Fatty Acid Oxidation Disorder

Fatty acid oxidation disorders are inherited conditions that prevent the body from breaking down fats to produce energy, leaving organs without the fuel they need during times of fasting, illness, or physical activity.

Table of contents

• What Are Fatty Acid Oxidation Disorders
• How These Disorders Are Inherited
• The Role of Fats in Energy Production
• Types of Fatty Acid Oxidation Disorders
• Signs and Symptoms
• Diagnosis and Screening
• Treatment and Management
• Medium-Chain Acyl-CoA Dehydrogenase Deficiency
• Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency
• Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

What Are Fatty Acid Oxidation Disorders

Fatty acid oxidation disorders are lipid metabolism disorders, which are conditions affecting how the body processes fats. These disorders occur when the body lacks or has a deficiency of the enzymes—special proteins that help chemical reactions happen in the body—needed to break down fats^[1]. Without these enzymes working properly, the body cannot convert fats into energy, resulting in delayed mental and physical development^[1].

These disorders are also called fatty acid oxidation deficiencies or FAODs. They are inborn errors of metabolism, meaning they are genetic problems present from birth that affect how the body processes nutrients^[2]. The disorders disrupt either mitochondrial β-oxidation—the process inside cell structures called mitochondria where fats are broken down—or the fatty acid transport using the carnitine transport pathway^[2].

How These Disorders Are Inherited

Fatty acid oxidation disorders occur when parents pass on to their children the defective genes that cause these conditions^[1]. In these disorders, both parents of the affected child carry one copy of the abnormal gene. Because usually two copies of the abnormal gene are necessary for the disorder to occur, usually neither parent has the disorder. This pattern is called autosomal recessive inheritance^[1][2].

The Role of Fats in Energy Production

Fats, also called lipids, are an important source of energy for the body^[1]. The body’s primary source of energy is glucose, a type of sugar. However, when all the glucose in the body has been used up, a normal body digests fats^[5]. The body’s store of fat is constantly broken down and reassembled to balance the body’s energy needs with the food available^[1].

When fat is needed as an energy source during periods of decreased intake, prolonged fasting, or increased energy demands due to illness, fatty acids are released from storage in the adipose tissue and undergo mitochondrial β-oxidation^[2]. Several enzymes help break down fats so that they may be turned into energy^[1]. This process is especially important for organs that require a lot of energy, such as the heart, skeletal muscles, and liver^[4].

Children who have a fatty acid oxidation disorder are missing or have a deficiency of the enzymes needed to break down fats. The lack of these enzymes leaves the body short of energy and allows breakdown products, such as acyl-CoA, to accumulate^[1]. This results in a build-up of fatty acids in the liver and other internal organs^[5][6].

Types of Fatty Acid Oxidation Disorders

There are different types of fatty acid oxidation disorders, each caused by the deficiency of a specific enzyme. The enzyme most commonly deficient is medium-chain acyl-CoA dehydrogenase (MCAD)^[1]. Other enzyme deficiencies include short-chain acyl-CoA dehydrogenase (SCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), glutaric acidemia type II, and mitochondrial trifunctional protein (TFP) deficiency^[1].

Long-chain fatty acid oxidation disorders (LC-FAODs) are a specific group of these disorders that prevent the body from breaking down long-chain fatty acids and converting them to energy^[4]. Specific LC-FAODs include deficiencies of very long-chain acyl-CoA dehydrogenase (VLCAD), carnitine palmitoyltransferase I (CPT I), carnitine palmitoyltransferase II (CPT II), and long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency/trifunctional protein (TFP)^[4].

Most of these disorders begin in infancy^[1].

Signs and Symptoms

The presentation of a fatty acid oxidation disorder depends upon the specific disorder, but common elements may be seen^[2]. Initial presentations in the neonatal period with severe symptoms include cardiomyopathy—a disease affecting the heart muscle^[2]. During infancy and childhood, liver dysfunction and hypoketotic hypoglycemia—dangerously low blood sugar with low ketone levels—are common^[2].

When babies with fatty acid oxidation disorders go long periods of time without eating, they often experience symptoms such as low blood sugar, sleeping longer than usual, changes in mood, poor appetite, diarrhea, and vomiting^[6]. Common symptoms also include extreme sleepiness, behavior changes, irritable mood, nausea, and fever^[5].

Episodic rhabdomyolysis—breakdown of muscle tissue—is frequently the initial presentation during or after adolescence, although these symptoms may develop at any age for most of the fatty acid oxidation disorders^[2]. Some people exhibit cardiac arrhythmia, which means irregular heartbeats, while at rest; others have a normal heart rhythm^[5].

If left untreated, fatty acid oxidation disorders can lead to life-threatening low blood sugar, heart disease, breakdown of muscle tissue, and high levels of ammonia in the body, which can cause damage to the liver and brain^[4]. This means that organs that depend on a lot of energy—such as the brain, heart, and muscles—may stop working properly^[4].

Diagnosis and Screening

All states in the United States require all newborns be screened for some fatty acid oxidation disorders with a blood test^[1]. Tests of the urine and other tissues may also be done. DNA testing can be done to confirm the diagnosis^[1].

The screening method commonly uses tandem mass spectrometry, a laboratory technique that measures specific substances in the blood^[1]. This method can detect elevated levels of different types of molecules that indicate specific enzyme deficiencies^[1].

Early diagnosis on newborn screening and early initiation of treatment are improving outcomes^[2]. Despite newborn screening, the importance of rapid and accurate identification of the key signs and symptoms remains critical to manage metabolic crises and prevent serious complications^[2].

Treatment and Management

Treatment of fatty acid oxidation disorders varies depending on the type of fatty substances that accumulate in the blood and tissues^[1]. However, the treatment of all fatty acid oxidation disorders includes avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine, if necessary^[2].

Treatment usually includes a special diet to keep blood glucose levels at an adequate level. This may require low-fat, high-carbohydrate nutrients every 2 to 6 hours^[6]. The long-chain fatty acid oxidation disorders differ by requiring a fat-restricted diet and supplementation of medium-chain triglyceride oil and often docosahexaenoic acid (DHA)—an essential fatty acid crucial for brain, visual, and immune functions—and prevention of fat-soluble vitamin deficiencies^[2].

Managing fatty acid oxidation disorders necessitates special care to maintain sufficient energy levels and prevent energy crashes^[8]. When a person’s oral intake cannot meet the energy demands, alternative fuel sources such as sugar or glucose may be administered orally or intravenously to prevent an energy crash and stabilize energy levels^[8].

The disease demands families and caregivers to immediately establish and closely follow a specific diet and monitor physical activity. Care of individuals may require an around-the-clock commitment to check for signs and symptoms of deterioration and fatigue^[17]. The management of caloric intake, avoidance of fasting, including overnight, and potential monitoring or maintenance of feeding tubes may result in restrictions on time and freedom^[17].

Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is one of the most common inherited disorders of metabolism, particularly among people of Northern European descent^[1].

Symptoms of MCADD 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, which depletes other sources of energy, or have an increased need for calories because of exercise or illness^[1]. The level of sugar in the blood drops significantly, causing confusion or coma. Children become weak and may have vomiting or seizures. Over time, children have delayed mental and physical development, an enlarged liver, heart muscle weakness, and an irregular heartbeat. Sudden death may occur^[1].

Immediate treatment of an MCADD attack is with dextrose given by vein. For long-term treatment, children must eat often, never skip meals, and consume a diet high in carbohydrates and low in fats^[1]. Supplements of the amino acid carnitine may be helpful. Cornstarch may need to be given at night to prevent the level of glucose in the blood from getting too low^[1].

The long-term outcome is generally good^[1].

Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is the second most common fatty acid oxidation disorder^[1]. It causes symptoms similar to those caused by MCADD. People may also have progressive impairment of the structure and function of the muscular walls of the heart chambers, damage to the nerves of the hands and feet, and abnormal liver function^[1].

When children exert themselves, such as when exercising, the muscle tissue may become destroyed and the damaged muscles may release the protein myoglobin, which turns the urine brown or bloody. This condition is called myoglobinuria^[1].

A woman whose fetus has LCHADD often has hemolysis, which is the breakdown of red blood cells, and elevated levels of liver enzymes^[1].

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is another type of fatty acid oxidation disorder. The deficiency of the enzyme impairs the conversion of dietary fats and fats stored in the body to energy^[1].

Signs and symptoms typically appear during infancy or early childhood and include low blood sugar, lack of energy, muscle weakness, and patients are at risk for serious complications such as liver abnormalities and heart problems^[1]. This disorder is sometimes mistaken for Reye syndrome^[1].