Carnitine palmitoyltransferase II (CPT II) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). There are three main types of CPT II deficiency: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a myopathic form.

The lethal neonatal form of CPT II deficiency becomes apparent soon after birth. Infants with this form of the disorder develop respiratory failure, seizures, liver failure, a weakened heart muscle (cardiomyopathy), and an irregular heart beat (arrhythmia). Affected individuals also have low blood glucose (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. In many cases, the brain and kidneys are also structurally abnormal. Infants with the lethal neonatal form of CPT II deficiency usually live for a few days to a few months.

The severe infantile hepatocardiomuscular form of CPT II deficiency affects the liver, heart, and muscles. Signs and symptoms usually appear within the first year of life. This form involves recurring episodes of hypoketotic hypoglycemia, seizures, an enlarged liver (hepatomegaly), cardiomyopathy, and arrhythmia. Problems related to this form of CPT II deficiency can be triggered by periods of fasting or by illnesses such as viral infections. Individuals with the severe infantile hepatocardiomuscular form of CPT II deficiency are at risk for liver failure, nervous system damage, coma, and sudden death.

The myopathic form is the least severe type of CPT II deficiency. This form is characterized by recurrent episodes of muscle pain (myalgia) and weakness and is associated with the breakdown of muscle tissue (rhabdomyolysis). The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). Myoglobin causes the urine to be red or brown. This protein can also damage the kidneys, in some cases leading to life-threatening kidney failure. Episodes of myalgia and rhabdomyolysis may be triggered by exercise, stress, exposure to extreme temperatures, infections, or fasting. The first episode usually occurs during childhood or adolescence. Most people with the myopathic form of CPT II deficiency have no signs or symptoms of the disorder between episodes.

Mutations in the CPT2 gene cause CPT II deficiency. This gene provides instructions for making an enzyme called carnitine palmitoyltransferase 2. This enzyme is essential for fatty acid oxidation, which is the multistep process that breaks down (metabolizes) fats and converts them into energy. Fatty acid oxidation takes place within mitochondria, which are the energy-producing centers in cells. A group of fats called long-chain fatty acids must be attached to a substance known as carnitine to enter mitochondria. Once these fatty acids are inside mitochondria, carnitine palmitoyltransferase 2 removes the carnitine and prepares them for fatty acid oxidation. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.

Mutations in the CPT2 gene reduce the activity of carnitine palmitoyltransferase 2. Without enough of this enzyme, carnitine is not removed from long-chain fatty acids. As a result, these fatty acids cannot be metabolized to produce energy. Reduced energy production can lead to some of the features of CPT II deficiency, such as hypoketotic hypoglycemia, myalgia, and weakness. Fatty acids and long-chain acylcarnitines (fatty acids still attached to carnitine) may also build up in cells and damage the liver, heart, and muscles. This abnormal buildup causes the other signs and symptoms of the disorder.

CPT II deficiency is a genetic condition. Babies inherit it from their biological (birth) parents.

• CPT II deficiency is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking CPT2 gene to their baby. Only babies with two nonworking CPT2 genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the CPT2 gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the CPT2 gene, they have a 1 in 4 chance of having a child with CPT II deficiency.
  • Carriers for CPT II deficiency often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with CPT II deficiency.
  • Parents who already have a child with CPT II deficiency still have a 1 in 4 chance of having another child with CPT II deficiency. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of the condition appear at different times depending on the type of CPT II deficiency. The newborn type shows signs soon after birth. The infant type shows signs within the first year of life. The milder myopathic type doesn’t begin showing signs until early in childhood or in adulthood.

Symptoms of CPT II deficiency can be triggered by common illnesses (like a cold or flu) or a long time without food.

Signs of CPT II deficiency in babies who have the newborn or infant forms of CPT II deficiency may include the following:

• Weak muscles (hypotonia)
• Muscle pain (myalgia)
• Heart problems and irregular heart beat (arrhythmia)
• Low blood sugar (hypoglycemia)
• Enlarged liver (hepatomegaly)
• Sleepiness
• Poor feeding
• Breathing problems
• Fever
• Diarrhea
• Vomiting
• Seizures

Newborn screening for CPT II deficiency is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much of certain substances (called acylcarnitines) are in your baby’s blood. The body produces these substances when it makes energy from fats. Babies with high levels of these substances might have CPT II deficiency.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for CPT II deficiency is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample
• Small skin sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. However, some situations can affect screening results:

• Screening samples were collected too early (before the baby is 24 hours old)
• Babies who were given carnitine may have false positive results for this condition.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Regular and frequent meals and snacks
• Diet high in carbohydrates and low in fat
• Medium chain triglyceride (MCT) oil supplements to provide fats the body can break down
• L-carnitine supplements to help the body break down fats (in some cases)
• Avoiding cold weather (in some cases)

Children who receive early and ongoing treatment for CPT II deficiency can have healthy growth and development. Some children will develop issues with their heart, lungs, or liver even with treatment.

CPT II deficiency is a rare disorder. The lethal neonatal form has been described in at least 18 families, while the severe infantile hepatocardiomuscular form has been identified in approximately 30 families. The myopathic form occurs most frequently, with more than 300 reported cases.