Carnitine Palmitoyltransferase 1A Deficiency

Excerpt

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 manifestations are usually rapid. The recognized presentations are: (1) out-of-range newborn screen (individual may be without features or with hepatic encephalopathy, hypoketotic hypoglycemia, and sudden onset of liver failure) and (2) later-onset manifestations (in the absence of newborn screening), including hepatic encephalopathy, hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and creatine kinase. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage. Acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A, has been rarely associated with CPT1A deficiency.

Diagnosis/testing: The diagnosis of CPT1A deficiency is established in a proband with biallelic pathogenic variants in CPT1A identified by molecular genetic testing. Diminished carnitine palmitoyltransferase 1 (CPT1) enzyme activity on cultured skin fibroblasts when molecular genetic testing is not definitive may be an available option in some countries. Residual enzyme activity is 1%-5% in most individuals with CPT1A deficiency.

Management: Prevention of primary manifestations: To prevent hypoglycemia, infants should eat frequently during the day, and cornstarch feedings may be considered continuously at night (typically after age one year); in older individuals 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 (MCT) to provide approximately one third of total calories. Prevention of hypoglycemia reduces the risk for related neurologic damage.

Targeted therapies: Triheptanoin (an odd-carbon triglyceride) or MCT oil.

Supportive care: Acute treatment includes 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 to replete hepatic glycogen stores. Increase frequency of feeding and provide one third of total calories as triheptanoin or MCT oil. Liver enzymes and functional liver tests; consider plasma creatine kinase and urine myoglobin; consider brief hospitalization in those fasting longer than 12 hours. Long-term treatment includes high-carbohydrate diet low in long-chain fat and frequent feeding supplemented with triheptanoin or MCT oil. Consider orthotic liver transplantation in those with liver failure; educate parents on factors that increase risk of metabolic decompensation; consultation with physical therapy, occupational therapy, speech and language pathology, and developmental pediatrician as needed.

Surveillance: Assess growth, feeding, and adherence to diet at each visit; plasma carnitine panel, acylcarnitine profile, essential fatty acids, vitamins A, D, and E, complete blood count, comprehensive metabolic panel, and creatine kinase at each visit or as needed; liver enzymes and liver function testing as clinically indicated; BUN, serum creatinine, and urinalysis as clinically indicated; assess for gastrointestinal side effects of triheptanoin or MCT oil at each visit; assess developmental and educational progress at each visit throughout childhood and adolescence; provide updated emergency management letter at each visit.

Agents/circumstances to avoid: Prolonged fasting; potentially hepatotoxic agents such as valproate and salicylate; viral or bacterial infections; avoid overfeeding in individuals without acute illness.

Evaluation of relatives at risk: Regardless of age, each sib of a proband should be evaluated for CPT1A deficiency, preferably by molecular genetic testing (if both pathogenic variants have been identified in the proband); enzyme analysis in cultured skin fibroblasts may be an option in some individuals.

Pregnancy management: Pregnant women heterozygous for a known CPT1A pathogenic variant should be monitored for development of acute fatty liver of pregnancy.

Genetic counseling: CPT1A deficiency is inherited in an autosomal recessive manner. When both parents are carriers of a CPT1A pathogenic variant, each sib of an affected individual has at conception 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. When one parent is a carrier and the other parent has two CPT1A pathogenic variants, each sib of an affected individual has at conception a 50% chance of being affected and a 50% chance of being an asymptomatic carrier. Heterozygotes (carriers) are asymptomatic, although heterozygous pregnant women may be at risk of developing acute fatty liver of pregnancy if the fetus has two pathogenic CPT1A alleles. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the CPT1A pathogenic variants in the family are known.