# Fatty Acid Oxidation Disorders: MCADD and VLCADD

## Overview

Fatty acid oxidation (FAO) disorders are a group of inborn errors affecting mitochondrial beta-oxidation of fatty acids. During fasting or periods of high energy demand, fatty acids become the primary fuel source; FAO defects cause energy failure and accumulation of toxic intermediates. Most present during metabolic stress (fasting, illness, exercise) and are detected by newborn screening through acylcarnitine profiling via tandem mass spectrometry. MCADD (medium-chain acyl-CoA dehydrogenase deficiency) is the most common clinically significant FAO disorder, while VLCADD (very long-chain acyl-CoA dehydrogenase deficiency) is more severe with a broader clinical spectrum.

## Mitochondrial Beta-Oxidation Pathway

### Overview of the Pathway

Long-chain fatty acids are activated to acyl-CoA esters in the cytoplasm. Long-chain acyl-CoAs require the carnitine shuttle (CPT-I, CACT, CPT-II) to enter the mitochondrial matrix, while medium- and short-chain fatty acids can enter independently. The beta-oxidation cycle consists of four sequential reactions repeated with each cycle removing a 2-carbon unit as acetyl-CoA: acyl-CoA dehydrogenation (chain-length specific: VLCAD, MCAD, SCAD), enoyl-CoA hydration, 3-hydroxyacyl-CoA dehydrogenation, and 3-ketoacyl-CoA thiolysis. Acetyl-CoA enters the TCA cycle or is converted to ketone bodies. ETF and ETF-dehydrogenase transfer electrons from the first step to the respiratory chain.

### Chain-Length Specificity

VLCAD handles C14-C20 substrates, MCAD handles C6-C12, and SCAD handles C4-C6. Long-chain FAO also involves the mitochondrial trifunctional protein (MTP/LCHAD) for steps 2-4.

| Disorder | Gene | Substrate Range | NBS Marker | Key Clinical Features | Dietary Management |
|---|---|---|---|---|---|
| VLCADD | ACADVL | C14–C20 | Elevated C14:1 | Cardiomyopathy, rhabdomyolysis, hypoglycemia | MCT oil supplementation; long-chain fat restriction |
| LCHADD/TFP | HADHA/HADHB | C12–C16 | Elevated C16-OH, C18:1-OH | Neuropathy, retinopathy, cardiomyopathy | MCT oil; DHA supplementation |
| MCADD | ACADM | C6–C12 | Elevated C8 | Hypoketotic hypoglycemia; Reye-like episodes | Fasting avoidance; normal diet |
| SCADD | ACADS | C4–C6 | Elevated C4 | Usually benign/asymptomatic | None required in most cases |
| CPT-II deficiency | CPT2 | Long-chain | Elevated C16, C18:1 | Myopathic (adult) or lethal neonatal form | Long-chain fat restriction; MCT oil |
| CACT deficiency | SLC25A20 | Long-chain | Elevated C16, C18:1 | Severe neonatal cardiomyopathy | Long-chain fat restriction; MCT oil |

<image>Diagram of the mitochondrial fatty acid beta-oxidation spiral showing the carnitine shuttle system, the four enzymatic steps of each beta-oxidation cycle, and the chain-length specificity of VLCAD, MCAD, and SCAD with their substrate ranges</image>

## Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD)

### Epidemiology and Genetics

MCADD is the most common FAO disorder with an incidence of approximately 1 in 10,000-17,000 in Northern European populations. It results from mutations in the ACADM gene (1p31.1) with autosomal recessive inheritance. The common mutation c.985A>G (p.K329E) accounts for approximately 80% of alleles in European populations through a founder effect. NBS has identified milder genotypes with uncertain clinical significance.

### Pathophysiology

The inability to oxidize medium-chain fatty acids (C6-C12) during fasting results in hypoketotic hypoglycemia (insufficient ketone body generation), accumulation of medium-chain acylcarnitines and dicarboxylic acids, and energy failure. The brain is particularly vulnerable during fasting because it cannot utilize fatty acids directly and depends on glucose and ketones. Toxic accumulation of octanoic acid may contribute to cerebral edema and hepatic dysfunction.

### Clinical Presentation

Historically, the first episode was often triggered by prolonged fasting during intercurrent illness, typically between 3-24 months of age, presenting with lethargy, vomiting, and hypoglycemia progressing to seizures, coma, and death. Mortality from the first episode was 20-25% in the pre-NBS era, with survivors often suffering permanent neurological sequelae. In the post-NBS era, most patients are identified presymptomatically, and metabolic crises are preventable with fasting avoidance. Biochemical findings during crisis include hypoketotic hypoglycemia (inappropriately low ketones for the degree of hypoglycemia), elevated liver enzymes, mild to moderate hyperammonemia, and late metabolic acidosis.

### Diagnosis

NBS acylcarnitine profile shows elevated C8 (octanoylcarnitine), elevated C8/C10 ratio, and elevated C6 and C10:1. Confirmatory testing includes repeat plasma acylcarnitine profile (which may normalize when well-fed), urine organic acids (elevated dicarboxylic acids during illness, possibly normal when well), and molecular testing of the ACADM gene.

### Management

Fasting avoidance is the cornerstone of treatment: feeding every 4-6 hours in infants, avoiding overnight fasting beyond 8-10 hours in infants, 10-12 hours in toddlers, and 12 hours in older children/adults. The emergency protocol for illness involves oral simple carbohydrates if able to drink, or immediate IV dextrose (D10) if unable to tolerate oral intake. An emergency letter/protocol card should be carried for ER visits. L-carnitine supplementation is controversial and varies by center. Dietary fat restriction is generally not required; a normal diet with regular meals suffices. Prognosis is excellent with NBS detection and fasting avoidance, with normal development expected.

<image>Acylcarnitine profile comparison showing normal pattern versus MCADD pattern (elevated C8 with characteristic C6 and C10:1 elevations) and VLCADD pattern (elevated C14:1 with long-chain acylcarnitine elevations)</image>

## Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD)

### Epidemiology and Genetics

VLCADD results from mutations in the ACADVL gene (17p13.1) with autosomal recessive inheritance and an incidence of approximately 1 in 30,000-100,000. A wide mutation spectrum exists with imperfect genotype-phenotype correlation. NBS has identified many mild/asymptomatic cases.

### Clinical Phenotypes

The severe neonatal/infantile cardiomyopathic form presents in the first days to months with hypertrophic or dilated cardiomyopathy, pericardial effusion, hepatomegaly, liver failure, and hypoketotic hypoglycemia, carrying high mortality without aggressive management. The moderate infantile hepatic form presents with recurrent episodes of hypoketotic hypoglycemia triggered by illness/fasting, similar to MCADD but potentially more severe, without initial cardiomyopathy (though it may develop later). The mild late-onset myopathic form presents in adolescence or adulthood with exercise-induced rhabdomyolysis, myalgia, muscle weakness, dramatically elevated CK (often above 10,000 IU/L), and myoglobinuria with risk of acute renal failure, triggered by prolonged exercise, cold exposure, or fasting.

### Management

Dietary management requires restriction of long-chain fat (unlike MCADD) with medium-chain triglyceride (MCT) supplementation. MCTs bypass the VLCAD enzyme defect as they are metabolized by MCAD and SCAD. Triheptanoin (Dojolvi), an odd-chain C7 fatty acid FDA-approved in 2020 for long-chain FAO disorders, provides both ketogenic and anaplerotic (TCA cycle-replenishing) substrates, offering better anaplerotic support than even-chain MCTs. Essential fatty acid supplementation (DHA, walnut oil) prevents deficiency from long-chain fat restriction. Fasting avoidance is even more stringent than in MCADD. Exercise management includes avoiding prolonged intense exercise without adequate carbohydrate intake and pre-exercise carbohydrate loading. Cardiac management involves regular echocardiography, with cardiomyopathy potentially reversible through aggressive dietary management and MCT supplementation.

## Other FAO Disorders (Brief Overview)

### LCHAD/MTP Deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or mitochondrial trifunctional protein (MTP) deficiency presents with hypoketotic hypoglycemia, cardiomyopathy, hepatopathy, and peripheral neuropathy. A unique feature is progressive pigmentary retinopathy. The common LCHAD mutation is c.1528G>C in HADHA. Maternal complications of AFLP (acute fatty liver of pregnancy) and HELLP syndrome in mothers carrying an affected fetus are important to recognize.

### CPT-II Deficiency

The adult myopathic form of CPT-II deficiency is the most common, presenting with exercise-induced rhabdomyolysis triggered by fasting, cold, and exercise. The common adult mutation is p.S113L.

### Multiple Acyl-CoA Dehydrogenase Deficiency (MADD/Glutaric Acidemia Type II)

This results from ETF or ETF-dehydrogenase deficiency. The mild/late-onset form presents as lipid storage myopathy, often riboflavin-responsive. NBS shows multiple acylcarnitine elevations across chain lengths (C4-C18).

<image>Clinical comparison table of major fatty acid oxidation disorders (MCADD, VLCADD, LCHAD/MTP, CPT-II) showing gene, key acylcarnitine markers, clinical features, unique complications, and management differences</image>

## Clinical Pearls

Hypoketotic hypoglycemia is the hallmark of FAO disorders -- inappropriately low ketones for the degree of hypoglycemia should always prompt investigation with acylcarnitine profile and urine organic acids. MCADD is effectively a "fasting intolerance disorder" with excellent outcomes and normal development achievable through fasting avoidance alone. The c.985A>G mutation in ACADM accounts for approximately 80% of clinically significant MCADD alleles, though NBS has identified many mild genotypes of uncertain clinical significance. VLCADD has three distinct clinical phenotypes (cardiac, hepatic, myopathic) with substantially different management approaches. Triheptanoin (Dojolvi) provides anaplerotic support that even-chain MCTs cannot and is the preferred MCT supplement for long-chain FAO disorders. Maternal AFLP or HELLP syndrome should prompt FAO testing of the newborn, particularly for LCHAD (c.1528G>C). Exercise-induced rhabdomyolysis in an adolescent or young adult has a differential that includes myopathic VLCADD, CPT-II deficiency, and MADD/glutaric acidemia type II. Carnitine supplementation in MCADD remains debated, with free carnitine levels guiding the decision.

## References

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- Matern D, Rinaldo P. "Medium-chain acyl-coenzyme A dehydrogenase deficiency." In: Adam MP, et al., editors. *GeneReviews*. University of Washington, Seattle. Updated 2023.
- Vockley J, Burton B, Berry GT, et al. "Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD)." *Journal of Inherited Metabolic Disease*. 2019;42(1):169-177.
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