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Carnitine-acylcarnitine translocase deficiency
CACT deficiency prevents the body from properly breaking down certain fats for energy, which can lead to serious health problems, particularly during times of fasting or illness. It typically affects infants and young children.
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Overview
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare genetic condition that affects the body's ability to convert certain types of fats into energy. This process usually happens within specialised compartments in cells called mitochondria. Individuals with CACT deficiency cannot efficiently transport long-chain fatty acids into their mitochondria for energy production because of a problem with a specific protein called carnitine-acylcarnitine translocase [PMID:16596162].
This condition is part of a group of disorders known as fatty acid oxidation disorders. When the body cannot use fat for energy, it must rely more heavily on glucose (sugar). During periods of fasting, illness, or increased energy demand, the body's sugar stores can quickly become depleted. This can lead to a metabolic crisis, where the body does not have enough fuel to function correctly.
CACT deficiency is considered a very rare condition. Early diagnosis and careful management are crucial for improving outcomes for affected individuals. It is typically identified in infancy or early childhood.
Symptoms & clinical features
The symptoms of CACT deficiency can vary in severity, but they often appear in the first few days or weeks of life. Common signs include extreme tiredness (lethargy), poor feeding, and low blood sugar (hypoglycaemia) [PMID:19007624]. Infants may also experience weakness in their muscles (hypotonia) and an enlarged liver (hepatomegaly).
In some cases, individuals may experience more severe symptoms such as heart problems (cardiomyopathy), irregular heart rhythms (arrhythmias), or even coma. These severe symptoms are often triggered by periods of fasting, infections, or excessive exercise, which increase the body's energy demands. Without timely treatment, recurrent metabolic crises can lead to significant health complications.
Some individuals might have a milder form of the condition, with symptoms only appearing later in childhood or being less severe. However, even milder forms still require careful management to prevent sudden metabolic decompensation.
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Affected organs
CACT deficiency primarily affects organs that have high energy demands or rely heavily on fat for energy. The liver is significantly impacted, leading to an enlarged liver (hepatomegaly) and impaired liver function, which contributes to low blood sugar levels. The liver typically plays a key role in regulating glucose production and fat metabolism.
The heart can also be affected, sometimes developing cardiomyopathy, where the heart muscle becomes weakened and enlarged. This can lead to heart failure if not managed. Skeletal muscles may also show weakness (myopathy) due to insufficient energy supply. The brain can be affected indirectly by repeated episodes of low blood sugar, which can lead to neurological damage if not promptly addressed.
Risks & severity
The severity of CACT deficiency varies among affected individuals, ranging from severe, life-threatening forms in infancy to milder presentations with later onset of symptoms. The most severe form typically presents shortly after birth with symptoms that can rapidly progress, including heart failure and severe metabolic crises that can be fatal [PMID:19007624].
Individuals with CACT deficiency face a lifelong risk of metabolic crises, especially during periods of fasting, illness, or increased energy expenditure. These crises are characterised by low blood sugar, lethargy, muscle weakness, and in severe cases, can lead to coma or heart complications. Continuous monitoring and strict adherence to dietary and management guidelines are essential to minimise these risks. Long-term complications can include developmental delays and neurological issues if metabolic control is poor.
Genetic causes
Carnitine-acylcarnitine translocase deficiency is caused by pathogenic variants in the SLC25A20 gene. This gene provides instructions for making the carnitine-acylcarnitine translocase protein, which is found in the inner membrane of mitochondria. Mitochondria are often called the 'powerhouses' of the cell because they generate most of the energy needed for cellular function.
The carnitine-acylcarnitine translocase protein is crucial for transporting long-chain fatty acids from the cytoplasm into the mitochondria. Inside the mitochondria, these fatty acids undergo a process called beta-oxidation to produce energy. When the SLC25A20 gene has pathogenic variants, the translocase protein is either missing or not functioning correctly [PMID:16596162].
As a result, long-chain fatty acids cannot be transported into the mitochondria for energy production. This leads to an accumulation of fatty acids and their derivatives outside the mitochondria, while the body lacks energy, especially during times when it relies on fat stores, such as during fasting or illness.
- SLC25A20 solute carrier family 25 member 20The SLC25A20 gene encodes the carnitine-acylcarnitine translocase (CACT) protein, which is vital for transporting fatty acids into mitochondria for energy production.
Inheritance pattern
CACT deficiency is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of a pathogenic SLC25A20 gene variant - one from each parent - to be affected by the condition.
If both parents are carriers of a pathogenic variant in SLC25A20, they each have one working copy of the gene and one non-working copy, but they typically do not show symptoms themselves. With each pregnancy, there is a 25% chance of their child inheriting two non-working copies and developing CACT deficiency. There is a 50% chance the child will be a carrier (like their parents) and a 25% chance the child will inherit two working copies of the gene and not be affected or 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
Diagnosis of CACT deficiency often begins with newborn screening in the UK, which includes tandem mass spectrometry to detect unusual patterns of acylcarnitines in blood spots. If the newborn screening results suggest CACT deficiency, further diagnostic tests are typically performed [PMID:19007624].
Confirmatory diagnosis relies on genetic testing of the SLC25A20 gene to identify pathogenic variants. This can be arranged through an NHS Genomic Medicine Service (GMS) laboratory, with referrals typically made by a paediatrician or clinical geneticist. Biochemical tests, such as measuring carnitine levels in blood and urine, and enzyme activity assays in cultured fibroblasts, may also support the diagnosis. The NHS Genomic Medicine Service uses specific R-codes for genetic testing, which clinical teams can refer to.
Management & lifestyle
Management of CACT deficiency focuses on preventing metabolic crises and providing adequate energy. This typically involves a special diet that is low in long-chain fats and high in carbohydrates, to reduce the reliance on fat metabolism. Medium-chain triglyceride (MCT) oil may be used as an energy source because it can be metabolised without needing the carnitine-acylcarnitine translocase [PMID:19007624].
Individuals often require frequent meals and avoidance of fasting. During illnesses or times of increased energy demand, emergency protocols are usually put in place, which may involve intravenous glucose administration to prevent low blood sugar. Carnitine supplementation may also be prescribed.
Care is usually coordinated by a multidisciplinary team from the NHS, including a metabolic specialist, dietitian, and genetic counsellor. Regular monitoring of metabolic markers and heart function is important. Genetic counsellors can provide essential information and support to families regarding the inheritance pattern and implications for other family members.
UK care pathway
In the UK, individuals suspected of having CACT deficiency are typically referred to a clinical genetics service or a specialist metabolic centre within the NHS. The diagnostic pathway often starts with abnormal newborn screening results but can also be prompted by clinical suspicion.
Genetic testing for CACT deficiency, specifically for pathogenic variants in the SLC25A20 gene, is available through the NHS Genomic Medicine Service (GMS) laboratories. Healthcare professionals can request these tests using the relevant GMS R-codes. Once a diagnosis is confirmed, ongoing care and management are provided by specialist NHS teams, including metabolic specialists, dietitians, and genetic counsellors, ensuring comprehensive support for affected individuals and their families.
Frequently asked questions
What should I do if my child has CACT deficiency and becomes ill?
If a child with CACT deficiency becomes ill, it is crucial to contact their metabolic team or hospital immediately. Minor illnesses can quickly lead to a metabolic crisis. Following their emergency plan, which often involves increased glucose intake or intravenous glucose, is vital to prevent severe complications.
Can CACT deficiency be cured?
There is currently no cure for CACT deficiency. However, it can be effectively managed through a specialised diet and close medical supervision. Adhering to the treatment plan helps prevent metabolic crises and allows individuals to lead healthier lives.
Is newborn screening for CACT deficiency available in the UK?
Yes, CACT deficiency is included in the routine newborn blood spot screening programme across the UK. This screening aims to identify affected infants early, allowing for prompt diagnosis and initiation of treatment, which significantly improves outcomes.
What are the long-term prospects for someone with CACT deficiency?
With early diagnosis and consistent management, many individuals with CACT deficiency can have a good long-term prognosis. However, ongoing adherence to dietary restrictions and medical advice is essential to avoid metabolic crises and potential complications. Regular follow-ups with a metabolic specialist are important.
How does CACT deficiency affect family planning for carriers?
If you are a carrier of a pathogenic variant for CACT deficiency and your partner is also a carrier, there is a 1 in 4 (25%) chance in each pregnancy that your child will inherit the condition. Genetic counselling can provide detailed information, discuss reproductive options, and explain antenatal testing possibilities.
References
- Pande SV. Carnitine-acylcarnitine translocase deficiency. The American journal of the medical sciences. 1999. PMID: 10408757
- Adam MP, Bick S, Mirzaa GM. Carnitine-Acylcarnitine Translocase Deficiency. 1993. PMID: 35862567
- Rubio-Gozalbo ME, Bakker JA, Waterham HR. Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Molecular aspects of medicine. 2004. PMID: 15363639
- Vitoria I, Martín-Hernández E, Peña-Quintana L. Carnitine-acylcarnitine translocase deficiency: experience with four cases in Spain and review of the literature. JIMD reports. 2015. PMID: 25614308
- Lund KC, Scottoline B, Jordan BK. Carnitine-Acylcarnitine Translocase Deficiency Masked by Extreme Prematurity. Journal of pediatric genetics. 2023. PMID: 37090833
- Lopriore E, Gemke RJ, Verhoeven NM. Carnitine-acylcarnitine translocase deficiency: phenotype, residual enzyme activity and outcome. European journal of pediatrics. 2001. PMID: 11271379
- Rubio-Gozalbo ME, Vos P, Forget PP. Carnitine-acylcarnitine translocase deficiency: case report and review of the literature. Acta paediatrica (Oslo, Norway : 1992). 2003. PMID: 12801121
- Ryder B, Inbar-Feigenberg M, Glamuzina E. New insights into carnitine-acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches. Journal of inherited metabolic disease. 2021. PMID: 33634872