Carnitine Palmitoyltransferase II (CPT2) deficiency is a rare inherited metabolic disorder. This condition impairs the body’s ability to process long-chain fatty acids for energy. Normally, the body breaks down these fats for fuel, especially during fasting, prolonged exercise, or illness. In CPT2 deficiency, this process is disrupted, leading to an energy shortage and the accumulation of unprocessed fatty acids.
The Genetic Basis of CPT2 Deficiency
CPT2 deficiency arises from mutations within the CPT2 gene. This gene provides instructions for the carnitine palmitoyltransferase II (CPT2) enzyme, which transports long-chain fatty acids into the mitochondrial matrix.
Mitochondria generate much of the cell’s energy. Located on the inner mitochondrial membrane, the CPT2 enzyme converts acylcarnitine back into acyl-CoA, enabling fatty acids to be broken down for energy through beta-oxidation. When the CPT2 gene has mutations, the enzyme’s activity is reduced, preventing long-chain fatty acids from being properly processed and used as fuel.
CPT2 deficiency is inherited in an autosomal recessive pattern, meaning an affected individual must inherit a mutated CPT2 gene from both parents. Carrier parents, who typically show no symptoms, can pass the condition to their children. Each child of two carriers has a 25% chance of developing the disorder and a 50% chance of being a carrier.
Forms and Symptoms of CPT2 Deficiency
CPT2 deficiency manifests in three distinct forms, with symptoms and severity varying significantly. The presentation depends on the age of onset and affected body systems, reflecting different levels of enzyme activity.
The myopathic form is the most common, with symptoms typically appearing in childhood or adulthood. Individuals experience recurrent episodes of muscle pain, weakness, and rhabdomyolysis (muscle tissue breakdown). These episodes can be triggered by prolonged exercise, fasting, infections, or exposure to extreme temperatures. Rhabdomyolysis can lead to the release of myoglobin, a muscle protein, into the bloodstream, which may cause the urine to appear dark, reddish-brown. Between episodes, individuals are usually without symptoms.
A more severe infantile hepatocardiomuscular form typically emerges within the first year of life. This form affects multiple organ systems, leading to serious health complications. Symptoms include liver failure, heart muscle disease (cardiomyopathy), seizures, and episodes of hypoketotic hypoglycemia (low blood sugar with low levels of ketones). These severe episodes are often triggered by fasting or illnesses.
The lethal neonatal form is the rarest and most severe, with symptoms becoming apparent shortly after birth. Infants with this form develop severe multisystemic issues, including respiratory failure, liver failure, and severe heart muscle weakness (cardiomyopathy). Other symptoms can include irregular heartbeats, structural brain abnormalities, and kidney disease. Due to the severity of these complications, infants often live only for a few days to several months.
The Diagnostic Process
Diagnosis begins with evaluating clinical symptoms, which vary by form. Suspicion often arises from recurrent muscle pain and weakness linked to triggers like fasting or exercise in the myopathic form, or unexplained seizures, respiratory distress, or liver issues in infants.
Blood tests are significant. Tandem mass spectrometry analyzes the acylcarnitine profile in blood or plasma, revealing elevated long-chain acylcarnitines. During rhabdomyolysis, creatine kinase (CK) levels are typically very high. Urine tests can detect myoglobin (myoglobinuria) and analyze organic acids, especially during symptomatic periods.
Molecular genetic testing identifies CPT2 gene mutations, providing definitive diagnosis. This accurate testing detects pathogenic variants in over 95% of patients. While muscle biopsies to measure CPT2 enzyme activity were historically used, genetic testing is now the preferred, less invasive method.
Management and Treatment Strategies
There is no cure for CPT2 deficiency, but the condition can be effectively managed through strategies aimed at preventing symptoms and minimizing complications. Management focuses on modifying diet and lifestyle to avoid triggers that can lead to metabolic crises.
Dietary management forms the cornerstone of treatment. Individuals must avoid prolonged fasting, as the body relies on fat breakdown for energy during these times. A diet low in long-chain fatty acids and high in carbohydrates is generally recommended to provide alternative energy sources. Medium-chain triglyceride (MCT) oil supplementation is often included because MCTs can be broken down for energy without requiring the CPT2 enzyme, bypassing the impaired metabolic pathway.
Individuals must avoid common triggers that can precipitate symptoms, including prolonged or strenuous exercise, exposure to cold temperatures, fever, and emotional stress. Maintaining a regular meal schedule and consuming high-carbohydrate snacks before physical activity or during illness can help prevent energy deficits.
During acute episodes, medical interventions often become necessary. Hospitalization may be required to administer intravenous (IV) glucose, which provides an immediate energy source and helps prevent further muscle breakdown. Adequate hydration protects the kidneys from damage caused by myoglobin released during rhabdomyolysis. Carnitine supplements may be considered, although their benefit can vary among individuals and is sometimes debated. Additionally, some experimental treatments, such as bezafibrate, have shown promise in clinical trials for improving fatty acid oxidation in the myopathic form, though more research is ongoing.