LCHAD deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is a fatty acid oxidation disorder with a clinical signature that extends beyond the metabolic crisis biology shared with other long-chain conditions. The retina, the peripheral nerves, and the pregnant mother of an affected fetus all carry a LCHAD-specific risk that is part of the disorder's distinctive identity. The screen prevents the worst of the metabolic crises. The chronic complications, particularly the progressive retinopathy, remain part of long-term management.

What LCHAD is

LCHAD deficiency is an autosomal recessive fatty acid oxidation disorder caused by variants in HADHA on chromosome 2p23. HADHA encodes the alpha subunit of mitochondrial trifunctional protein, MTP, which performs three sequential reactions in long-chain fatty acid oxidation: long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (the LCHAD activity), and long-chain 3-ketoacyl-CoA thiolase. Variants that selectively impair the LCHAD activity produce isolated LCHAD deficiency. Variants that impair all three activities produce trifunctional protein deficiency, which has overlapping but distinct features.

The most common pathogenic variant in HADHA, c.1528G>C (p.Glu474Gln), is responsible for the majority of LCHAD cases of European ancestry. The variant selectively impairs the LCHAD enzymatic activity while preserving the other two trifunctional protein functions.

The clinical phenotype includes hypoketotic hypoglycemic crises during fasting or illness in infancy and childhood, hepatic decompensation with elevated transaminases and coagulopathy during acute episodes, dilated cardiomyopathy that can present in infancy or develop later, rhabdomyolysis precipitated by exercise or illness, peripheral neuropathy that progresses through childhood and adolescence, and progressive pigmentary retinopathy that can lead to vision loss in adulthood. The retinopathy and neuropathy are LCHAD-specific complications among the FAO disorders and reflect the chronic accumulation of long-chain hydroxyacyl intermediates in tissues with high lipid turnover.

The maternal-fetal LCHAD association is clinically important. Heterozygous women carrying a fetus homozygous or compound heterozygous for HADHA variants are at elevated risk of acute fatty liver of pregnancy, AFLP, and HELLP syndrome. The recognition of this association in the 1990s and 2000s changed obstetric management of women whose previous pregnancies were complicated by AFLP or who carry an affected fetus.

Reported live-birth incidence in newborn screening programs runs roughly 1 in 100,000 to 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 trifunctional protein deficiency, and second-tier testing distinguishes the two through HADHA and HADHB sequencing. Confirmation uses plasma acylcarnitines, plasma amino acids, urine organic acids, and gene sequencing.

What management looks like

Standard of care is avoidance of prolonged fasting, frequent feeds appropriate to age, a long-chain-fat-restricted diet using medium-chain triglyceride supplementation, and prompt intravenous dextrose during illness. The MCT supplementation provides medium-chain fatty acids that bypass the LCHAD enzymatic block and can be oxidized in the mitochondrion. L-carnitine supplementation is used in selected cases with documented secondary carnitine depletion.

Triheptanoin (Dojolvi) was approved by the FDA in June 2020 for long-chain fatty acid oxidation disorders including LCHAD. Triheptanoin is a synthetic odd-chain fatty acid that, after oxidation, produces propionyl-CoA, which feeds into the citric acid cycle as anaplerotic substrate. The drug provides an additional energy substrate that bypasses the long-chain block and may improve clinical outcomes in selected cases, although the evidence base is still developing.

Cardiac surveillance with echocardiography is part of routine follow-up, with intervals shortening if cardiomyopathy is detected. Ophthalmology surveillance for retinopathy begins in early childhood and continues across decades, with optical coherence tomography and electroretinography adding objective measures to clinical examination. The retinopathy is one of the conditions where chronic supplementation with docosahexaenoic acid has been studied, with mixed results.

Sick-day protocols and emergency cards travel with the child. The metabolic team is the central long-term care relationship, with cardiology, ophthalmology, and neurology participating as the chronic complications develop.

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 sequencing returns the c.1528G>C variant in homozygous form. The metabolic team starts MCT-supplemented formula and instructs on fasting avoidance and sick-day protocols.

That child grows up. The neonatal hepatic crisis that historically presented at the first viral illness never happens. Annual ophthalmology examinations begin in toddlerhood. Cardiac surveillance is annual. In the second decade, retinopathy on optical coherence tomography is detected at an early stage. Vision is monitored. Triheptanoin may be added depending on the clinical course.

The mother's next pregnancy, with knowledge of the family's HADHA status, is monitored at a maternal-fetal medicine center experienced in LCHAD pregnancies. AFLP and HELLP risk are tracked through the third trimester.

That is what LCHAD care looks like in practice. The screen prevents the metabolic deaths the unscreened cohorts experienced. The retinopathy and the maternal pregnancy risk are chronic management problems that the screen identifies but does not solve.