Carnitine-Acylcarnitine Translocase Deficiency

CLINICAL CHARACTERISTICS

Carnitine-acylcarnitine translocase (CACT) is a critical component of the carnitine shuttle, which facilitates the transfer of long-chain fatty acylcarnitines across the inner mitochondrial membrane. CACT deficiency causes a defect in mitochondrial long-chain fatty acid β-oxidation, with variable clinical severity. Severe neonatal-onset disease is most common, with symptoms evident within two days after birth; attenuated cases may present in the first months of life. Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies. Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome. Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability. Affected individuals with later-onset disease have milder symptoms and are less likely to experience recurrent hyperammonemia, allowing a better developmental outcome. Prompt treatment of the presenting episode to prevent hypoglycemic, hypoxic, or hyperammonemic brain injury may allow normal growth and development.

DIAGNOSIS/TESTING: Characteristic elevation of long-chain acylcarnitines C16, C18, and C18:1 on acylcarnitine profile suggests a diagnosis of CACT or CPT II deficiency. The diagnosis of CACT deficiency is confirmed by identification of biallelic pathogenic variants in , or in some cases by identifying reduced CACT enzyme activity in skin fibroblasts.

MANAGEMENT

The mainstay of therapy is a high-carbohydrate diet (>60% of total caloric intake) with restriction of long-chain dietary fat (to <10% of total calories) and treatment with the anaplerotic agent triheptanoin (to provide 25%-35% of total calories). If triheptanoin is not available, medium-chain triglyceride (MCT) oil (10%-30% of total calories) could be used as a substitute. Fasting is avoided or limited, and carnitine supplemented at ~100 mg/kg/day is recommended. Goals of care include optimization of caloric intake to avoid or reduce hyperammonemia (ammonia scavenger medications are of limited efficacy in this condition) and aggressive rehabilitation therapy, including physical and occupational therapy, to address motor delays. Placement of a feeding tube and/or feeding therapy may be required in those with feeding issues. : Administration of high-dextrose-containing fluids: oral/enteral carbohydrate polymer (at home) or intravenous dextrose (in the hospital). Hyperammonemia is most sensitive to high rates of dextrose infusion (12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children age 1-6 years), while ammonia scavenging medications (sodium benzoate, sodium phenylbutyrate) are of limited efficacy. Cardiac arrhythmias, cardiomyopathy, rhabdomyolysis, and acute renal impairment should be treated per standard of care, typically in the intensive care unit. Consideration should be given for triheptanoin treatment in those with cardiogenic shock. A home emergency plan for prompt illness management should be provided to parents, primary care providers, teachers, and school staff. When undergoing surgeries or procedures (e.g., dental interventions or neuroimaging requiring sedation), pre-procedure hospital management includes IV dextrose with electrolytes appropriate for age. Provide the family with an emergency plan and letter for use during emergency department visits. : Regular evaluations by a metabolic specialist and metabolic dietitian. Measurement of growth parameters (including head circumference) and monitoring of developmental milestones at each visit. Neuropsychological testing using age-appropriate tools as clinically indicated. Laboratory monitoring to include serum ammonia level, total CK level, ALT, AST, glucose, electrolytes, and albumin levels for periodic surveillance as clinically indicated. Measurement of complete blood count, ferritin level, prealbumin, CRP, essential fatty acids, calcium, magnesium, phosphate, copper, zinc, selenium, folate, and vitamins A, D, E, and B annually after the first year of life. Measurement of plasma electrolytes, creatinine, blood urea nitrogen, and/or cystatin C levels for renal monitoring as clinically indicated. Echocardiogram to assess for cardiomyopathy or cardiac dysfunction annually and as clinically indicated. EKG or 24-hour Holter test periodically, as clinically indicated. Consider EEG or neuroimaging in those with new neurologic symptoms or altered mental status. Prolonged fasting, catabolic illness (fever, intercurrent infection), inadequate caloric provision during times of catabolic stress (including during fasting), prolonged strenuous physical activity, and prolonged administration of anesthetics containing high levels of long-chain fatty acids (e.g., propofol). Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of CACT deficiency. For at-risk newborn sibs when prenatal testing was not performed, in parallel with newborn screening either test for the familial pathogenic variants or measure acylcarnitine profile.

GENETIC COUNSELING

CACT deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an 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 inheriting neither of the familial pathogenic variants and being unaffected. Heterozygotes (carriers) are asymptomatic. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.