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Carnitine-acylcarnitine translocase deficiency

ORPHA159
Synonym(s) CACT deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E71.3
OMIM
UMLS
  • C0342791
MeSH -
MedDRA -

Summary

Carnitine-acylcarnitine translocase (CACT) deficiency is a life-threatening, inherited disorder of fatty acid oxidation which usually presents in the neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.

The prevalence is unknown. Less than 60 cases have been reported worldwide to date.

Most patients with CACT deficiency have a severe phenotype presenting within the first 48 hours of life as hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and arrhythmias, skeletal muscle damage, liver dysfunction and hypothermia. Neurological involvement with encephalopathy, epilepsy and developmental delay are also noted. Some patients present as a sudden infant death. A rare milder phenotype presenting in infancy/early childhood is also described which manifests with episodes of hypoketotic hypoglycemia and hyperammonemia often precipitated by fasting and/or intercurrent illness.

Mutations in the SLC25A20 gene (3p21.31) are responsible for CACT deficiency. CACT is located in the inner mitochondrial membrane and operates a carnitine/acylcarnitine exchange across this membrane. It is an essential component of the carnitine cycle that regulates the transport of long chain fatty acids into the mitochondria where fatty acid oxidation takes place. The milder phenotype results from significant mutant protein activity.

Patients with CACT deficiency present with a non-specific dicarboxylic aciduria. Blood acylcarnitine analysis shows a very high acyl fraction with marked increase in C16, C18, and C18:1 species. Free carnitine is very low. Specific enzyme analysis in cultured fibroblasts or lymphocytes will confirm a diagnosis as will the demonstration of two pathogenic mutations in the SLC25A20 gene. Newborn screening for CACT deficiency is available in Austria, Czech Republic, Germany, Hungary, Iceland, Portugal and Spain.

The neonatal and severe infantile forms of carnitine palmitoyl transferase II (CPT II) deficiency (see this term) need to be excluded as they have an identical acylcarnitine profile to CACT. Clinically these two disorders are virtually indistinguishable, although congenital abnormalities are not reported in CACT and only sometimes in CPT II.

Prenatal diagnosis is possible by mutation analysis of chorionic villus tissue when two pathogenic mutations have been established in a family. Specific enzyme analysis is also available for cultured chorionic villus cells.

CACT is an autosomal recessive condition and genetic counseling is available.

Strict avoidance of fasting along with the institution of a low long-chain fat diet and medium chain triglyceride (MCT) supplementation is necessary. However, the MCT formula should be as low as possible in C10 and C12 fatty acids as high dietary intake of these can lead to decompensation. Carnitine supplementation is also recommended. During an acute episode, intravenous glucose is administered in order to inhibit lipolysis.

Severe CACT deficiency generally has a poor prognosis, with most patients dying before the age of 3 months, although a few infants treated early on in the neonatal period have had a favorable outcome in the medium term. Patients with a mild phenotype generally have a good prognosis given adherence to the treatment regimen.

Expert reviewer(s)

  • Dr Simon OLPIN

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Detailed information

Emergency guidelines
  • EN (2012,pdf)
Article for general public
  • EN (2013)
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