Carnitine palmitoyltransferase 1 deficiency
Description, Causes and Risk Factors:
Carnitine palmitoyltransferase 1 deficiency
Carnitine palmitoyltransferase 1 deficiency is an autosomal-recessively inheriated condition afftecting an enzyme that is most active in liver, heart, and muscle. CPT-1 is one of several enzymes required for the transport of fatty acids bound to carnitine into mitochondria for the generation of energy.
Carnitine palmitoyltransferase 1 deficiency is inherited in an autosomal-recessive manner. The gene is located on chromosome 11q13. Long chain fatty acids are the predominant fuel for aerobic metabolism. They enter mitochondria attached to carnitine by a transport system that is composed of carnitine translocase. In the absence of sufficient long-chain fatty acids to support adenosine triphosphate and phosphocreatinine synthesis, glucose and medium-chain fatty acids become other available fuels. Thus, the most metabolically active tissue are most susceptible to damage. The enormous relative size of the liver and its high metabolic requirements in infancy ensure that the liver becomes the first and major target organ for metabolic decompensation. The hypoketosis develops from failure to import fatty acids for catabolism and the hypoglycemia reflects increased dependency on other fuels.
Carnitine palmitoyltransferase 1 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 long-chain fatty acids (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.
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.
Classically, infants present from birth through early childhood with hypoglycemia, hypoketosis (low level of ketones), hepatomegaly
, and hepatocellular dysfunction, persistent neurological damage, probably due to hypoglycemia, frequently occurs. Heart and muscle involvement is rarely of significance; kidney involvement can cause renal tubular malabsorption.
Diagnosis of Carnitine palmitoyltransferase 1 deficiency:
Differential diagnosis includes fatty acid and ketogenesis disorders such as medium-chain acyl-CoA dehydrogenase (MCAD deficiency), other long-chain fatty acid oxidation disorders such as carnitine palmitoyltransferase 2 deficiency (CPT-2 deficiency), and Reye's syndrome.
Newborn screening of the heel stick dried blood spot using tandem mass spectrometry finds elevation of free carnitine and reduction of long-chain acylcarnitines (i.e. C16:0 and C18:0), resulting in an increased ratio of free carnitine to C16:0 and C18:0 acylcarnitines. The definitive diagnosis of CPT 1 deficiency is made by measuring enzyme activity in fibroblasts, leukocytes, or liver. A variety of mutations have been detected in the gene for hepatic CPT I, but no common mutations have been found to allow easy DNA diagnosis.
Any intercurrent infection or illness is potentially life-threatening to affected patients. Carnitine palmitoyltransferase 1 deficiency is treated by preventing prolonged fasting and administering IV glucose during acute episodes to prevent hypoglycemia and suppress release of fatty acids from adipose stores. Medium-chain fatty acids bypass the metabolic block, because they do not require conversion to acylcarnitine esters in order to enter the mitochondria. Medium-chain triglyceride oil may therefore be beneficial to patients. Because the diagnosis and therapy of CPT I deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist.
Liver transplantation should cure all tendency to hypoglycemia; the long-term consequences of the defect in other tissue is unknown.
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