Newborn screening · Fatty acid oxidation disorder
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency · LCHAD
Long-chain fatty acid oxidation defect. Maternal HELLP risk during pregnancy is a distinctive feature.
Description
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, LCHAD, 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 alpha subunit carries the long-chain enoyl-CoA hydratase and long-chain 3-hydroxyacyl-CoA dehydrogenase activities. Isolated LCHAD deficiency is caused by HADHA variants that selectively reduce the dehydrogenase activity while sparing the other two enzymes of the complex. A single common HADHA variant, c.1528G>C (p.Glu474Gln), accounts for the majority of pathogenic alleles in populations of Northern European ancestry.
Clinical presentation falls along a severity spectrum. Severe neonatal disease presents with hypoketotic hypoglycemia, cardiomyopathy, hepatic dysfunction, and sudden death during fasting illness. Milder later-onset disease presents with episodic rhabdomyolysis triggered by fasting, illness, or sustained exercise. Pigmentary retinopathy and progressive peripheral neuropathy develop in long-term survivors and distinguish LCHAD from most other fatty acid oxidation disorders. Pregnancy of a fetus affected with LCHAD is associated with maternal acute fatty liver of pregnancy and HELLP syndrome, an obstetric red flag 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. Confirmation uses plasma acylcarnitine, fibroblast or lymphocyte enzyme assay, and HADHA sequencing. Reported live-birth incidence is roughly 1 in 50,000 to 1 in 250,000. LCHAD 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.
Triheptanoin, marketed as Dojolvi, 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. LCHAD is included on the label. 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.
No gene therapy is approved. Pre-clinical work in HADHA-edited induced pluripotent stem cell models has examined cardiomyopathy mechanisms and supports candidate therapeutic targets. Pregnant women carrying a fetus at risk for LCHAD receive obstetric monitoring for HELLP and acute fatty liver of pregnancy.