Newborn screening · Fatty acid oxidation disorder
Trifunctional Protein Deficiency · TFP
Severe fatty acid oxidation defect. Cardiomyopathy and rhabdomyolysis are major complications.
Description
Mitochondrial trifunctional protein deficiency, TFP, is an autosomal recessive long-chain fatty acid oxidation disorder. The mitochondrial trifunctional protein is a heterotetramer of four alpha subunits encoded by HADHA and four beta subunits encoded by HADHB. The complex carries three sequential enzyme activities of long-chain beta-oxidation: long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase on the alpha subunit, and long-chain 3-ketoacyl-CoA thiolase on the beta subunit. Variants that destabilize the assembled complex reduce all three activities and produce generalized TFP deficiency. Variants in HADHA that selectively reduce the dehydrogenase activity while sparing the other two produce isolated LCHAD deficiency, a clinically related entity managed on the same metabolic principles.
Clinical presentation falls along a severity spectrum. Severe neonatal disease presents with hypoketotic hypoglycemia, cardiomyopathy, hepatic dysfunction, and sudden death during fasting illness. Intermediate disease presents in infancy or early childhood with episodic hepatic crisis. Milder later-onset disease presents with rhabdomyolysis triggered by fasting, illness, or sustained exercise, and with progressive peripheral neuropathy. Pigmentary retinopathy develops in long-term survivors. Pregnancy of a fetus affected with TFP or LCHAD is associated with maternal acute fatty liver of pregnancy and HELLP syndrome, an obstetric finding that has prompted retrospective diagnosis of the infant.
Detection is by newborn screening on the dried blood spot using tandem mass spectrometry. Long-chain hydroxyacylcarnitines, particularly C16-OH and C18:1-OH, are the primary markers and overlap with the LCHAD profile. Confirmation uses plasma acylcarnitine, fibroblast or lymphocyte enzyme assay, and HADHA and HADHB sequencing. Reported live-birth incidence is rare, on the order of 1 in 250,000 or less for generalized TFP, with regional variation. TFP is on the US RUSP core panel.
Treatments to date
Standard of care is restriction of long-chain fat, replacement of long-chain fat calories with medium-chain triglyceride oil, frequent feeding, and avoidance of fasting. Cornstarch supports overnight glucose stability in older children. Carnitine use is selective and debated. Annual ophthalmology and neurology surveillance addresses the retinopathy and neuropathy that accumulate over time. Cardiac surveillance with echocardiogram is part of routine follow-up given the risk of cardiomyopathy.
Triheptanoin, marketed as Dojolvi by Ultragenyx, was approved by the FDA in June 2020 as a source of medium and odd-chain fatty acids for long-chain fatty acid oxidation disorders in adults and children at least six months of age. The label includes TFP deficiency. The seven-carbon fatty acid in triheptanoin enters both beta-oxidation and the citric acid cycle through anaplerosis, restoring intermediates that long-chain fatty acid oxidation cannot supply.
During acute illness, standard metabolic emergency protocols apply, with intravenous dextrose to suppress lipolysis. No gene therapy is approved. Pregnant women carrying a fetus at risk for TFP or LCHAD receive obstetric monitoring for HELLP and acute fatty liver of pregnancy.