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

Updated: Mar 31, 2021
Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG 



The study of fatty acid metabolism gained importance during the 1970s when investigators and clinicians recognized patients who appeared to have genetic defects in this area. In 1973, carnitine palmitoyltransferase (CPT) deficiency became the first fatty acid metabolism condition to be defined. With attention focused on the definition of additional disorders, researchers described patients with a Reye syndrome–like presentation who excreted dicarboxylic acids of chain lengths C6-C10 in their urine.

In 1976, Gregersen and colleagues described a patient with similar findings and theorized that a beta-oxidation defect was responsible; thus, expectations were raised that this type of defect would soon be identified.[1] By 1982, at least 2 reports of patients thought to suffer from defects in beta-oxidation were published. In 1983, Gregersen et al demonstrated a medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency in a patient with hypoketotic hypoglycemia.[2] Stanley and colleagues described several children with similar clinical presentations who were MCAD deficient and confirmed the demonstration in the same year.[3]

The clinical entity known as MCAD deficiency was biochemically defined less than 35 years ago; however, some believe the condition to be at least as common in newborns as phenylketonuria, with an incidence approximating 1 per every 12,000 live births. A recent report from Europe indicates an incidence in Bavaria of 1:8456 in more than 500,000 newborns screened.[4]


The beta-oxidation cycle permits the cell to extract energy from the breakdown of fatty acids with linkage to an accessory pathway for the formation of acetoacetate. Beta-oxidation is a complex mitochondrial pathway that is dependent on the presence of adequate cytosolic carnitine and 2 mitochondrial membrane-bound enzymes: CPT I and CPT II.

In the cytosol, a saturated, straight-chain fatty acid molecule with no double bonds is activated by the action of fatty acyl-CoA synthetase to form its corresponding acyl-CoA. This acyl-CoA is linked to carnitine by the action of CPT I, with simultaneous transport across the mitochondrial membrane barrier. Once inside the mitochondrion, the action of CPT II at the inner surface of the membrane releases free carnitine, which exits to the cytosol and leaves behind the acyl-CoA molecule.

Beta-oxidation cycle

Entry into the beta-oxidation cycle requires the action of acyl-CoA dehydrogenase, the first enzyme in the sequence, which removes electrons from the alpha-carbon and the beta-carbon, introducing a double bond. The electrons are transferred to the flavin cofactor essential for normal enzyme activity. These are, in turn, transferred to the electron transport chain with the production of ATP.

The next step is the introduction of a water molecule and resaturation of the double bond to form fatty enoyl-CoA.

Oxidation of the hydroxyl substituent group on the beta-carbon creates an inherently unstable beta-ketoacyl-CoA compound. In the process, another electron transfer occurs, this time to nicotinamide-adenine dinucleotide (NAD), and more ATP is produced by passage down the electron transport chain.

Cleavage of the 3-keto compound at the now unstable alpha-beta carbon bond and transfer of another CoA moiety to the new fragment results in 2 products: acetyl-CoA, composed of the carbonyl and original alpha-carbon from the starting molecule, and a new fatty acyl-CoA that is 2 carbons shorter than the original molecule.

In addition to its intrinsic importance in the use of alternative fuels, the process of beta-oxidation clearly illustrates the role of vitamin cofactors in metabolism. Both riboflavin and nicotinamide are key to the ferrying of electrons to the cytochromes for production of ATP, without which the breakdown of fatty acid would be utterly useless to the cell's energy economy.

The following 2 additional points are noteworthy regarding beta-oxidation:

  • Fatty acids shorter than C12 do not require CPT activity for mitochondrial entry.

  • At least 3 separate acyl-CoA dehydrogenases are known; they are as follows:

    • Long-chain acyl-CoA dehydrogenase (Length of fatty acid greater than C12)

    • Medium-chain acyl CoA dehydrogenase (Length of fatty acid C6-C12)

    • Short-chain acyl-CoA dehydrogenase (Length of fatty acid less than C6)

Fatty acids longer than C12 can be oxidized by beta-oxidation down to a 12-carbon fatty acyl-CoA; those shorter than C6 are also normally oxidized.

The pathophysiology of MCAD deficiency results from the inability to carry out the first step of beta-oxidation. The molecular implication of most mutations in this disorder is a loss of enzymatic function due to protein misfolding; the amino acid substitutions secondary to the genetic mutations impairs the acquisition of a normal 3-dimensional shape.[5, 6, 7] Any clinical situation in which fatty acid oxidation is required, such as fasting or metabolic stress due to illness, results in continued glucose consumption and a markedly reduced or absent corresponding increase in ketone body production. A 2016 study has suggested that metabolic stress causing flooding of the β-oxidative pathway with substrate may contribute to competitive inhibition, thus enhancing metabolic decompensation.[8]

The ultimate clinical result is severe hypoglycemia and hypoketonuria with accumulation of monocarboxylic fatty acids and dicarboxylic organic acids, which are structural analogues of the fatty acids that cannot pass through the MCAD step. These dicarboxylic acids include adipic (C6), suberic (C8), sebacic (C10), and dodecanedioic (C12). Each is formed by an alternative metabolic pathway called Ω-oxidation that attempts, without success, to begin oxidation at the opposite end of the fatty acid. These omega-oxidation products appear in urine; an appropriately equipped laboratory can identify them and a diagnosis can be expeditiously made. As in propionic acidemia, the cell attempts to conserve free CoA by substitution with carnitine, with a resultant urinary excretion of acyl-carnitine compounds.

Octanoic acid (a C8 fatty acid), which accumulates during an impending metabolic decompensation in an affected patient, is a well-known mitochondrial toxin; this may account for the disruption of ammonia metabolism that often accompanies the clinical presentation of MCAD deficiency. In addition, octanoate has also been shown to reduce oxidation of glucose by rat cerebral homogenates by 70%, which may significantly contribute to the neurological abnormalities. The hypoglycemia and hyperammonemia combine to account for the lethargy and coma that culminate in cerebral edema if left untreated.

Finally, gluconeogenesis is effectively disabled in MCAD deficiency because it depends on the activity of pyruvate carboxylase to produce oxaloacetate, a reaction that is downregulated by diminished mitochondrial acetyl-CoA. Consequently, gluconeogenesis cannot compensate for the continuing consumption of existing glucose and the inability to shift to oxidation of alternative fuels, specifically fatty acids.



United States

Inherited as an autosomal recessive trait, MCAD deficiency was found in at least one series, which used a population-screening technique, to occur in approximately 1 in every 8500 live births.[4]  

Autosomal recessive inheritance. Autosomal recessive inheritance.

This figure seems somewhat high, but the true incidence rate is almost certainly among the highest of the inborn errors of metabolism, rivaling that of phenylketonuria. In part because of the supposed frequency of the disorder, nationwide debate has resulted in many states adding MCAD to their existing newborn metabolic screening programs. Although screening is feasible, each of the available methodologies has drawbacks. Tandem mass spectrometry requires a very large capital investment in instrumentation, whereas molecular probes are not yet commercially available for all mutations that result in clinical disease. Many additional states are likely to add MCAD deficiency soon to their routine newborn metabolic screening program, and the true incidence of the disease in the United States will be revealed.


The application of tandem mass spectrometry to newborn metabolic screening in many other countries throughout the world has supplied a better understanding of the worldwide incidence of MCAD deficiency.[9, 10] The average incidence rate among more than 8 million babies was 1 per 14,600 live births, with a range of 1 per 13,500 to 1 per 15,900.[11] A single mutation accounted for more than 50% of all diagnosed cases.


Some authors note that MCAD deficiency may be a cause of sudden infant death syndrome (SIDS), a concept that has largely been discredited by extensive postmortem study over the past decade. The tendency for development of very severe hypoglycemia is associated with a risk of serious damage to the CNS and other organs. The possibility of cerebral edema and coma leading to death is a cause of legitimate concern.


Because the mutation is an autosomal recessive trait, equal gender distribution is anticipated.


Because MCAD deficiency is a genetically transmitted disorder, it is present from conception. Clinical onset can occur at any time during infancy; however, the tendency is for onset in infants aged 3 months and older, when overnight feedings begin to diminish in frequency. One report suggests the potential for neonatal decompensation associated with compound heterozygosity of a c.199T>C mutation and the common c.985A>G mutation.[12] The increase in fasting time exposes the underlying defect, which leads to the clinical presentation.

Early diagnosis is imperative because serious morbidity and mortality is associated with initial onset in more than 25% of undiagnosed individuals. A recent report[13] suggests that residual enzyme activity of greater than 10% of normal is either sufficient for most metabolic needs, and/or may delay onset and determine clinical severity. This observation deserves greater attention in order to expedite clinical prognosis.

As is the case in many other inherited metabolic disorders, adult-onset MCAD has been reported as well. The individuals reported have been previously healthy adults. Although reports of affected adults are not surprising because of the high incidence rate of the disease, the absence of symptoms prior to clinical onset is surprising. A recent report of a newborn screened out as abnormal led to identification of the asymptomatic mother as an affected individual.[14]




Because medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive trait, other affected members of a family pedigree are unlikely to be historically available to assist in diagnosis.

The naturally frequent feeding of a very young infant tends to offset the need for reliance on alternative fuel for fasting; however, as the infant begins to extend the interval between feedings, the need for fatty acid catabolism correspondingly increases. Historically, this need may correlate with increased preprandial irritability, lethargy, jitteriness, sweating, and, possibly, seizures, which are all symptomatic of hypoglycemia.

Exaggerated lethargy accompanied by vomiting and acidosis with previous viral illness, often requiring intravenous fluid replacement therapy, is common. Indeed, in unrecognized cases, routine intravenous glucose and electrolyte rehydration may further obscure the underlying condition. It would be prudent to evaluate any infant or child with a repetitive history of postinfectious decompensation for fatty acid oxidative disorders.

Although early development is usually normal, growth may be somewhat slow. Repeated episodes of metabolic decompensation may result in poor intellectual development.[15]


Prior to acute clinical presentation, physical examination findings may be entirely normal or may be remarkable only for a growth rate below the reference range.

Upon acute presentation, the infant is likely to be tachypneic, somnolent, and have a mildly enlarged liver, which is due to fatty infiltration. Hepatomegaly is a cardinal feature of MCAD, as well as of other fatty acid oxidative disorders.[16]

Neurological examination is nonspecific, without localizing signs.

If the infant has experienced a hypoglycemic seizure, distinguishing a postictal state from coma due to cerebral edema is vital.

The adult presentation may be characterized by headaches and vomiting, probably relating to hyperammonemia and to the cerebral metabolic effects of accumulated octanoate.


The gene has been mapped to locus 1p31; more than 80 allelic variations have been reported.[17] The most common mutation is 985A>G, which refers to a substitution of a guanine nucleotide for an adenine nucleotide at the 985th residue. A second mutation, 583G>A, is reportedly common in certain populations. One study reported that individuals homozygous for 985A>G or 583G>A mutations had the highest levels of octanoylcarnitine, even when asymptomatic, and had the most severe clinical manifestations.[18] This has not been confirmed to date.

Phenotype-genotype relationships have been sought, with little success. As an example, although the common 985A>G mutation is frequently responsible for infantile onset, the same mutation has been reported in a patient with adult onset.

Acute hepatic failure in a previously healthy gravid female who is homozygous for the 985A>G mutation has been reported, thus confirming the potential for later onset, as well as the severity of complications with this specific mutation.[19]



Laboratory Studies

Measurement of serum electrolyte levels may reveal depressed bicarbonate and an anion gap in medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency.

Blood glucose levels are low in asymptomatic individuals, although symptoms may be present prior to onset of hypoglycemia.

Blood ammonia levels may be mildly to moderately elevated.

Urinalysis is helpful in ruling out ketonuria; urine should be submitted for organic acid profile and acylcarnitine excretion pattern.

Other Tests

Molecular genetic testing can identify the nature of the mutation for purposes of prenatal diagnosis.

As suggested by Touw et al,[13] measurement of residual enzyme activity may be of value in prognosis and/or treatment.

Histologic Findings

Liver tissue findings reveal large-droplet steatosis, electron-dense mitochondrial matrices, and increased width of the mitochondrial membrane. These changes are suggestive of a mitochondrial oxidative disorder but are not specific to MCAD deficiency.



Medical Care

A major component of the medical treatment of medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency is a diet that permits adequate nutrition and avoids any fasting period longer than 4-5 hours.

Carnitine administration has been advocated on the basis of recognition of the biochemical role of carnitine in permitting conjugation and excretion of toxic intermediates. However, the evidence for any therapeutic effect is sparse and mostly anecdotal.

A recent study provides no evidence that supplemental carnitine administration is beneficial in moderate exercise states.[20] Moreover, patients with MCAD deficiency can replenish their stores of carnitine to compensate for carnitine losses with exercise.


Consider obtaining the following consultations:

  • Biochemical geneticist

  • Nutritionist


Diet should be adjusted to supply requisite nutrition for normal growth and avoid fasting periods of more than 4-5 hours in infants younger than 6 months. Thereafter, fasting of more than 8 hours should be avoided in infants aged 6-12 months, and fasting of more than 10 hours should be avoided in patients aged 12-24 months. Subsequently, no affected individual should be permitted to fast longer than 12 hours.

Because the fundamental biochemical defect is in fatty acid oxidation, the composition of the diet should be adjusted to provide greater caloric density in carbohydrates and proteins and minimize lipids.[21]



Medication Summary

The only appropriate medication is carnitine, although this remains controversial among specialists of inherited biochemical diseases.



Further Outpatient Care

Affected individuals require close monitoring of growth to make appropriate dietary changes. A skilled nutritionist should direct such changes.

If the condition remains stable, blood studies beyond those required in routine pediatric care are not needed.

Further Inpatient Care

In patients with medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) deficiency, because of the risk of severe hypoglycemia during fasts, any intercurrent illness that reduces or interrupts food intake may require admission for intravenous glucose support.

Inpatient & Outpatient Medications

Other than daily carnitine administration, no medication has been proven effective.


Transfer is indicated when severe ketoacidosis, coma, seizures, or cerebral edema is present.


Strategies include the following:

  • Avoidance of fatty foods

  • Early treatment and blood glucose support during intercurrent illness


Frequent episodes of severe hypoglycemia carry a great risk of adverse effects on CNS integrity.

Hypoglycemia and hyperammonemia may cause cerebral edema and prolonged coma.

Patients with MCAD deficiency have a tendency to develop prepubertal obesity, which can be exceptionally difficult to treat because of the need for a relatively constant caloric intake to prevent acute decompensation.


Prognosis is difficult because of the broad clinical spectrum among affected patients.

When appropriately treated, most children have a good prognosis.(Anderson DR, Viau K, Botto, LD, et al. Clinical and biochemical outcomes of patients with medium-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab 2020; 129:13-19)

Experience is too limited to predict life span, although with expanded newborn screening in most developed countries it is becoming clear that a normal lifespan may be predictable with good care.

Patient Education

Genetic counseling should be provided for family members.

The frequency of the homozygous state warrants testing for the gene in first-degree relatives of the affected child.