Acknowledgement of Carnitine-Acylcarnitine Translocase Deficiency has not been added yet.

CACT deficiency is extremely rare, with an estimated prevalence of less than 1 in 1,000,000 live births worldwide. Higher frequencies have been reported in certain populations due to random mutations, including individuals of East Asian (Hong Kong and Taiwan specifically), Middle Eastern, or Mediterranean descent. Because of its severity, many cases are identified through newborn screening or early metabolic crises.

Name	Abbreviation
SLC25A20 deficiency
CACT deficiency
Carnitine–acylcarnitine carrier deficiency
Mitochondrial carnitine–acylcarnitine translocase deficiency

CACT deficiency is caused by mutations in the SLC25A20 gene, which encodes the carnitine–acylcarnitine translocase (CACT) protein located in the inner mitochondrial membrane. This protein is essential for transporting long-chain fatty-acids stored in the cell’s cytoplasm into the mitochondrial matrix for β-oxidation, the process of breaking them down into energy. Mutations lead to a lack of this ‘carnitine shuttle’ and failure to transport fatty acids, resulting in energy deficiency, accumulation of toxic fatty acid intermediates, and impaired ketone production. This is especially damaging to cells in organs that require a lot of energy, such as the heart, liver, and muscles. 

The disorder is inherited in an autosomal recessive pattern (see RareShare Guide to Genetic Inheritance), or by a random mutation in offspring. CACT cannot be caused by environmental factors, though events such as long-term fasting can trigger symptoms in individuals with these disease mutations.

Symptoms typically present in the neonatal period or early infancy, often triggered by fasting or illness, and may include:

• Hypoketotic hypoglycemia (low blood sugar without ketone production) - In the absence of glucose (fasting), the body breaks down long-chain fatty acids to form ketones. However, individuals with CACT cannot break down fatty acids effectively, and thus have lower ketone production

• Cardiomyopathy and cardiac arrhythmias

• Liver dysfunction, including hepatomegaly and elevated liver enzymes

• Severe muscle weakness or hypotonia - due to the body’s lack of energy to function

• Respiratory distress

• Lethargy, seizures, or coma - due to the build-up of ammonia in the blood (see below)

• Hyperammonemia and metabolic acidosis - Without the ability to convert fatty acids to energy, the body begins to break down proteins in the muscle. This leads to an ammonium byproduct, which builds up in the blood and can become toxic to organs and the brain

In rare milder or later-onset cases, symptoms may include episodic muscle weakness, rhabdomyolysis, or exercise intolerance, though these forms are uncommon.

 

CACT deficiency is suspected based on clinical presentation, abnormal newborn screening results, and biochemical findings consistent with a long-chain fatty acid oxidation disorder. Characteristic elevation of long-chain acylcarnitines (special fatty-acids) C16, C18, and C18:1 can lead to further investigation. Definitive diagnosis requires genetic confirmation of mutations to the SLC25A20 gene. Early diagnosis is critical, as prompt treatment can be lifesaving.

• Newborn screening: Elevated long-chain acylcarnitines (e.g., C16, C18:1) with low free carnitine

• Plasma acylcarnitine profile: Characteristic accumulation of long-chain acylcarnitines

• Urine organic acids: May show secondary abnormalities related to metabolic stress

• Genetic testing: Identification of biallelic pathogenic variants in the SLC25A20 gene

• Cardiac evaluation: Echocardiography and ECG to assess cardiomyopathy or arrhythmias

Laboratory studies during crises: Hypoglycemia (low blood sugar), metabolic acidosis (low ketones), elevated ammonia (due to breakdown of protein in muscles), and liver dysfunction

There is no cure for CACT deficiency, and management focuses on preventing metabolic decompensation:

• Strict avoidance of fasting, with frequent feeding

• Low–long-chain-fat diet and restriction of long-chain fatty acids

• Supplementation with medium-chain triglycerides (MCTs), which bypass the defective transport system

• Emergency protocols during illness, including intravenous glucose to prevent catabolism

• Carnitine supplementation is controversial and used cautiously under specialist guidance

• Cardiac and metabolic monitoring by a multidisciplinary metabolic care team

Early and aggressive management is essential to reduce the risk of metabolic crises

The prognosis of CACT deficiency is generally poor, particularly for the classic neonatal-onset form, which is often associated with high mortality in infancy despite treatment. Survivors may experience recurrent metabolic crises, cardiomyopathy, and developmental impairment. Even in less severe forms of the disease, individuals with CACT are at lifelong risk of complications such as heart-failure, seizure, coma, and death. Rare milder or later-onset forms have a more favorable prognosis but still require lifelong dietary management and careful monitoring. Early detection through newborn screening and strict adherence to treatment protocols can improve survival and outcomes, though the disorder remains one of the most severe fatty acid oxidation defects.

Tips or Suggestions of Carnitine-Acylcarnitine Translocase Deficiency has not been added yet.

1. Medline Plus - Carnitine–acylcarnitine translocase deficiency

2. NCBI - Carnitine–acylcarnitine translocase deficiency 

3. NORD - Carnitine–acylcarnitine translocase deficiency