Mitochondrial trifunctional protein deficiency (TFP)
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A child presents with cardiomyopathy, peripheral neuropathy, and pigmentary retinopathy. Acylcarnitine profile shows elevated long-chain hydroxy-acylcarnitines (C16-OH, C18-OH). The mother had HELLP syndrome during pregnancy.
AR; HADHA (alpha subunit) or HADHB (beta subunit). The trifunctional protein is a hetero-octamer (4 alpha + 4 beta) that catalyzes three sequential steps of long-chain beta-oxidation:
- Long-chain enoyl-CoA hydratase (alpha)
- Long-chain 3-hydroxyacyl-CoA dehydrogenase (alpha), the LCHAD activity
- Long-chain 3-ketoacyl-CoA thiolase (beta)
Isolated LCHAD deficiency is a special case in which only the dehydrogenase activity is lost (typically the HADHA c.1528G>C variant); the other two enzymes remain intact. Complete TFP deficiency loses all three activities and is more severe.
- Phenotype overlaps LCHAD: cardiomyopathy, hepatopathy, rhabdomyolysis, peripheral neuropathy, pigmentary retinopathy
- TFP tends to be more severe than isolated LCHAD; neonatal-onset and sudden death are more common
- Maternal HELLP and acute fatty liver of pregnancy (AFLP) are characteristic when the fetus is affected; the mother is an obligate heterozygote
- Same NBS biomarker as LCHAD: C16-OH (with C14-OH, C18-OH)
- On RUSP
- Detected on newborn screening: elevated C16-OH, with C14-OH and C18-OH long-chain hydroxyacylcarnitines (same profile as isolated LCHAD)
- Confirmation: HADHA/HADHB molecular testing; trifunctional protein enzyme assay distinguishes complete TFP (all three activities lost) from isolated LCHAD
- Hypoketotic hypoglycemia during catabolic stress
- Avoid fasting; emergency IV glucose during illness
- Low long-chain-fat diet with MCT supplementation
- Triheptanoin (an odd-chain triglyceride) is approved for long-chain FAO disorders and improves cardiac and metabolic outcomes
- Surveillance for retinopathy, neuropathy, and cardiomyopathy
LCHAD is one leg of the TFP stool. LCHAD = the dehydrogenase activity only; TFP = all three activities. Same biomarker (C16-OH), broader enzyme loss, worse phenotype.
Maternal HELLP or AFLP in a heterozygous mother carrying an affected fetus is the classic pregnancy clue for TFP or LCHAD. The fetal liver cannot oxidize long-chain fats, and toxic intermediates cross into the maternal circulation.