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Carnitine palmitoyl transferase 1A deficiency

Orpha number ORPHA156
Synonym(s) CPT1A deficiency
Carnitine palmitoyl transferase IA deficiency
Hepatic carnitine palmitoyl transferase 1 deficiency
Hepatic carnitine palmitoyl transferase I deficiency
L-CPT1 deficiency
L-CPTI deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E71.3
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Carnitine palmitoyltransferase 1A (CPT-1A) deficiency is an inborn error of metabolism that affects mitochondrial oxidation of long chain fatty acids (LCFA) in the liver and kidneys, and is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure.

Since the description of the disease in 1981, less than 50 cases have been reported.

CPT-1A deficiency manifests between birth and 18 months of age with recurrent attacks of hypoketotic hypoglycemia of varying severity, triggered by fasting or intercurrent illness, that can lead to severe neurological sequelae. CPT-1A-deficient patients can also present with hepatic encephalopathy with loss of consciousness, seizures, coma, or even sudden death. There may be a risk of progression to liver failure. Patients with severe CPT-1A deficiency may also have renal tubular acidosis.

CPT-1A deficiency is due to mutations in the CPT1A gene that codes for the liver isoform of the CPT1 enzyme located within the external mitochondrial membrane and whose function is to conjugate LCFAs to carnitine. This allows the transfer of LCFAs from the cytosol to mitochondria where they will be oxidized. CPT1 enzyme has three isoforms with tissue-specific expression and encoded by different genes: the 'L' isoform, expressed in the liver and kidney by the CPT1A gene (11q13), the 'M' isoform, synthesized in the skeletal and cardiac muscle by the CPT1B gene (22qter), and the brain type isoform expressed by the CPT1C gene (19q13). No clinical cases of deficiency of the muscle or brain type isoform have been described. A genetic variant of CPT1A (which results in a P479L protein change) that is very common in individuals of Alaskan and Greenland Inuit origin and some Canadian Native Americans has been described. The significance of this variant is not yet established and the risk of severe disease association as a result of the variation is uncertain. A single case of an adult who was homozygous for the P479L variant presented with muscular symptoms (muscle cramps), but an association with the variant seems doubtful.

During metabolic crisis, blood tests reveal hypoglycemia, elevated levels of plasma carnitine and liver transaminases, and mild hyperammonemia. Urine tests may show unusually low levels of ketones, and medium-chain dicarboxylic aciduria. When well, the total free carnitine level may still be elevated but all other metabolic tests will be normal. Molecular testing and evidence of enzyme deficiency by CPT-1A assay (reduction to 5-20% of normal CPT1 activity) in the liver, lymphocytes or cultured fibroblasts, confirm the diagnosis.

Differential diagnosis includes fatty acid and ketogenesis disorders such as medium-chain acyl-CoA dehydrogenase (MCAD deficiency; see this term), other long-chain fatty acid oxidation disorders such as carnitine palmitoyltransferase (CPT) 2 deficiency and Reye's syndrome (see these terms).

Antenatal diagnosis is possible by mutational analysis if the mutations in a proband have been identified.

Transmission is autosomal recessive. Genetic counseling should be proposed to parents of an affected individual informing them of the 25% chance the offspring has of inheriting the disease-causing mutations.

Treatment consists primarily of avoidance of fasting. Additional measures may be considered, including nighttime feeds with uncooked cornstarch during childhood and/or a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from the carnitine cycle. Regular surveillance of liver enzymes and function is necessary.

With treatment, prognosis is good and neurological damage resulting from recurrent hypoglycemia may be prevented.

Expert reviewer(s)

  • Pr Michael BENNETT
  • Dr Charles STANLEY

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Detailed information

Summary information
Emergency guidelines
  • EN (2012,pdf)
Clinical genetics review
  • EN (2013)
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