CPT2 Deficiency

Introduction

Carnitine palmitoyl transferase 2 deficiency, or CPT2, is the most common of the fatty acid oxidation disorders (FAODs) and occurs most often in a mild form. At the International Network for Fatty Acid Oxidation Research and Management (INFORM), we strive to educate people about these disorders and what it means if someone you love if diagnosed with this problem.

What is CPT2 Deficiency?

Carnitine palmitoyl transferase 2 deficiency (CPT2) is a rare inherited disorder that occurs when the last step in the entry of fats into sac-like bodies called mitochondria is blocked. Mitochondria are the site within cells where energy from fat is generated. When the body has exhausted its stores of available sugars, it must turn to fats to produce energy. This change in energy source is particularly important during stress, illness, fasting, and intense exercise. The entry of fats into mitochondria is highly regulated at the point where they cross the inner membrane. In order to cross, free fats, known as fatty acids, must be linked to a molecule called carnitine. This fatty acylcarnitine next crosses the inner mitochondrial membrane via a carnitine translocase protein. In the last step of this transit, CPT2 returns this fatty acylcarnitine to its original fatty acyl-coenzyme A form that can enter the pathways to generate energy (fatty acid oxidation). People with a CPT2 deficiency have problems which prevent them from efficiently completing this last step.

Genetics

Like other FAODs, the CPT2 deficiency is genetic. It occurs when an individual inherits a mutation in the gene for CPT2 from each parent making it autosomal recessive. The parents are carriers of the disorder but have no symptoms. When both parents are carriers, there is a 25% chance that any child they conceive will have the CPT2 deficiency. Genetic counseling will benefit affected individuals, as well as their families. Existing and subsequent siblings of the index case should be tested for CPT2 defects.

With the mild form of the disorder, the children may not have been symptomatic during newborn screening or older siblings may not have been screened. With the severe form in particular, the family should be asked whether there have been episodes of sudden infant death (SID) or unexplained infant deaths, which may have been caused by previously unrecognized CPT2.

Signs and Symptoms of CPT2 Deficiency

CPT2 deficiency can occur is both mild and severe forms. Patients usually present in adolescence or early adulthood. The first signs of CPT2 deficiency include brownish red urine (myoglobinuria) and muscle weakness or pain after prolonged exercise or other physical stress.

Patients with this fatty acid oxidation disorder may exhibit these common symptoms:

  • High blood ammonia
  • Enlarged liver (hepatomegaly), especially when sick
  • Severe skeletal muscle weakness or pain
  • Muscle breakdown such as myoglobinuria
  • Heart enlargement
  • A specific life-threatening low blood sugar (hypoketotic hypoglycemia)

When healthy people fast or burn excessive calories in exercise, they burn fat to maximize calorie efficiency and to save glucose. At the end of this fat oxidation, some of its products are turned into protective molecules called ketones that provide energy for the brain. Since patients with a severe CPT2 deficiency and other fatty acid oxidation disorders have a limited ability to break down fats, this low blood sugar can lead to:

  • Lack of ketones (hypoketotic)
  • Coma or seizures (days or weeks after birth)
  • Increased risk of brain damage from lack of ketones

When CPT2 defect present themselves in babies, infants will show signs of lethargy, irritability, and a poor appetite. From ages two or three months to about two years, affected infants are at risk for many serious heart problems including:

  • A weakened heart muscle (cardiomyopathy)
  • Abnormal heart rhythms
  • Total failure of the combined lung and heart function

During acute episodes, patients will have elevated blood levels of creatine kinase (CPK), a marker for muscle injury (rhabdomyolysis), but they rarely will have low blood sugar (hypoglycemia).

How to Diagnose CPT2 Deficiency

If a thorough clinical evaluation reveals many of the symptoms previously mentioned, CPT2 deficiency is a likely suspect.

Older children or younger adults will have characteristics of muscle breakdown such as myoglobinuria, elevated CPK, and severe skeletal muscle pain. Once a FAOD is suspected, clinical studies of blood and urine by tandem mass spectrometry (acylcarnitine analysis) and GC-mass spectrometry (organic acid analysis), respectively, will be used to differentiate CPT2 and its associated translocase defect from other fatty acid defects with similar characteristics.

Specifically, CPT2 deficiency has a characteristic blood pattern that includes increases in long chain fatty acids (16-18-carbon), as well as their long chain dicarboxylic acids, all complexed to carnitine (acylcarnitines). Free carnitine levels are low, and organic acids are usually normal.

Unfortunately, this laboratory profile is identical to that of the carnitine translocase (CACT) deficiency. To differentiate the two, the specific diagnosis must be confirmed by genetic testing for CPT2 mutations or by measurement of CPT2 activity in blood or skin cells. For mild CPT2 deficiency, there is a common CPT2 mutation that can be used as a mutation analysis starting point. Patients with the common mild CPT2 deficiency can have a normal fatty acid carnitine pattern on newborn screening (222) if they are not stressed. Fortunately, the medical treatments of CACT and CPT2 defects are identical. Consequently, as soon as the newborn screening results are verified, treatment can begin, minimizing damage from the defect.

Prenatal diagnosis is available by CPT2 enzyme measurement of either cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta (the sack in the uterus that holds and feeds the fetus). If the mutations in a previously affected family member are known, direct mutation testing of prenatal samples is possible.

Treatment

As with most fatty acid oxidation defects, fasting should be avoided. As the child gets older, they will become more stable and can go longer between feedings, up to 6-8 hours from the initial 2-3 hours. Since prevention of fasting is the mainstay of therapy, in severe cases continuous feeding by a stomach tube may be necessary, especially at night. Medium chain triglycerides (MCT oils) and artificial fats can be given as a supplement because they do not depend on CPT1a to enter the inner mitochondrial space. With more fatty acid oxidation research in the future, treatments may change.

Investigative Therapies and Fatty Acid Oxidation Research

If you or a loved one is diagnosed with a fatty acid oxidation disorder like CPT2, it is important that you do your research. Our founder of INFORM Network, Jerry Vockley, suggests looking for more information at ClinicalTrials.gov, where you may be able to find the latest investigative therapies for these disorders.

While FAODs are rare, you are not alone. At the International Network for Fatty Acid Oxidation Research and Management (INFORM), we want to be your reliable source of information for these disorders and connect you with FAODs support groups so that you can learn to manage this disorder.

Related Readings:

CACT Deficiency Versus CPT2 Deficiency

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