Clinical characteristics: Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical manifestations usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of symptoms is usually rapid. The recognized phenotypes are: acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that causes CPT1A deficiency; and hepatic encephalopathy, in which individuals (typically children) present with hypoketotic hypoglycemia and sudden onset of liver failure. Individuals with hepatic encephalopathy typically present with hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and total carnitine. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.
Diagnosis: The diagnosis of CPT1A is established in a proband by the detection of biallelic pathogenic variants in CPT1A on molecular genetic testing or diminished carnitine palmitoyltransferase 1 (CPT 1) enzyme activity on cultured skin fibroblasts when molecular genetic testing is not definitive. Residual enzyme activity is 1%-5% in most individuals with CPT1A deficiency.
Management: Treatment of manifestations: Prompt treatment of hypoglycemia with intravenous fluid containing 10% dextrose; the dextrose infusion should be maintained past the time that the blood glucose concentration has normalized in order to replete hepatic glycogen stores. Affected individuals, parents/guardians, and health care providers need to have readily available emergency treatment protocols for catastrophic metabolic crises. Prevention of primary manifestations: To prevent hypoglycemia, infants should eat frequently during the day and have cornstarch continuously at night; fasting should not last more than 12 hours during illness, surgery, or medical procedures; adults need a high-carbohydrate, low-fat diet to provide a constant supply of carbohydrate energy and medium-chain triglycerides to provide approximately one third of total calories (C6-C10 fatty acids do not require the carnitine shuttle for entry into the mitochondrion). Prevention of secondary complications: Prevention of hypoglycemia reduces the risk for related neurologic damage. Surveillance: Individuals with CPT1A deficiency should have testing of liver enzymes (AST, ALT, alkaline phosphatase) and liver function (including PT and PTT) at clinic appointments, even when asymptomatic, and during periods of reduced caloric intake and febrile illness. Agents/circumstances to avoid: Prolonged fasting; potentially hepatotoxic agents such as valproate and salicylate. Evaluation of relatives at risk: Regardless of age, each sib of a proband should be evaluated for CPT1A deficiency by either molecular genetic testing (if both pathogenic variants have been identified in the proband) or by enzyme analysis in cultured skin fibroblasts. Pregnancy management: Heterozygous pregnant women should be monitored for acute fatty liver of pregnancy.
Genetic counseling: CPT1A deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic, although heterozygous pregnant women may be at risk of developing acute fatty liver of pregnancy if the fetus has CPT1A deficiency. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible by biochemical testing if the enzyme defect has been confirmed in an affected family member or by molecular genetic testing if both pathogenic variants have been identified in an affected family member.
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