoms may appear in infancy or early childhood, or in milder forms, not until adolescence or adulthood.
A common symptom is hypoglycemia, or low blood sugar, as the body cannot produce glucose from fat stores. Individuals may also experience muscle weakness, muscle pain (myalgia), and exercise intolerance, sometimes leading to rhabdomyolysis. This muscle breakdown can result in dark urine due to muscle protein release.
Heart problems, such as cardiomyopathy or arrhythmias, are observed. Liver dysfunction, including an enlarged liver or elevated liver enzymes, can also occur. Other symptoms include fatigue, developmental delays, and in some types, eye problems like retinopathy. These symptoms highlight the widespread impact of impaired fatty acid oxidation on high-energy-demanding organs.
Diagnosis and Management
Early identification of long-chain fatty acid oxidation disorders improves outcomes. Many countries include LC-FAODs in their newborn screening programs, allowing detection shortly after birth. Newborn screening involves analyzing a dried blood spot, often using tandem mass spectrometry (MS/MS). This method detects specific markers, like acylcarnitines, which are fatty acids attached to carnitine, indicating a problem with fat metabolism.
If newborn screening suggests an LC-FAOD, further confirmatory tests are performed. These may include detailed blood tests to analyze the acylcarnitine profile, urine organic acid analysis, and genetic testing. Genetic testing looks for mutations in genes associated with LC-FAODs, providing a definitive diagnosis.
Management of LC-FAODs focuses on preventing metabolic crises and ensuring adequate energy supply. A primary strategy involves dietary modifications, often including a low-fat, high-carbohydrate diet to reduce reliance on long-chain fatty acid breakdown. Medium-chain triglycerides (MCTs) are frequently used as a dietary supplement because they can be metabolized for energy through a pathway that bypasses the affected enzymes.
Avoiding prolonged fasting is also a cornerstone of management; individuals are advised to eat frequent meals and snacks to prevent reliance on fat stores. During illness or increased metabolic stress, emergency protocols may involve administering intravenous dextrose to provide immediate energy and prevent severe hypoglycemia. Ongoing care involves a multidisciplinary medical team, including metabolic specialists and dietitians.
Genetic Basis and Inheritance
Long-chain fatty acid oxidation disorders are inherited genetic conditions, caused by changes in specific genes passed down through families. These disorders follow an autosomal recessive inheritance pattern. This means a person must inherit two copies of a mutated gene, one from each parent, to develop an LC-FAOD.
Parents who carry one mutated gene copy are generally unaffected, as their normal gene copy compensates; they are called “carriers.” If both parents are carriers of the same mutated gene, there is a 25% chance with each pregnancy that their child will develop the condition. There is a 50% chance the child will be a carrier, and a 25% chance they will inherit two normal gene copies, being neither affected nor a carrier.
Specific genes associated with LC-FAODs include ACADVL (for VLCAD deficiency), CPT1A (for Carnitine Palmitoyltransferase I deficiency), CPT2 (for Carnitine Palmitoyltransferase II deficiency), and HADHA and HADHB (for LCHAD and TFP deficiencies). These genes provide instructions for producing the enzymes involved in breaking down long-chain fatty acids for energy.