Fatty acid oxidation disorder Basic Information

Understanding Fatty Acid Oxidation Disorders

Fatty acid oxidation disorders are genetic conditions that affect how the body processes and uses fats as a source of energy. These disorders occur when certain enzymes—special proteins that help chemical reactions happen in the body—are missing or not working correctly. Without these enzymes, the body cannot properly break down fats stored in tissues or obtained from food, leaving it unable to produce the energy needed for normal bodily functions.1

Fats, also called lipids, are one of the body's most important energy sources. The body constantly breaks down and rebuilds its fat stores to balance energy needs with the food that is available. When glucose, the body's primary energy source, runs low—such as during sleep, fasting, illness, or exercise—the body naturally turns to burning fat for fuel. For people with fatty acid oxidation disorders, this backup energy system does not work properly, which can lead to serious health problems.1

These disorders are inherited from parents in a specific pattern. Both parents of an affected child carry one copy of an abnormal gene, but they typically do not have the disorder themselves. Because two copies of the abnormal gene are usually needed for the disorder to occur, this is called an autosomal recessive pattern of inheritance.1

Epidemiology

Fatty acid oxidation disorders are rare conditions, but their frequency varies depending on the specific type and the population studied. Medium-chain acyl-CoA dehydrogenase deficiency, commonly known as MCADD, is one of the most common inherited disorders of metabolism, particularly among people of Northern European descent.1

The cumulative incidence of all fatty acid oxidation disorders combined has been estimated to range from approximately 1 in 6,500 to 1 in 110,000 births.2 More specifically, MCADD affects roughly 1 in 10,000 births, while very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) affects approximately 1 in 85,000 births.3 Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) occurs in about 1 in 250,000 births, and trifunctional protein deficiency affects roughly 1 in 750,000 births.3

These disorders can affect anyone regardless of gender or ethnic background, though certain types show higher prevalence in specific populations. Most of these disorders begin to show symptoms during infancy, but some may not become apparent until later in childhood, adolescence, or even adulthood.1

Causes

Fatty acid oxidation disorders are caused by changes, or mutations, in the genes that provide instructions for making enzymes involved in fat breakdown. These genetic changes prevent the enzymes from working properly or being made at all. The affected genes are passed down from parents to their children.4

When parents pass on defective genes to their children, the child's body cannot produce the specific enzyme needed to break down certain types of fatty acids. The enzyme most commonly deficient is medium-chain acyl-CoA dehydrogenase (MCAD). Other enzyme deficiencies include short-chain acyl-CoA dehydrogenase (SCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), very long-chain acyl-CoA dehydrogenase (VLCAD), and mitochondrial trifunctional protein (TFP). Additional deficiencies can affect enzymes and transport proteins involved in the carnitine system, which helps move fatty acids into the parts of cells where they are broken down.1

Because the necessary enzymes are missing or deficient, the body cannot complete the process of fatty acid oxidation—the breakdown of fats to produce energy. This leaves the body short of energy during times when it needs to rely on fat as fuel. At the same time, breakdown products such as acyl-CoA begin to accumulate in the blood and tissues, which can be toxic to organs and systems throughout the body.1

Risk Factors

The primary risk factor for developing a fatty acid oxidation disorder is having two parents who each carry one copy of the abnormal gene. If both parents are carriers, there is a 25 percent chance with each pregnancy that their child will inherit two abnormal copies and have the disorder. There is a 50 percent chance the child will be a carrier like the parents, and a 25 percent chance the child will inherit two normal copies of the gene.1

Certain ethnic backgrounds may carry higher risks for specific types of fatty acid oxidation disorders. For example, MCADD is more common in people of Northern European descent.1

While the genetic mutation is present from birth, certain situations can trigger symptoms or make the condition worse. These triggering situations include prolonged periods without eating, which depletes other sources of energy and forces the body to try to use fats. Illness, fever, infection, and increased physical activity or exercise can also increase the body's energy demands and trigger symptoms. During these times, the body needs more energy than usual, and the inability to break down fats becomes more problematic.1

Symptoms

The symptoms of fatty acid oxidation disorders can vary widely depending on which specific enzyme is affected, how severe the deficiency is, and the age of the person when symptoms appear. Symptoms typically develop when the body needs to rely on fat for energy but cannot do so effectively.2

In medium-chain acyl-CoA dehydrogenase deficiency (MCADD), symptoms usually develop after 2 to 3 months of age. Children are most likely to develop symptoms if they go without food for a period of time or have an increased need for calories because of exercise or illness. The level of sugar in the blood, called glucose, drops significantly—a condition known as hypoglycemia. This drop in blood sugar causes confusion or even coma. Children may become weak and may have vomiting or seizures. Over time, children can develop delayed mental and physical development, an enlarged liver, heart muscle weakness, and an irregular heartbeat. In severe cases, sudden death may occur.1

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) causes symptoms similar to MCADD. People may also develop progressive impairment of the structure and function of the heart muscle, called cardiomyopathy, as well as damage to the nerves of the hands and feet, and abnormal liver function. When children with LCHAD exert themselves, such as during exercise, muscle tissue may become destroyed—a condition called rhabdomyolysis. The damaged muscles release a protein called myoglobin, which turns the urine brown or bloody, a condition known as myoglobinuria.1

Common symptoms across many types of fatty acid oxidation disorders include extreme sleepiness, behavior changes, irritable mood, poor appetite, fever, nausea, diarrhea, and vomiting. Some people experience an enlarged heart, muscle weakness, and heart failure. While at rest, some individuals may have irregular heart rhythms, including various forms of fast heartbeat or, more rarely, conduction disorders or slow heartbeat.5

Long-chain fatty acid oxidation disorders can cause both acute symptoms that develop suddenly and chronic symptoms that develop over time. Acute symptoms usually appear during illness or after skipping a meal, but they may also occur spontaneously or unpredictably. Chronic symptoms develop over months to years and can be brought on or worsened by fasting, illness, sustained exercise, or physiologic stress.6

Prevention

Because fatty acid oxidation disorders are inherited genetic conditions, they cannot be prevented. However, early detection through newborn screening can help prevent serious complications. All states in the United States require newborns to be screened for MCADD with a blood test, and many screen for other fatty acid oxidation disorders as well.1

For individuals diagnosed with a fatty acid oxidation disorder, preventing symptom episodes and complications requires careful management. The most important preventive measure is avoiding fasting. Children must eat often and should never skip meals. For infants, this means feeding every few hours, even during the night in some cases. Parents may need to set alarms to wake the baby for nighttime feedings.1

During illness, when appetite may be poor or vomiting occurs, it is critical to maintain calorie intake. Families should have an emergency plan that includes knowing when to contact their healthcare provider and when to go to the hospital for intravenous glucose administration. Some families keep emergency supplies at home, such as high-calorie drinks or cornstarch, which can help maintain blood sugar levels.1

Dietary management is essential for prevention. People with fatty acid oxidation disorders typically need to consume a diet high in carbohydrates and low in fats. Those with long-chain fatty acid oxidation disorders may need even more specific dietary restrictions, including limitation of long-chain fats and supplementation with medium-chain triglyceride oil. Some individuals also benefit from supplementation with carnitine, an amino acid that helps transport fatty acids, though this must be done under medical supervision.2

For some individuals, especially those with MCADD, cornstarch may be given at bedtime to help prevent blood glucose levels from dropping too low during the overnight fast. Cornstarch is a complex carbohydrate that is digested slowly, providing a steady release of glucose throughout the night.1

Pathophysiology

To understand fatty acid oxidation disorders, it helps to know how the body normally uses fats for energy. When the body needs energy and has used up available glucose, it releases fatty acids from fat stores in adipose tissue. These fatty acids travel through the bloodstream to cells that need energy, particularly in the liver, heart, and muscles.2

Inside cells, fatty acids must enter the mitochondria, which are small structures often called the powerhouses of the cell because they produce energy. Short-chain and medium-chain fatty acids can enter the mitochondria directly. However, long-chain fatty acids require a special transport system involving three enzymes or transport proteins and a substance called carnitine. This system moves long-chain fatty acids across the mitochondrial membrane.7

Once inside the mitochondria, fatty acids undergo a process called beta-oxidation. This process involves a cycle of four chemical steps that repeatedly remove two-carbon units from the fatty acid chain. Different enzymes work on fatty acid chains of different lengths—very long, long, medium, and short. Each cycle of beta-oxidation produces molecules that feed into another energy-producing process called the tricarboxylic acid cycle (also called the Krebs cycle). The end result is the production of energy in the form of ATP, which cells use to power their activities.2

In fatty acid oxidation disorders, specific enzymes in this process are missing or do not work properly. When an enzyme is deficient, the fatty acid breakdown process stops at that step. This creates two major problems. First, the body cannot produce enough energy from fats, which can lead to dangerously low blood sugar levels because the liver cannot make enough glucose from fat. This lack of energy particularly affects organs with high energy demands, such as the brain, heart, and muscles.4

Second, partially broken-down fatty acids and their byproducts accumulate in the blood and tissues. These accumulating substances, such as acyl-CoA compounds, can be toxic to organs. The buildup can damage the liver, causing it to enlarge and function poorly. It can damage the heart muscle, leading to cardiomyopathy and irregular heartbeats. It can also damage skeletal muscles, causing weakness and potentially rhabdomyolysis.1

During times of increased energy demand or decreased intake—such as illness, prolonged exercise, or fasting—the body tries harder to break down fats for energy. In people with fatty acid oxidation disorders, this increased demand reveals the underlying defect more clearly, leading to acute crises characterized by severely low blood sugar with unusually low levels of ketones (a condition called hypoketotic hypoglycemia), high levels of ammonia in the blood, and potentially life-threatening complications.2

In some types of fatty acid oxidation disorders, such as LCHAD and trifunctional protein deficiency, additional complications occur. These can include damage to the retina of the eye, leading to vision problems, and damage to peripheral nerves, causing peripheral neuropathy with numbness, tingling, or pain in the hands and feet. These complications appear to be related to the specific metabolic disruptions caused by these particular enzyme deficiencies.8