Trifunctional protein deficiency

Trifunctional protein deficiency, TFP, is the more severe sibling of LCHAD. The same protein complex is involved. The same screening signal flags both conditions on the dried blood spot. The same dietary management framework applies. The clinical course in TFP, however, is generally more severe than in isolated LCHAD, with cardiomyopathy that more often presents in infancy and a clinical phenotype that historically had high mortality before screening was implemented and effective dietary intervention became standard.

What TFP is

Trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder caused by variants in HADHA or HADHB on chromosome 2p23. HADHA encodes the alpha subunit and HADHB encodes the beta subunit of mitochondrial trifunctional protein. The complex performs three sequential reactions in long-chain fatty acid oxidation: long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD activity), and long-chain 3-ketoacyl-CoA thiolase. Variants that affect protein assembly or stability impair all three activities and produce TFP deficiency. Variants that selectively impair only the LCHAD activity, particularly the c.1528G>C HADHA variant, produce isolated LCHAD deficiency.

The clinical phenotype of TFP deficiency includes neonatal-onset cardiomyopathy that can be the presenting feature, hypoketotic hypoglycemic crises, hepatic dysfunction, peripheral neuropathy that often presents earlier and more severely than in LCHAD, rhabdomyolysis precipitated by exercise or illness, and progressive pigmentary retinopathy. The natural history before screening included substantial neonatal mortality from cardiomyopathy in some cohorts.

The same maternal-fetal association documented in LCHAD applies to TFP deficiency. Heterozygous women carrying a fetus with biallelic HADHA or HADHB variants are at elevated risk of acute fatty liver of pregnancy and HELLP syndrome.

Reported live-birth incidence is well below 1 in 250,000.

Detection

Newborn screening uses tandem mass spectrometry on the dried blood spot to flag elevated long-chain hydroxyacylcarnitines, particularly C16-OH and C18:1-OH. The same markers flag isolated LCHAD deficiency. Distinguishing TFP deficiency from LCHAD requires gene sequencing: HADHA variants other than c.1528G>C, particularly biallelic loss-of-function variants, and HADHB variants identify TFP deficiency. Functional assay of the three trifunctional protein activities in cultured fibroblasts can support the diagnosis when sequencing is ambiguous.

What management looks like

Standard of care follows the LCHAD framework with attention to the more severe cardiac risk. Avoidance of prolonged fasting, frequent feeds, long-chain-fat-restricted diet using medium-chain triglyceride supplementation, prompt intravenous dextrose during illness, and L-carnitine supplementation in selected cases are all part of management. Triheptanoin (Dojolvi) was approved by the FDA in June 2020 for long-chain fatty acid oxidation disorders including TFP deficiency, and is used in selected cases for additional metabolic support.

Cardiac surveillance with frequent echocardiography is more important in TFP than in isolated LCHAD because of the higher rate and earlier onset of cardiomyopathy. Some affected infants present with cardiomyopathy at the time of newborn screening and require both metabolic management and pediatric cardiology involvement from the first weeks of life. Heart transplantation has been performed in selected cases with severe and progressive cardiomyopathy.

Peripheral neuropathy and retinopathy follow the same long-term surveillance framework as LCHAD, with ophthalmology and neurology adding to the multidisciplinary clinic. The neuropathy can be more progressive in TFP than in LCHAD and can become a significant functional issue in adolescence and adulthood.

What this looks like for a family

A baby is born and the heel-prick is sent. On day 4, the state lab reports elevated C16-OH and C18:1-OH. On day 7, HADHA or HADHB sequencing returns biallelic loss-of-function variants consistent with TFP deficiency. An echocardiogram is performed early in the workup because cardiomyopathy can be the presenting feature. The metabolic team starts MCT-supplemented formula and frequent feeds. Cardiology evaluates baseline cardiac function.

Some affected infants are well at the screening age and remain well on the dietary regimen. Others have detectable cardiomyopathy at presentation and require additional cardiac management. The first decade involves the same recurrent metabolic management as LCHAD, with heightened cardiac surveillance and earlier onset of peripheral neuropathy in many cases.

That is what TFP care looks like in practice. The same screening pattern as LCHAD identifies it. The dietary and emergency framework is shared. The cardiac trajectory and the more aggressive peripheral neuropathy course are the features that distinguish the long-term clinical management from the milder LCHAD course.