Carnitine Palmitoyltransferase II (CPT2) deficiency is a rare, inherited metabolic disorder that significantly impairs the body’s ability to generate energy from long-chain fatty acids. This condition stems from a defect in the CPT2 gene, which codes for the CPT2 enzyme. The resulting enzyme deficiency prevents the proper processing of fat molecules, leading to an energy shortage, especially in tissues like muscle and liver. This failure in fat processing causes both a lack of energy and a buildup of toxic intermediates, which collectively result in the varied symptoms of the disorder.
The Role of CPT2 in Energy Metabolism
The body relies on a process called long-chain fatty acid oxidation (L-CFAO) to convert stored fats into usable energy, a process that becomes particularly important during periods of fasting, prolonged exercise, or illness. L-CFAO takes place within the mitochondria. Long-chain fatty acids, which cannot cross the mitochondrial membranes alone, require a specialized transport system known as the carnitine shuttle.
The CPT2 enzyme is a component of this shuttle, located on the inner mitochondrial membrane. Its function is to take the long-chain acylcarnitine molecules that have been transported across the membrane and convert them back into long-chain acyl-CoAs. This regeneration step is the final requirement for the fatty acid to enter the beta-oxidation pathway, where it is broken down sequentially to produce acetyl-CoA for the generation of ATP energy.
When the CPT2 enzyme is deficient, this critical conversion step is stalled, preventing long-chain fatty acids from being oxidized for energy. The resulting energy deficit disproportionately affects organs that rely heavily on fat for fuel, such as the heart and skeletal muscles. Furthermore, the unprocessed long-chain acylcarnitines accumulate within the cells and bloodstream, which can become toxic to tissues, contributing to organ damage and metabolic crises.
The body’s inability to properly utilize fat also leads to a failure in ketone body production. This metabolic failure results in hypoketotic hypoglycemia, where both blood sugar (glucose) and ketones are abnormally low. The severity of symptoms correlates directly with the amount of residual enzyme activity, ranging from near-total absence to a minor reduction in function.
Clinical Forms and Specific Symptoms
CPT2 deficiency presents in three distinct clinical forms, each defined by its age of onset and the severity of its symptoms. The least common but most severe presentation is the Neonatal Lethal Form, which becomes evident shortly after birth. Infants experience profound multi-organ failure, including respiratory failure, severe liver dysfunction, and an enlarged heart (cardiomyopathy) with irregular heartbeats (arrhythmia). This form often includes seizures, structural abnormalities in the brain and kidneys, and rapid progression toward early death within the first few months of life.
A less severe presentation is the Severe Infantile Hepatocardiomuscular Form, which typically appears within the first year of life. This form involves recurring, life-threatening episodes of hypoketotic hypoglycemia and liver failure, sometimes presenting as an enlarged liver (hepatomegaly). Patients frequently exhibit heart involvement, such as cardiomyopathy, and episodes of muscle weakness (myopathy) in the limbs. These metabolic crises are often triggered by prolonged fasting or intercurrent infections.
The Myopathic Form is the most frequently encountered type of CPT2 deficiency, presenting in childhood, adolescence, or even adulthood. This form is characterized primarily by recurrent, exercise-induced episodes of muscle pain (myalgia) and profound muscle breakdown, rhabdomyolysis. These attacks are typically precipitated by strenuous or prolonged physical activity, extended periods without food, exposure to cold, or general illness.
During a rhabdomyolysis episode, damaged muscle cells release myoglobin into the bloodstream, which is then excreted in the urine. This process leads to the hallmark symptom of dark, reddish-brown urine, known as myoglobinuria. Severe rhabdomyolysis can still lead to acute kidney injury due to the high levels of myoglobin. Between symptomatic episodes, most individuals with the myopathic form are entirely asymptomatic, with normal muscle strength and function.
Diagnosis and Disease Management
The identification of CPT2 deficiency often begins with newborn screening programs, which utilize tandem mass spectrometry (TMS) to analyze a blood spot sample. This test looks for elevated levels of specific long-chain acylcarnitines, such as C16 and C18:1, indicating a fat oxidation disorder. If the screening is abnormal, definitive diagnosis is confirmed through further biochemical tests, including a plasma acylcarnitine profile, or by directly measuring CPT2 enzyme activity in muscle or other cells.
Genetic testing, involving sequencing of the CPT2 gene, can also provide a confirmation of the diagnosis by identifying the specific disease-causing variations. For the myopathic form, which may be missed by newborn screening if the patient is not metabolically stressed, the presence of myoglobinuria and elevated creatine kinase (CK) levels during an attack strongly suggests the diagnosis.
Management of CPT2 deficiency focuses on two main strategies: dietary modification and avoidance of metabolic triggers. Patients are typically advised to follow a diet that is low in fat, particularly long-chain fats, and high in carbohydrates to ensure a steady supply of glucose energy. A foundational treatment involves supplementation with Medium-Chain Triglycerides (MCTs), which bypass the defective CPT2 enzyme and are used directly for mitochondrial energy production.
To prevent the onset of symptoms, individuals must avoid prolonged fasting, as this forces the body to rely on the impaired fat-burning pathway. They should consume frequent, small meals and carbohydrate-rich snacks, especially before strenuous activity. During periods of illness, such as fever or infection, patients must receive immediate medical attention, often requiring intravenous (IV) glucose administration to prevent catabolism and a metabolic crisis. Staying well-hydrated during muscle pain episodes is important to flush out myoglobin and protect the kidneys from damage.