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Carnitine palmitoyltransferase II deficiency
This disorder of fat metabolism can lead to muscle pain, weakness, and other symptoms, particularly during periods of fasting or illness. It typically affects individuals from childhood into adulthood, with varying severity.
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Overview
Carnitine Palmitoyltransferase II (CPT2) deficiency is an inherited metabolic disorder where the body has difficulty processing certain types of fat for energy. This is due to a problem with the CPT2 enzyme, which plays a crucial role in transporting long-chain fatty acids into the mitochondria - the 'powerhouses' of cells - where they can be used for fuel [PMID:32060144].
When the CPT2 enzyme is not working correctly, the body cannot efficiently break down fats for energy, especially during prolonged fasting, strenuous exercise, or illness. This energy deficit can lead to a range of symptoms, primarily affecting muscle function. The condition is part of a larger group of disorders known as fatty acid oxidation disorders.
Symptoms & clinical features
The symptoms of CPT2 deficiency can vary significantly in their severity and presentation. The most common form, often referred to as the myopathic form, typically appears in adolescence or adulthood. Key symptoms include recurrent episodes of muscle pain (myalgia), muscle weakness, and muscle breakdown (rhabdomyolysis), which can cause dark-coloured urine due to the release of myoglobin. These episodes are often triggered by prolonged exercise, prolonged fasting, cold exposure, or infections [PMID:32060144].
In some rarer and more severe forms, symptoms can appear in infancy or childhood. These can include liver problems, heart issues, seizures, and developmental delays, alongside muscle weakness. The severity of symptoms depends on how much the CPT2 enzyme's function is impaired. Some individuals might experience symptoms only under specific triggers, while others could have more persistent issues.
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Affected organs
The primary organs affected by CPT2 deficiency are the skeletal muscles, which rely heavily on fatty acids for energy, especially during sustained activity. During metabolic stress, the inability to properly utilise fats can lead to muscle damage and pain.
In more severe infantile or neonatal forms of the condition, other organs can be significantly impacted. These may include the liver, leading to liver dysfunction; the heart, potentially causing cardiomyopathy; and the brain, which can manifest as neurological symptoms such as seizures or developmental delays. The kidneys can also be indirectly affected by complications arising from severe muscle breakdown.
Risks & severity
CPT2 deficiency exists on a spectrum of severity. The most common form, the myopathic type, generally has a good prognosis, with individuals learning to manage their triggers and typically experiencing symptoms only during specific events. The estimated prevalence for this milder form is around 1 in 300,000 people, though the exact prevalence for all forms combined is not well established [PMID:32060144].
The most serious complications in the myopathic form involve severe rhabdomyolysis, which can lead to acute kidney injury if not managed promptly. Rarer, more severe infantile and neonatal forms are often much more serious, with a higher risk of significant health problems affecting multiple organs and, in some cases, can be life-threatening. These severe forms may manifest early in life and require intensive medical management.
Genetic causes
CPT2 deficiency is caused by pathogenic variants in the CPT2 gene. This gene provides instructions for making the carnitine palmitoyltransferase II enzyme [PMID:36504289]. This enzyme is crucial for fatty acid oxidation, the process by which fats are broken down to produce energy, particularly long-chain fatty acids.
The CPT2 enzyme works within the mitochondria, the energy-producing organelles in cells. It helps transport long-chain fatty acids into the mitochondrial matrix so they can be converted into acetyl-CoA, a molecule used in the citric acid cycle to generate ATP, the cell's main energy currency. When there are pathogenic variants in the CPT2 gene, the enzyme either isn't produced in sufficient quantities or doesn't function correctly, impairing the body's ability to use fat for energy [PMID:36504289].
- CPT2 carnitine palmitoyltransferase 2The CPT2 gene provides instructions for making carnitine palmitoyltransferase 2, an enzyme vital for metabolising fatty acids into energy, particularly for muscles and during fasting.
Inheritance pattern
CPT2 deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of a pathogenic variant in the CPT2 gene - one from each parent - to develop the condition. Individuals who inherit only one pathogenic variant are called carriers. Carriers typically do not show symptoms of the condition themselves.
If both parents are carriers of a pathogenic CPT2 variant, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two copies of the variant and develop CPT2 deficiency. There is a 50% (1 in 2) chance the child will be a carrier, and a 25% (1 in 4) chance the child will inherit no pathogenic variants and neither have the condition nor be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing CPT2 deficiency typically involves a combination of clinical evaluation and genetic testing. If symptoms like recurrent muscle pain, weakness, or rhabdomyolysis occur, particularly after fasting or exercise, a doctor may suspect the condition. Blood tests can show elevated levels of creatine kinase (an enzyme released during muscle damage) and sometimes carnitine species.
Confirmation of CPT2 deficiency is often achieved through genetic testing, which looks for pathogenic variants in the CPT2 gene. This specific genetic testing falls under the NHS Genomic Medicine Service (GMS) pathways. A referral to a clinical genetics service or a metabolic specialist is usually made to arrange appropriate testing.
Management & lifestyle
Management of CPT2 deficiency primarily focuses on preventing symptomatic episodes and managing any acute crises. For the common myopathic form, this generally involves lifestyle adjustments. Individuals are typically advised to avoid prolonged fasting, eat frequent meals, and ensure adequate carbohydrate intake, especially before and during exercise. Avoiding triggers such as extreme cold and intense, sustained physical activity is also important.
During acute episodes of muscle pain or rhabdomyolysis, hospital admission may be necessary to manage symptoms, prevent kidney complications, and ensure adequate hydration. There is no specific cure for CPT2 deficiency, so management aims to minimise symptoms and improve quality of life. For more severe forms, medical management will be more comprehensive and require close monitoring by a specialist metabolic team, often involving dietary modifications and other supportive therapies. Patients are encouraged to discuss their specific management plan with their healthcare team.
UK care pathway
In the UK, individuals suspected of having CPT2 deficiency would generally be referred through their GP or a specialist physician to an NHS clinical genetics service or a specialist metabolic centre. These services can confirm a diagnosis through genetic testing, which is part of the NHS Genomic Medicine Service (GMS) testing directory. Genetic counsellors within these services provide vital support, helping individuals and families understand the diagnosis, inheritance patterns, and implications for family planning. The relevant tests for conditions like CPT2 deficiency can be found within the Genomics England PanelApp.
Frequently asked questions
What triggers CPT2 deficiency symptoms?
Symptoms of CPT2 deficiency are often triggered by situations where the body heavily relies on fat for energy. Common triggers include prolonged fasting, strenuous or sustained exercise, exposure to cold, fever, and certain infections.
Can CPT2 deficiency be cured?
Currently, there is no cure for CPT2 deficiency. Management focuses on preventing symptoms and episodes by avoiding triggers and making lifestyle adjustments, such as dietary modifications, to reduce the reliance on fat metabolism.
How does CPT2 deficiency affect daily life?
For most people with the myopathic form, CPT2 deficiency can be managed by avoiding specific triggers like prolonged fasting and intense exercise. With careful management, many individuals can lead full and active lives, though they may need to plan meals and activities carefully.
What should I do if I have a CPT2 deficiency episode?
During an episode of severe muscle pain or dark urine (a sign of rhabdomyolysis), it is important to seek immediate medical attention. Hospital care may be needed for assessment, hydration, and to prevent complications like kidney damage.
Are there different types of CPT2 deficiency?
Yes, there are different forms of CPT2 deficiency. The most common is the myopathic form, which typically appears in adolescence or adulthood. Rarer, more severe forms can affect infants and children, presenting with a broader range of symptoms including liver, heart, and brain involvement.
References
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- Sigauke E, Rakheja D, Kitson K. Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Laboratory investigation; a journal of technical methods and pathology. 2003. PMID: 14615409
- Tan A, Stepien KM, Narayana STK. Carnitine palmitoyltransferase II deficiency and post-COVID vaccination rhabdomyolysis. QJM : monthly journal of the Association of Physicians. 2021. PMID: 33871650
- Lehmann D, Motlagh L, Robaa D. Muscle Carnitine Palmitoyltransferase II Deficiency: A Review of Enzymatic Controversy and Clinical Features. International journal of molecular sciences. 2017. PMID: 28054946
- Tajima G, Hara K, Yuasa M. Carnitine palmitoyltransferase II deficiency with a focus on newborn screening. Journal of human genetics. 2019. PMID: 30514913
- Mccormick BJ, Chirila RM. Carnitine palmitoyltransferase-II deficiency: case presentation and review of the literature. Romanian journal of internal medicine = Revue roumaine de medecine interne. 2021. PMID: 34118800
- Tein I. Neonatal metabolic myopathies. Seminars in perinatology. 1999. PMID: 10331465
- Verderio E, Cavadini P, Montermini L. Carnitine palmitoyltransferase II deficiency: structure of the gene and characterization of two novel disease-causing mutations. Human molecular genetics. 1995. PMID: 7711730