Clinical characteristics: Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. In individuals with LCHAD deficiency, there is isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, while deficiency of all three enzymes occurs in individuals with TFP deficiency.

Individuals with TFP deficiency can present with a severe-to-mild phenotype, while individuals with LCHAD deficiency typically present with a severe-to-intermediate phenotype.

1. Neonates with the severe phenotype present within a few days of birth with hypoglycemia, hepatomegaly, encephalopathy, and often cardiomyopathy.

2. The intermediate phenotype is characterized by hypoketotic hypoglycemia precipitated by infection or fasting in infancy.

3. The mild (late-onset) phenotype is characterized by myopathy and/or neuropathy.

Long-term complications include peripheral neuropathy and retinopathy.

Diagnosis/testing: The diagnosis of LCHAD/TFP deficiency is established in a proband with elevation of long-chain 3-hydroxyacylcarnitine species in plasma and/or increased excretion of 3-hydroxy-dicarboxylic acids in urine in combination with identification of biallelic pathogenic variants in HADHA or HADHB by molecular genetic testing.

Distinguishing LCHAD deficiency from TFP deficiency requires identification of isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency on enzymatic assay in lymphocytes or skin fibroblasts. TFP deficiency is confirmed by the identification of deficiencies in all three TFP enzymatic activities (long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase) in lymphocytes or skin fibroblasts.

Management: Treatment: Avoidance of fasting using frequent feeds, decreasing feeding intervals and supplemental carbohydrates during illness, and continuing overnight feeds in older children as needed for hypoglycemia; medium-chain triglyceride (MCT) or triheptanoin supplementation; low-fat diet; carnitine supplementation in those with carnitine deficiency; feeding therapy and gastrostomy tube as needed; developmental services; and treatment of cardiac dysfunction, peripheral neuropathy, and retinopathy by relevant specialists. Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics as needed for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy for severe metabolic acidosis; management of hyperammonemia and rhabdomyolysis; and management of cardiomyopathy per cardiologist.

Prevention of primary manifestations: Avoidance of fasting; supplementation with MCT or triheptanoin; strict dietary management; education of parents and caregivers to ensure prompt treatment; written protocol for emergency treatment.

Surveillance: Monitor nutrition, serum plasma free and total carnitine, acylcarnitine profile, creatine kinase, AST, and ALT with frequency based on age; annual comprehensive fatty acid profile; monitor head size, growth, and development at each visit throughout childhood; neuropsychological testing and quality of life assessments as needed; EKG and echocardiography annually or more frequently as needed; annual neurology evaluation with nerve conduction velocity and electromyography as needed; annual ophthalmology evaluation with electroretinography every two to three years.

Agents/circumstances to avoid: Fasting; inadequate calories during stressors; dehydration; high-fat diets including ketogenic and carbohydrate restricted diet; anesthetics that contain high doses of long-chain fatty acids; intravenous intralipids during acute metabolic crisis.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted (targeted molecular genetic testing if the familial pathogenic variants are known or plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid assay if the pathogenic variants in the family are not known) to allow for early diagnosis and treatment of LCHAD/TFP deficiency.

Pregnancy management: Increase MCT intake in the third trimester; high dextrose infusion in the peripartum period. Monitor for HELLP syndrome and acute fatty liver of pregnancy in pregnant females who are heterozygous for an HADHA or HADHB pathogenic variant (including suspected carriers).

Genetic counseling: LCHAD/TFP deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HADHA or HADHB 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. Once the HADHA or HADHB pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.