Carnitine-Acylcarnitine Translocase Deficiency

Disease Overview

Summary

Carnitine-acylcarnitine translocase deficiency (CACT deficiency) is a rare genetic condition that prevents the body from using certain fats (specifically long-chain fats) for energy. The condition is due to a problem in the carnitine shuttle system that is essential for moving fats into the mitochondria, which are cell structures responsible for energy production in the body. Given that these fats are not moved into the mitochondria to subsequently be turned into energy, the body experiences an energy shortage as well as build-up of toxic compounds, both of which contribute to the symptoms seen in CACT deficiency.

Symptoms typically appear early, sometimes just days after birth, and can include low blood sugar without the expected increase in ketones (hypoketotic hypoglycemia), high levels of ammonia in the blood (hyperammonemia), muscle weakness (myopathy), heart muscle issues (cardiomyopathy) and serious health problems during fasting or illness. These symptoms are indicative of metabolic crises, which are sudden, life-threatening disruptions in the body’s ability to turn food into energy (metabolism).

CACT deficiency is caused by changes (disease-causing variants) in the SLC25A20 gene. It is passed down in an autosomal recessive pattern, meaning both parents must carry and pass on the gene variant for their child to have the condition. While there is no cure for CACT deficiency, management involves a high-carbohydrate diet with limited long-chain fats, supplemented with triheptanoin or MCT oil to reduce the high ammonia levels. Treatment often includes physical or occupational therapy and care from a multi-disciplinary metabolic team, emphasizing the importance of dietary regulation and comprehensive support for people who have the condition.

Introduction

CACT deficiency is a rare genetic condition that was first identified in the late 20th century. It belongs to a group of conditions known as fatty acid oxidation disorders. Fatty acid oxidation disorders occur when the body has trouble converting fats from food into energy. This process is essential for providing energy for the body, especially during periods of not eating (fasting) or exercise.

Newborn screening programs can identify the condition shortly after birth, allowing for prompt initiation of treatment. Early treatment significantly reduces the risk of severe complications. By managing the condition from an early age, people with CACT deficiency can lead healthier lives with fewer health-related challenges.

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Synonyms

carnitine-acylcarnitine translocase deficiency
CACT deficiency
carnitine acylcarnitine carrier deficiency
CACT
CAC

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Signs & Symptoms

Symptoms of CACT deficiency can range from severe forms, appearing within days of birth, to milder forms recognized later in infancy or childhood.

In the most severe form, newborns may experience life-threatening episodes of metabolic crisis which can include:

Hypoketotic hypoglycemia: low blood sugar levels (hypoglycemia) without the expected increase in ketones, which are usually produced when the body breaks down fat for energy
Lethargy and poor feeding: infants may appear excessively tired and have difficulty feeding
Cardiomyopathy: a disorder of the heart muscle. The heart muscle may become thickened (hypertrophic) or weakened (dilated), leading to heart failure. In CACT deficiency, cardiomyopathy can be severe and is often a leading cause of death in infants with this condition
Arrhythmias: irregular heartbeats that can be life-threatening. These are a common feature of CACT deficiency and can be a result of the accumulation of long-chain acylcarnitines
Liver dysfunction: can manifest as an enlarged liver (hepatomegaly), elevated liver enzymes and in some people, a Reye-like syndrome that includes fatty liver (a sudden, sometimes fatal, buildup of fat in the liver and other organs) with elevated levels of ammonia in the blood (hyperammonemia) which can be toxic to the brain
Myopathy: muscle weakness that can include reduced muscle tone (hypotonia) and muscle breakdown (rhabdomyolysis) in response to metabolic stress

In milder forms of the disorder, symptoms may not appear until later in infancy or childhood and can be triggered by fasting, illness, or physical stress. These symptoms can include:

Exercise intolerance: Difficulty with physical exertion due to the body’s inability to utilize fat for energy
Recurrent episodes of hypoketotic hypoglycemia: Low blood sugar, especially during fasting or illness, without the presence of ketones in the urine
Muscle weakness: Weakness can come and go (episodic) and can be related to a metabolic crisis and, over time, individuals with CACT deficiency can become chronic
Growth delay and developmental delays

The progression of CACT deficiency can be variable, with some individuals experiencing frequent and severe metabolic crises, while others may have a milder course with fewer episodes, even among people with the same gene variants.

The quality of life for individuals with CACT deficiency can vary significantly depending on the severity of the condition, the timeliness of diagnosis and the effectiveness of treatment. Early detection through newborn screening and prompt initiation of treatment can significantly improve the likely course and outcome of the condition (prognosis) and reduce the risk of severe complications. With proper management, including dietary modifications, avoidance of fasting, and prompt treatment of metabolic crises, individuals with milder forms of CACT deficiency can have relatively typical lives.

Those with severe neonatal-onset forms of the condition may face more significant challenges, including chronic health issues and developmental delays. Lifelong monitoring and medical care are essential to manage the symptoms and prevent metabolic crises. Advances in medical research and treatment options continue to improve the outlook for individuals with CACT deficiency, but the condition still requires careful management and support from a multidisciplinary healthcare team.

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Causes

CACT deficiency is a condition caused by variants in the gene known as SLC25A20. This gene is important because it makes an enzyme known as carnitine acylcarnitine translocase (CACT). Enzymes are proteins that help speed up chemical reactions in the body. CACT is needed for a process called fatty acid β-oxidation, which enables the body to make energy from fats, especially when a person has not eaten for a while or needs extra energy.

In individuals without CACT deficiency, certain types of fats (long-chain fatty acids) are moved from the liquid part of the cell (cytosol) into the energy factories of the cell (mitochondria) through a system that involves carnitine, a substance that helps transport fats. Once inside the mitochondria, these fats are broken down to produce energy. The CACT enzyme is a key part of this system because it helps move the fats into the mitochondria.

However, when there are disease-causing variants in both copies of the SLC25A20 gene, the CACT enzyme’s function is impaired. As a result, long-chain fatty acids cannot be moved into the mitochondria and broken down to make energy. Cells, especially in the liver, muscles and heart, end up facing an energy deficiency. This shortage of energy in the body can cause the following symptoms:

Hypoketotic hypoglycemia: Normally, when the body runs low on blood sugar (glucose), it starts breaking down fats to produce ketones, which can be used as an alternative energy source. This process is known as ketogenesis. However, in CACT deficiency, the breakdown of fats is impaired, so the body cannot produce enough ketones. As a result, when glucose levels drop, the body cannot compensate by using ketones, leading to low blood sugar (hypoglycemia) without the expected increase in ketones (hypoketotic).
Hyperammonemia: Since the body cannot use fats properly for energy in CACT deficiency and due to secondary inhibition of urea cycle, it starts breaking down proteins from muscles as an alternative source. The breakdown of proteins releases ammonia, a by-product of protein metabolism. Normally, the liver converts ammonia into urea, which is then excreted in urine. However, when too much protein is broken down, the amount of ammonia can overwhelm the liver’s ability to convert it into urea, leading to high levels of ammonia in the blood (hyperammonemia). A urea cycle disorder is a genetic condition caused by a gene variant that leads to a shortage of one of the six enzymes in the urea cycle. These enzymes help remove ammonia, a toxic waste product of protein digestion, from the body. Normally, the urea cycle turns nitrogen into urea, which is eliminated through urine. When the cycle doesn’t work properly, ammonia builds up in the blood (hyperammonemia), reaching the brain and potentially causing permanent damage, coma, or death.
Rhabdomyolysis: The breakdown of muscle proteins also causes muscle damage, known as rhabdomyolysis. Muscle fiber content is released into the bloodstream which can cause kidney damage and other serious complications.

CACT deficiency follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Environmental factors do not cause CACT deficiency. However, certain situations like fasting, getting sick, or experiencing other metabolic stresses can trigger symptoms in people with this condition.

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Affected populations

CACT deficiency can occur either as a severe condition in a newborn or as a milder form in infants. It is very rare, with medical literature showing that 89 individuals have been diagnosed at birth and 14 individuals have been diagnosed during infancy. Males and females are equally affected by CACT deficiency; it can affect anyone, regardless of their gender or the sex they were assigned at birth.

Based on newborn screening data from Australia, Germany and the United States, around 1 in 750,000 to 1 in 2,000,000 people have been diagnosed with CACT deficiency. In Hong Kong and Taiwan, 1 in 60,000 and 1 in 400,000 people respectively have been found to have CACT deficiency. CACT deficiency appears to be more common in East Asian populations, possibly due to a specific gene varian , c.199-10T>G, that is more prevalent in these populations.

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Disorders with Similar Symptoms

When diagnosing CACT deficiency, it is important to consider other conditions that may have similar symptoms.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD): VLCAD is also a condition in which the body is unable to break down long fat molecules. Symptoms can include muscle weakness with rhabdomyolysis, low blood sugar (hypoketotic hypoglycemia) and cardiomyopathy. Although clinical symptoms are similar to those of CACT, VLCAD has different metabolic lab results that differentiate it from CACT.

Carnitine Palmitoyltransferase II deficiency (CPT II): In this condition, the body cannot break down long fat molecules for energy, resulting in symptoms such as muscle pain, weakness and potentially severe kidney problems. CPT II deficiency shares similar symptoms with CACT deficiency, especially in episodes triggered by prolonged fasting or physical stress, such as muscle pain, rhabdomyolysis, weakness, low blood sugar and liver dysfunction. Early onset CPT II deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, seizures, liver failure and cardiomyopathy as well as hypotonia, generalized muscle weakness and difficulty growing and gaining weight. Both conditions, CPTII and CACT deficiency can lead to severe neonatal presentations and are associated with high mortality if untreated, but CACT deficiency tends to be more severe, often fatal in neonates. In addition, children with neonatal CACT deficiency have more prominent encephalopathy and hypotonia. The metabolic lab results are also similar. Thus, molecular genetic testing and/or enzyme activity tests are required to differentiate these disorders.

TANGO2-related metabolic encephalopathy and arrhythmias: TANGO2 is characterized by severe arrhythmias and neurological symptoms, with relatively normal acylcarnitine profiles, while CACT deficiency involves severe metabolic and cardiac manifestations such as cardiomyopathy but not severe arrhythmias and significant long-chain acylcarnitine elevations and profound carnitine deficiency. People with TANGO2 also have episodes of low blood sugar, mild accumulation of ammonia in the blood (hyperammonemia), increased levels of creatine kinase (hyperCKemia) and liver enzyme abnormalities). It is also associated with an increased risk for motor and intellectual disability, brain abnormalities, hypothyroidism, seizures and hypotonia that contribute to developmental delay. Thus, differentiating TANGO2-related encephalopathy from CACT deficiency relies on cardiac findings, absence of hyperthyroidism in CACT deficiency, biochemical testing (especially acylcarnitine profile and free carnitine levels) and genetic testing.

Carnitine transporter deficiency (CT): CT deficiency is a condition where the body lacks the ability to transport a substance called carnitine into cells, leading to low levels of carnitine in the body. This deficiency can result in symptoms such as weakness in the muscles, low blood sugar and disease of the heart muscle, which are similar to those seen in CACT deficiency. However, the primary issue in CT deficiency is the transport of carnitine, not the breakdown of long fat molecules (long-chain fatty acids), which differentiates it from CACT deficiency. Both conditions present during infancy or early childhood with fasting-induced metabolic crises. However, newborn babies appear asymptomatic at birth but develop symptoms as carnitine stores deplete.

Mitochondrial trifunctional protein deficiency (MTP): MTP deficiency affects the body’s ability to break down long-chain fatty acids, leading to symptoms such as low blood sugar, muscle weakness, heart muscle disease and chronic weakness, similar to CACT deficiency. It is characterized by hypoglycemia, cardiomyopathy, neuropathy and rhabdomyolysis. However, people with MTP deficiency also have unique metabolic lab results and may include additional symptoms such as nerve damage (peripheral neuropathy).

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Diagnosis

Diagnosing CACT deficiency involves observing clinical signs and conducting specific tests. Early signs that may suggest CACT deficiency include blood sugar levels dropping below normal without the usual increase in ketones in the body (hypoketotic hypoglycemia), hyperammonemia, tiredness, liver problems, heart muscle problems and muscle weakness shortly after birth. These symptoms, especially when they occur in the newborn period and are accompanied by sudden, life-threatening states where the body’s metabolism becomes severely disrupted (metabolic crises), can prompt further investigation for CACT deficiency.

Since CACT deficiency is included in the newborn screening panel in many states in the U.S., this condition can be detected at birth, even before symptoms develop. If the screening indicates a possible CACT deficiency, further tests are recommended to confirm the diagnosis. This further testing typically includes blood tests called acylcarnitine profiles (or acylcarnitine plasma levels) which assess the body’s ability to convert certain fats into energy. Abnormal patterns in these results may indicate CACT deficiency. Abnormal metabolites commonly seen in plasma acylcarnitines for CACT deficiency include elevated levels of long-chain acylcarnitines, such as C16, C18:1 and C18:2.

If these blood tests are suggestive of CACT deficiency, genetic testing can confirm the diagnosis by identifying disease-causing variants in the SLC25A20 gene which are responsible for the condition. This testing confirms the diagnosis of CACT deficiency, regardless of the presence or severity of symptoms.

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Standard Therapies

It is important for children with CACT deficiency to receive care from specialists in metabolic disorders (conditions that affect the body’s conversion of food into energy). These specialists include metabolic physicians or biochemical geneticists who conduct a comprehensive set of baseline metabolic tests. These tests check the levels of different chemicals in the body to identify any issues, such as too much acid in the body (metabolic acidosis).

Managing CACT deficiency involves regular visits with the healthcare team to monitor the child’s health and adjust their treatment as needed. This includes tests to check liver and kidney function, blood sugar levels ammonia and CK levels, and heart function to find any problems early and address any complications before they arise. Developmental assessments may also be recommended to monitor the child’s growth and development milestones.

Because CACT deficiency can affect different parts of the body, it is important for the child to have a team of doctors and healthcare providers. This team can include dietitians and nutritionists specialized in metabolic conditions, heart doctors (cardiologists), brain and nerve doctors (neurologists), genetic counselors (providers who can help people understand the genetics of the condition), psychologists and social workers (providers who offer support and resources for life challenges) and therapists (including physical, occupational, or speech therapists), tailored to meet the unique needs of the individual.

Through a collaborative approach, healthcare providers and families can develop an effective management strategy for individuals with CACT deficiency, emphasizing the importance of early detection, accurate diagnosis and comprehensive care to improve quality of life.

The main approach to treatment involves managing symptoms through diet and avoiding situations that could lead to a metabolic crisis. This condition, for which there is currently no cure, requires a high-carbohydrate diet, with generally at least 60% of total caloric intake being carbohydrates, along with restricting long-chain dietary fats to less than 10% of total calories. Individuals with CACT deficiency also take the supplements carnitine and triheptanoin, with medium-chain triglyceride (MCT) oil as an alternative if triheptanoin is unavailable. To prevent crisis states, it is important for individuals to avoid fasting or prolonged periods without food.

In patients where ammonia levels rise significantly, signaling a metabolic crisis, urgent intervention is needed. This includes giving fluids containing a type of sugar called dextrose with electrolytes. During such emergencies, healthcare providers must be cautious about the potential for severe complications like heart muscle disease (cardiomyopathy), irregular heart rhythms (cardiac arrhythmia), muscle damage (rhabdomyolysis) and kidney issues. Preparation for emergency situations should involve having a plan in place, which includes communication (e.g. emergency letter) from the patient’s primary doctor to other healthcare professionals who may be unfamiliar with CACT deficiency.

As described previously, managing CACT deficiency involves lifelong care from a multidisciplinary team tailored to the individual’s needs. Regular follow-ups with metabolic physicians or biochemical geneticists are important to adjust care as needed. Ensuring a smooth transition from child (pediatric) to adult care is essential for maintaining health and well-being for people living with CACT deficiency.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS

Morris AAM and Spiekerkoetter U. Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism. In Saudubray JR, Baumgartner MR, García-Cazorla A and Walter J (Eds.). Inborn Metabolic Diseases: Diagnosis and Treatment. (pp. 287–301). Springer; 2022.

Stanley CA, Palmieri F, Bennett MJ. Disorders of the Mitochondrial Carnitine Shuttle. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill Education; 2019.

Hoffmann GF, Zschocke J and Nyhan W L. (Eds.). Inherited Metabolic Diseases: A Clinical Approach (2nd ed.). Springer Berlin Heidelberg; 2017.

JOURNAL ARTICLE

Rossi A, Hoogeveen IJ, Lubout CMA, et al. A generic emergency protocol for patients with inborn errors of metabolism causing fasting intolerance: A retrospective, single-center study and the generation of www.emergencyprotocol.net. J Inherit Metab Dis. 2021;44(5):1124-1135. doi:10.1002/jimd.12386

INTERNET

Morales Corado JA, Lee CU, Enns GM. Carnitine-Acylcarnitine Translocase Deficiency. 2022 Jul 21. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK582032/ Accessed Nov 6, 2024.

INFORM Network. INFORM Conference explores future of disorders of fatty acid oxidation. Feb 15, 2023. https://informnetwork.org/hypoketotic-hypoglycemia-explained-in-simple-terms/ Accessed Nov 6, 2024.

Baby’s First Test. Newborn screening information for carnitine acylcarnitine translocase deficiency. 2024. https://www.babysfirsttest.org/newborn-screening/conditions/carnitine-acylcarnitine-translocase-deficiency Accessed Nov 6, 2024.

Genetic and Rare Diseases Information Center. Carnitine-Acylcarnitine Translocase Deficiency. Carnitine-acylcarnitine translocase deficiency | About the Disease | GARD Accessed Nov 6, 2024.

Health Resources and Services Administration. Carnitine-Acylcarnitine Translocase Deficiency. Sept 2024. Carnitine-acylcarnitine translocase deficiency | Newborn Screening Accessed Nov 6, 2024.

El Bacha T, Luz MR, Da Poian, A T. Dynamic adaptation of nutrient utilization in humans. https://www.nature.com/scitable/topicpage/dynamic-adaptation-of-nutrient-utilization-in-humans-14232807/ Accessed Nov 6, 2024.

New England Consortium of Metabolic Programs
Website: newenglandconsortium.org Accessed Nov 6, 2024.

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Programs & Resources

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