The fatty acid oxidation family

The fatty acid oxidation disorders are a family of inherited conditions that share a metabolic problem: when a person cannot mobilize fat for energy during fasting or illness, glucose stores deplete, hypoglycemia develops, and the affected tissues (liver, heart, skeletal muscle) lack the alternative fuel they would normally use. The most common condition in the family, MCADD, is covered separately because its history is its own story. The rest of the family shares MCADD's screening framework and clinical management while differing in which fatty acid chain length is affected and which secondary complications are most prominent.

This piece is a reference. Each fatty acid oxidation disorder linked here has its own page.

What fatty acid oxidation does

When a person fasts overnight or burns through glucose stores during illness, the liver begins to mobilize fat. Fatty acids enter the mitochondrion and are progressively shortened by two-carbon increments, producing acetyl-CoA that fuels ATP production and ketone body synthesis. The shortening is performed by a series of enzymes that act on different chain lengths: very-long-chain acyl-CoA dehydrogenase on chains of 14 to 20 carbons, long-chain hydroxy and trifunctional protein on chains of 12 to 18 carbons, medium-chain acyl-CoA dehydrogenase on chains of 6 to 12 carbons, and short-chain acyl-CoA dehydrogenase on chains of 4 to 6 carbons. Each enzyme depends on its own genes and folding partners.

Carnitine is the cofactor that imports long-chain fatty acids into the mitochondrion. Defects in carnitine import (carnitine uptake defect) or in the carnitine shuttle enzymes (CPT1, CPT2, translocase) produce a phenotype that resembles a fatty acid oxidation disorder even though the enzymes themselves are normal.

The clinical phenotype follows the chain length affected. Short-chain disorders are often clinically mild or asymptomatic. Medium-chain disorders, like MCADD, present with hypoketotic hypoglycemia and acute encephalopathy during fasting or illness. Long-chain and very-long-chain disorders add cardiomyopathy, rhabdomyolysis, retinopathy (in long-chain hydroxy and trifunctional protein deficiency), and peripheral neuropathy to the picture, because the longer the chain length the more critical the residual oxidation pathway is for cardiac and skeletal muscle energy.

Carnitine uptake defect, CUD

Variants in SLC22A5 cause primary carnitine deficiency. Without functional carnitine transporter, carnitine is not retained by the kidney and is lost in urine, plasma carnitine collapses, and long-chain fatty acid import into the mitochondrion fails. The clinical picture includes cardiomyopathy (often dilated, sometimes presenting in adulthood), hypoglycemia during fasting, hepatomegaly, and skeletal muscle weakness. Treatment is high-dose oral L-carnitine supplementation, lifelong, which fully or near-fully corrects the clinical course in most cases identified through screening.

Long-chain hydroxy-acyl-CoA dehydrogenase deficiency, LCHAD

Variants in HADHA cause LCHAD deficiency. The clinical course includes hypoketotic hypoglycemic crises, cardiomyopathy, rhabdomyolysis precipitated by exercise or illness, peripheral neuropathy, and progressive pigmentary retinopathy that can lead to vision loss. Pregnancies of mothers carrying an LCHAD-affected fetus are associated with elevated risk of acute fatty liver of pregnancy and HELLP syndrome, the recognition of which has expanded fetal screening considerations. Treatment is avoidance of fasting, a long-chain-fat-restricted diet using medium-chain triglyceride supplementation, frequent feeds, and L-carnitine supplementation in selected cases.

Trifunctional protein deficiency, TFP

Variants in HADHA or HADHB affecting the trifunctional protein complex produce TFP deficiency. The complex performs three sequential reactions in long-chain fatty acid oxidation. TFP deficiency clinically resembles LCHAD with the addition of a more severe cardiomyopathy and peripheral neuropathy phenotype in some cases. The same maternal acute fatty liver of pregnancy association applies. Treatment is the same dietary and supplementation framework as LCHAD.

Very long-chain acyl-CoA dehydrogenase deficiency, VLCADD

Variants in ACADVL cause VLCADD. Three clinical phenotypes are recognized: severe early-onset with neonatal cardiomyopathy and high mortality, intermediate childhood-onset with hypoglycemia and hepatic episodes, and mild adult-onset with rhabdomyolysis precipitated by exercise. The clinical course depends on residual enzyme activity. Treatment is avoidance of fasting, a long-chain-fat-restricted diet with medium-chain triglyceride supplementation, frequent feeds, and triheptanoin (Dojolvi), an FDA-approved odd-chain fatty acid that bypasses the long-chain enzyme block in long-chain fatty acid oxidation disorders. Triheptanoin was FDA-approved in June 2020 for long-chain fatty acid oxidation disorders including VLCADD, LCHAD, and TFP deficiency, and the label indication explicitly excluded MCADD.

What the family shares

Detection across the family uses tandem mass spectrometry on the dried blood spot, with each condition flagged by its characteristic acylcarnitine pattern: C0 (free carnitine) low in CUD, C16-OH and C18:1-OH elevated in LCHAD and TFP, C14:1 elevated in VLCADD. Confirmation uses plasma acylcarnitines, urine organic acids, and gene sequencing.

Standard of care across the family is avoidance of prolonged fasting plus prompt intravenous dextrose during illness. Long-chain fatty acid restriction with MCT supplementation is the chain-length-specific dietary intervention. Cardiac surveillance is part of routine follow-up for all the long-chain disorders. Triheptanoin is an option for the long-chain disorders. L-carnitine supplementation is standard in CUD and selected in the others.

The screening case across the FAO family rests on prevention of the first hypoketotic hypoglycemic crisis or the first cardiac decompensation. In screened cohorts, mortality at first crisis has dropped from substantial fractions in the pre-screening era to near zero with prompt sick-day management.