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Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Synonym: MCAD Deficiency

, MD and , MD, PhD.

Author Information
, MD
Co-Director, Biochemical Genetics Laboratory
Mayo Clinic College of Medicine
Rochester, Minnesota
, MD, PhD
Co-Director, Biochemical Genetics Laboratory
Mayo Clinic College of Medicine
Rochester, Minnesota

Initial Posting: ; Last Update: January 19, 2012.


Disease characteristics. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid β-oxidation, which fuels hepatic ketogenesis, a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. In a typical clinical scenario, a previously healthy child with MCAD deficiency presents with hypoketotic hypoglycemia, vomiting, and lethargy triggered by a common illness. Seizures may occur. Hepatomegaly and liver disease are often present during an acute episode, which can quickly progress to coma and death. Children are normal at birth and – if not identified through newborn screening – typically present between ages three and 24 months; later presentation, even into adulthood, is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged period of fasting.

Diagnosis/testing. Diagnosis requires the integrated interpretation of multiple analyses, including consideration of the clinical status of the affected individual (i.e., acutely symptomatic vs asymptomatic) at the time of sample collection. Initial testing should include the following analyses and their proper interpretation:

  • Plasma acylcarnitines
  • Urine organic acids
  • Urine acylglycines

The biochemical diagnosis of MCAD deficiency can be confirmed by:

  • Determination of fatty acid β-oxidation in fibroblasts;
  • Measurement of MCAD enzyme activity in fibroblasts or other tissues; and/or
  • Molecular genetic testing of ACADM.

The latter two tests can be used for prenatal diagnosis. Based on newborn screening results, approximately 50% of individuals are homozygous for the common mutation p.Lys304Glu, and approximately 40% are heterozygous for p.Lys304Glu and one of more than 90 rarer alleles.

Management. Treatment of manifestations: Most important is giving simple carbohydrates by mouth (e.g., glucose tablets, or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism.

Prevention of primary manifestations: The mainstay is avoidance of fasting: infants require frequent feedings; toddlers could be placed on a relatively low-fat diet (e.g., <30% of total energy from fat) and could receive 2 g/kg of uncooked cornstarch at bedtime to ensure sufficient glucose overnight.

Prevention of secondary complications: Weight control measures including proper nutrition and exercise.

Agents/circumstances to avoid: Hypoglycemia (e.g., from excessive fasting); infant formulas that contain medium-chain triglycerides as the primary source of fat.

Evaluation of relatives at risk: Evaluate plasma acylcarnitine concentration and urine acylglycine in sibs and parents to permit early diagnosis and treatment of previously asymptomatic at-risk family members.

Genetic counseling. MCAD deficiency is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual are at a 25% risk of being affected, a 50% risk of being asymptomatic carriers, and a 25% risk of being unaffected and not carriers. The risk of being affected could be 50% if one of the parents is also affected. Because asymptomatic parents and sibs may have MCAD deficiency, biochemical evaluation and/or molecular genetic testing should be offered to both parents and all sibs. Because of the high carrier frequency for the p.Lys304Glu mutation in individuals of northern European origin, carrier testing should be offered to reproductive partners of individuals with MCAD deficiency. Prenatal testing for pregnancies at 25% or higher risk is possible by biochemical methods or, if both parental mutations are known, by molecular genetic testing.


Clinical Diagnosis

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of fatty acid oxidation. Fatty acid oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and periods of higher energy demands. In a typical clinical scenario, a previously healthy individual with MCAD deficiency presents with:

  • Hypoketotic hypoglycemia, lethargy, seizures, and coma triggered by a common illness
  • Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver)
  • Sudden and unexplained death

The first acute episode usually occurs before age two years, but affected individuals may present at any age including adulthood [Raymond et al 1999, Schatz & Ensenauer 2010].

Rapid clinical deterioration that is disproportionate in the setting of a common and generally benign infection should raise the suspicion of MCAD deficiency or other fatty acid β-oxidation disorders and should prompt administration of intravenous glucose and the collection of urine and blood samples for metabolic testing (see Testing Strategy).


Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in the pathway of mitochondrial fatty acid β-oxidation (FAO). This pathway consists of four sequential reactions catalyzed first by a set of membrane-bound enzymes and then by a different set of matrix-soluble enzymes, producing at the end of each cycle a molecule of acetyl-CoA and a molecule of acyl-CoA with two fewer carbons. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. A defect of the MCAD enzyme leads to accumulation of medium-chain fatty acids, which lead to the accumulation of glycine- and carnitine-esters and to dicarboxylic acids. These metabolites are detectable in body fluids (blood, urine, bile) by gas chromatography-mass spectrometry (GC-MS) and tandem mass spectrometry (MS/MS).

Because of the nonspecific clinical presentation of MCAD deficiency, the differential diagnosis from other FAO disorders is an increasingly complex process that can hardly be achieved by a single test. The diagnosis of MCAD deficiency therefore requires the integrated interpretation of multiple analyses, including consideration of the clinical status of the affected individual (acutely symptomatic vs asymptomatic) at the time of sample collection. Initial testing should include the following analyses and their proper interpretation.

Plasma acylcarnitine analysis. The acylcarnitine profile of individuals with MCAD deficiency is characterized by accumulation of C6 to C10 species, with prominent octanoylcarnitine [Millington et al 1990, Chace et al 1997, Smith et al 2010].

Note: A potential pitfall of acylcarnitine analysis in the diagnosis of MCAD deficiency is the possibility that individuals with secondary carnitine deficiency may not show a significant elevation of C6-C10 acylcarnitines [Clayton et al 1998]. Although free carnitine and acetylcarnitine are abnormally low in the profile of such individuals, such findings are nonspecific but indicative of a possible underlying metabolic disorder. For this reason, reliance on plasma acylcarnitine analysis as the sole biochemical screen is not advisable, and either urine organic acids (in acute episodes) or acylglycines should be analyzed to reach a correct biochemical diagnosis.

Urine organic acid analysis. In symptomatic individuals, medium-chain dicarboxylic acids are elevated with a characteristic pattern (C6>C8>C10), while ketones are inappropriately low. During acute episodes, 5-hydroxy hexanoic acid, hexanoylglycine, phenylpropionylglycine, and particularly suberylglycine represent additional biochemical markers of MCAD deficiency [Gregersen et al 1983].

Note: (1) Although hypoketotic dicarboxylic aciduria is a common finding, ketone body production could be normal at times of acute decompensation [Patel & Leonard 1995; personal observations]; therefore, the detection of ketonuria by routine urinalysis should not be taken as evidence against a possible diagnosis of MCAD deficiency. (2) Standard urine organic acid profiles are often uninformative in individuals with MCAD deficiency who are stable and are not fasting [Rinaldo et al 2001] because under these conditions the urinary excretion of the three acylglycines is often less than 10 mmol/mol creatinine, levels not readily detectable by routine organic acid analysis. (3) Care should be taken not to interpret as possible MCAD deficiency the elevated concentrations of octanoic acid and decanoic acid with normal cis-4 decenoic acid seen in individuals receiving MCT-oil supplements.

Urine acylglycine analysis is based on the quantitative determination by stable isotope dilution analysis of urinary n-hexanoylglycine, 3-phenylpropionylglycine, and suberylglycine [Rinaldo et al 1988]. The corresponding free acids are endogenous intermediates of fatty acid metabolism or, for phenylpropionic acid, an end product of the anaerobic metabolism of intestinal bacteria. During an acute episode, affected individuals excrete large amounts of hexanoylglycine and suberylglycine, which are readily detected by organic acid analysis. The test, requiring only a random urine sample from asymptomatic individuals and no provocative tests, is informative immediately after birth [Bennett et al 1991].

Note: Most individuals with MCAD deficiency remain asymptomatic for long periods of time, some for their entire lives [Fromenty et al 1996]. Therefore, diagnostic methods for MCAD deficiency should be sensitive enough to identify asymptomatic affected individuals without provocative tests.

Analysis of fatty acid β-oxidation in cultured fibroblasts involves acylcarnitine analysis of culture medium or a mix of culture medium and disrupted cells following the incubation of fibroblast cultures with labeled or non-labeled palmitic acid and non-labeled L-carnitine [Schmidt-Sommerfeld et al 1998]. The accumulation of C6-C10 acylcarnitines as described above for plasma analysis confirms the diagnosis [Matern 2008].

An alternative cell-based method determines the release of tritiated water in the medium of fibroblasts following incubation with labeled medium-chain fatty acids [Olpin et al 1999].

Analysis of MCAD enzyme activity. Measurement of the activity of the MCAD enzyme in leukocytes, cultured fibroblasts, liver, heart, skeletal muscle, or amniocytes by the ETF reduction assay can be used to confirm the diagnosis of MCAD deficiency. Hale and colleagues [1990] showed that individuals with MCAD deficiency usually exhibit less than 10% of normal MCAD enzymatic activity. The same group found carriers to have on average 49% of normal MCAD enzymatic activity [Hale et al 1990].

Very similar results were obtained by a different assay that uses ferricenium hexafluorophosphate as electron acceptor and 3-phenylpropionyl-CoA as substrate followed by measurement of the product of the reaction catalyzed by MCAD using HPLC coupled to UV detection or MS/MS. This assay is currently available in Europe [Wanders et al 2010].

Molecular Genetic Testing

Gene. ACADM is the only gene in which mutations cause medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
ACADMTargeted mutation analysisp.Lys304Glu (985A>G) ~47%~40%
p.Tyr42His (199C>T)0%~13%
Sequence analysisSequence variants (not including p.Lys304Glu or p.Tyr42His) 3~4% 2~13%

1. The ability of the test method used to detect a mutation that is present in the indicated gene
2. Andresen et al [2001], Maier et al [2005], Waddell et al [2006], Nichols et al [2008], Smith et al [2010]
3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a symptomatic child. In order to rapidly reach a conclusive diagnosis in young children who present with acute liver dysfunction associated with impaired vigilance, it is recommended that a number of diagnostic laboratory tests be performed on specimens collected early in the metabolic decompensation [Rinaldo et al 2002], including:

  • At least two of the three following screening methods (Note: Urine acylglycine analysis is the preferred test when patients are clinically asymptomatic.):
    • Plasma acylcarnitine
    • Urine organic acids
    • Urine acylglycines
  • Confirmatory testing by:
    • Determination of fatty acid β-oxidation in fibroblasts;
    • Measurement of MCAD enzyme activity in fibroblasts or other tissues; and/or
    • Molecular genetic testing of ACADM.
  • Molecular genetic testing. Perform targeted mutation analysis for the two most common ACADM mutations:
    • If both are identified, the diagnosis is confirmed;
    • If neither or only one mutation is identified, perform sequence analysis.

Note: The diagnostic algorithm (Image mcad-Image002.jpg) provided by the American College of Medical Genetics for follow up of an abnormal newborn screening result suggestive of MCAD deficiency can also be applied to clinically presenting patients.

Newborn screening. MCAD deficiency meets existing newborn screening criteria [Chace et al 1997, Charrow et al 2000]; several studies have demonstrated that newborn screening for MCAD deficiency is cost-effective [Insinga et al 2002, Venditti et al 2003, Pandor et al 2004]. Since the early 1990s, tandem mass spectrometry (MS/MS) has been applied to the analysis of newborn screening blood spots. Today, all states [National Newborn Screening Status Report (pdf)] and many countries have adopted this technology and include MCAD deficiency in newborn screening programs.

To follow up in an effective and efficient manner on an abnormal screening result suggestive of MCAD deficiency, the American College of Medical Genetics developed an ACTion sheet (Image mcad-Image003.jpg) and diagnostic algorithm (Image mcad-Image002.jpg).

Of note, a newborn whose blood sample has been submitted for newborn screening may become symptomatic before the screening results are available [Ensenauer et al 2005]; thus, clinical suspicion of conditions such as MCAD deficiency must remain high. The diagnostic algorithm provided by the American College of Medical Genetics for follow up of an abnormal newborn screening result suggestive of MCAD deficiency can be applied to clinically presenting patients (Image mcad-Image002.jpg).

The specificity of MS/MS to identify MCAD deficiency appears to be 100%, with a few false negative results having been reported as a result of inappropriate cut-off selection [Maier et al 2009, McHugh et al 2011].

The positive predictive value (PPV) of acylcarnitine analysis to identify MCAD deficiency varies significantly (8%-78%) among screening laboratories [Lindner et al 2010]; nonetheless, it is generally much higher than the PPV for the disorders screened by the traditional, non-MS/MS methods (0.5%-6.0%) [Kwon & Farrel 2000]. Of note, it is also possible to encounter newborns with evidence of carnitine deficiency born to an affected, but previously undiagnosed, mother with MCAD deficiency [Leydiker et al 2011].

The false positive rate for MCAD deficiency most likely varies among screening programs because of differences in acylcarnitine analysis and profiling [Lindner et al 2010]. Programs that screen for MCAD deficiency but not other fatty acid oxidation disorders often limit their analysis to octanoylcarnitine, the predominant marker for MCAD deficiency. However, octanoylcarnitine is not specific for MCAD deficiency and is expected to be elevated in other disorders (i.e., glutaric acidemia type II, and possibly medium-chain 3-keto acyl-CoA thiolase deficiency) and in newborns treated with valproate or fed a diet rich in medium-chain triglycerides [Smith & Matern 2010]. Consideration of disorders included in the differential diagnosis of octanoylcarnitine and participation in the MS/MS Data Project of the Region 4 Collaborative project [McHugh et al 2011] should minimize the false positive rate and eliminate false negative results.

Postmortem testing. MCAD deficiency frequently manifests with sudden and unexpected death [Rinaldo et al 2002]. The following information and testing can help diagnose MCAD deficiency post mortem:

  • A family history of sudden death or Reye syndrome in sibs
  • Evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death
  • Frequently, diffuse fatty infiltration of the liver and potentially other organs on autopsy (if performed)
  • Collection and biochemical testing of tissues and cultured skin fibroblasts [Boles et al 1994]. However, these approaches have been deemed impractical and thus have had limited application.
  • Routine collection of postmortem blood [Chace et al 2001] and bile [Rashed et al 1995] spots on filter paper cards of the type used for newborn screening for subsequent acylcarnitine analysis. Collection of both specimens provides a better chance of detecting affected individuals and independently confirming the diagnosis.

    Most FAO disorders can present with sudden unexpected death, but acylcarnitine analysis in dried blood and/or bile spots allows identification of a diagnosis that can then often be confirmed by molecular genetic testing using the postmortem blood spots.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Fatty acid oxidation fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and periods of higher energy demands.

Classic MCAD deficiency. Individuals with MCAD deficiency appear normal at birth and usually present between ages three and 24 months, although presentation in adulthood is also possible [Duran et al 1986, Raymond et al 1999, Lang et al 2009]. Affected individuals tend to present in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or intercurrent and common infections (e.g., viral gastrointestinal or upper respiratory tract infections), which typically cause loss of appetite and increased energy requirements when fever is present. Such instances of metabolic stress lead to vomiting and lethargy, which may quickly progress to coma and death. The episodes may also begin with or be accompanied by seizures.

Sudden and unexplained death is often the first manifestation of MCAD deficiency [Iafolla et al 1994, Rinaldo et al 1999, Chace et al 2001]. If the diagnosis of MCAD has not been previously established, at least 18% of affected individuals die during their first metabolic crisis [Iafolla et al 1994].

Hepatomegaly is usually present during acute decompensation, which is also characterized by hypoketotic (not necessarily nonketotic) hypoglycemia, increased anion gap, hyperuricemia, elevated liver transaminases, and mild hyperammonemia.

Individuals with classic MCAD deficiency are at risk of losing developmental milestones and acquiring aphasia and attention deficit disorder, which are thought to be secondary to brain injury occurring during the acute metabolic event. Chronic muscle weakness is observed in 18% of individuals who experience several episodes of metabolic decompensation [Iafolla et al 1994].

McCandless et al [2002] reported that all of 41 newborns with MCAD deficiency identified by newborn screening in North Carolina since 1997 were developing normally. None experienced hypoglycemic episodes, but some required precautionary hospitalization during intercurrent illnesses. Although the prognosis is excellent once the diagnosis is established, unexpected death during the first metabolic decompensation is common [Iafolla et al 1994, Rinaldo et al 1999, Chace et al 2001] and may occur as late as adulthood (e.g., during metabolic stress precipitated by surgery) [Raymond et al 1999]. Findings at autopsy include cerebral edema and fatty infiltration of the liver, kidneys, and heart [Boles et al 1998].

In a long-term study of individuals with MCAD deficiency who were diagnosed prior to newborn screening, many tended to complain about fatigue, muscle pain, and reduced exercise tolerance; however, no physical correlate, in particular no cardiac involvement, was identified [Derks et al 2006].

Maternal pregnancy complications such as HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and acute fatty liver of pregnancy (AFLP) may be more frequent (as for other fatty acid β-oxidation disorders) when the fetus has MCAD deficiency [Nelson et al 2000, Rinaldo et al 2001, Yang et al 2002].

"Mild" MCAD deficiency. The expansion of newborn screening programs using MS/MS had led to the identification of individuals with milder abnormalities in their acylcarnitine profiles (see Genotype-Phenotype Correlations). Over a relatively short follow-up period, none of these individuals identified through newborn screening had metabolic crises while being treated. However, one person with a mild biochemical phenotype who was compound heterozygous for the common p.Lys304Glu mutation and a new mutation (p.Gln24Glu) developed hypoglycemia and became comatose during a second metabolic decompensation [Dessein et al 2010]. Therefore, despite having higher residual MCAD enzymatic activity [Zschocke et al 2001], such individuals should be considered at risk of developing clinical manifestations and treatment should be initiated [Rinaldo et al 2002]. To determine disease risk, detailed investigations, including carefully executed fasting challenges as have been conducted for persons with "severe" mutations [Derks et al 2007], should be considered. (See Management: Evaluations Following Initial Diagnosis for more details.)

Genotype-Phenotype Correlations

Inclusion of MCAD deficiency in newborn screening programs has led to the identification of individuals with less pronounced abnormalities in their acylcarnitine profiles who are compound heterozygotes either for the common ACADM mutation (p.Lys304Gly) and another mutation or for two non-p.Lys304Glu mutations [Albers et al 2001, Andresen et al 2001, Zschocke et al 2001, Maier et al 2005, Smith et al 2010]. One of these other mutations, p.Tyr42His, has an allele frequency of approximately 6% in MCAD-deficient newborns [Waddell et al 2006, Nichols et al 2008, Maier et al 2005, Andresen et al 2001] and is associated with some residual MCAD enzymatic activity [Andresen et al 2001].

Because individuals with a “milder” biochemical phenotype can still develop life-threatening symptoms [Dessein et al 2010] and because intrafamilial differences in the phenotypic expression of MCAD deficiency are commonly seen, a consistent genotype-phenotype correlation does not exist. It is reasonable to assume that environmental factors (e.g., diet, stress, intercurrent illnesses) are critical in determining the natural history of this disorder [Andresen et al 1997].


MCAD deficiency was first described in individuals presenting with a Reye-like syndrome and urine organic acid analysis that revealed overexcretion of medium-chain dicarboxylic acids and hexanoylglycine in the absence of significant ketosis [Kølvraa et al 1982]. Accordingly, it is likely that prior to MCAD deficiency having been better delineated, affected individuals were misdiagnosed as having Reye syndrome.


MCAD deficiency is prevalent in individuals of European (especially northern) descent. The overall frequency of the disorder has been estimated to range between 1:4,900 and 1:17,000; variability is related to the ethnic background of the population studied.

The number of newborns detected with MCAD deficiency through newborn screening programs exceeds that expected based on the population frequency of the common 985A>G mutation [Andresen et al 2001, Maier et al 2005, Wilcken et al 2009, Vilarinho et al 2010].

Based on newborn screening programs worldwide, the incidence of MCAD deficiency has been defined in:

Maier et al [2005] found the disorder to be equally common among Germans and Turks.

MCAD deficiency is considered less common in the Hispanic population, a view that may be called into question by the detection of several Hispanic children in the California newborn screening program; only a few affected African Americans and Native Americans have been reported.

The carrier frequency for the ACADM p.Lys304Glu mutation is between 1:40 and 1:100 in northern Europeans, suggestive of a founder effect [Gregersen et al 1993, Tanaka et al 1997].

Differential Diagnosis

MCAD belongs to the acyl-CoA dehydrogenase (ACAD) gene family, which also includes three other dehydrogenases involved in the fatty acid oxidation pathway [Swigonova et al 2009]: short-chain acyl-CoA dehydrogenase (SCAD), long-chain acyl-CoA dehydrogenase (LCAD), and very long-chain acyl-CoA dehydrogenase (VLCAD) [Ikeda et al 1985, Izai et al 1992]. Another gene, ACAD9, encodes a protein that has been reported to possibly play a role in fatty acid oxidation and in stabilization of complex I of the respiratory chain [Haack et al 2010]. Additional dehydrogenases with homology to MCAD are isovaleryl-CoA dehydrogenase (encoded by IVD), 2-methyl branched-chain acyl-CoA dehydrogenase (encoded by ACADSB) [Alfardan et al 2010], and isobutyryl-CoA dehydrogenase (encoded by ACAD8) [Pedersen et al 2006].

  • SCAD deficiency is a highly heterogeneous disorder [Pedersen et al 2008] with phenotypic manifestations possibly modulated by two polymorphisms that are found in 7% to 14% of the general population [Corydon et al 1998, Corydon et al 2001, Nagan et al 2003].
  • Although the presentation of VLCAD deficiency is in some cases similar to that of MCAD deficiency, the majority of individuals with VLCAD present with cardiomyopathy [Mathur et al 1999].
  • The first individual to be diagnosed with LCAD deficiency was recently described. Contrary to manifestations in other ACAD deficiencies and expectations based on LCAD-deficient mice [Kurtz et al 1998], this individual presented with congenital surfactant deficiency and hypothyroidism [Kristen et al 2011].
  • The phenotype of ACAD9 deficiency has not been fully delineated; however, recent reports suggest involvement in the stabilization of the respiratory chain complex I in persons with cardiomyopathy, encephalopathy, and lactic acidosis who have ACAD9 mutations [Haack et al 2010].

All causes of a Reye-like syndrome (i.e., acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) need to be considered, including other disorders of fatty acid β-oxidation, defects in ketogenesis, urea cycle disorders, organic acidurias, respiratory chain defects, and inborn errors of carbohydrate metabolism (e.g., hereditary fructose intolerance).

Although the same biochemical markers elevated in MCAD deficiency are also elevated in glutaric acidemia type 2, the presence of several additional organic acids (glutaric acid, 2-hydroxy glutaric acid, ethylmalonic acid), C4 and C5 carnitine, and glycine esters [Millington et al 1992], and the normal excretion of phenylpropionylglycine [Rinaldo et al 1988] are important discriminators.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image mcad-Image004.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease in an asymptomatic individual diagnosed with MCAD deficiency, the following evaluations are recommended:

  • Plasma acylcarnitine analysis
  • Plasma free and total carnitine measurement
  • Urine acylglycine analysis
  • Urine organic acid analysis

In a symptomatic individual the following additional laboratory studies should be considered:

  • Blood glucose concentration
  • Blood gas analysis
  • Ammonia
  • Lactic acid
  • CBC with differential
  • Electrolytes
  • Liver function tests
  • Blood cultures (in case of fever)

Although development is typically normal for individuals treated prospectively, those who experience metabolic decompensations requiring hospitalization often demonstrate developmental and neurologic disabilities. Neurodevelopmental assessments and intervention should therefore be considered for such individuals [Derks et al 2006].

Treatment of Manifestations

The most important aspect of treating symptomatic patients is reversal of catabolism and sustained anabolism by provision of simple carbohydrates by mouth (for example, glucose tablets, or sweetened, non-diet beverages) or IV if the patient is unable or unlikely to maintain or achieve anabolism through oral intake of food and fluids. IV administration of glucose should then be initiated immediately with a bolus of 2 mL/kg 25% dextrose, followed by 10% dextrose with appropriate electrolytes at a rate of 10-12 mg glucose/kg/minute and to achieve/maintain a blood glucose higher than 5 mmol/L [Saudubray et al 1999].

All affected individuals should have a frequently updated "emergency" letter to be given, if needed, to health care providers who may not be familiar with MCAD deficiency. This letter should include a detailed explanation of the management of acute metabolic decompensation, emphasizing the importance of preventive measures (e.g., intravenous glucose regardless of "normal" laboratory results, overnight in-hospital observation), and the telephone numbers of the individual's metabolic specialist.

Prevention of Primary Manifestations

The mainstay in the treatment of MCAD deficiency is avoidance of fasting. Derks et al [2007] studied the length of time that MCAD-deficient but asymptomatic individuals should be able to fast. Based on their findings, they recommend maximum fasting times of:

  • Up to eight hours in infants between ages six and 12 months
  • Up to ten hours during the second year of life
  • Up to 12 hours after age two years

To avoid excessive fasting:

  • Infants require frequent feedings.
  • Toddlers could receive 2 g/kg of uncooked cornstarch as a source of complex carbohydrates at bedtime to ensure sufficient glucose supply overnight. A relatively low-fat diet (e.g., <30% of total energy from fat) may be beneficial.

Prevention of Secondary Complications

Recent long-term outcome studies revealed that persons treated for MCAD deficiency are prone to excessive weight gain [Derks et al 2006]. Accordingly, follow up should include weight control measures such as regular education about proper nutrition and allowed physical exercise.

Agents/Circumstances to Avoid

Hypoglycemia must be avoided by frequent feedings to avoid catabolism, if necessary by intravenous administration of glucose.

Infant formulas containing medium-chain triglycerides as the primary source of fat are contraindicated in MCAD deficiency.

Evaluation of Relatives at Risk

Sibs and parents should be tested by plasma acylcarnitine and urine acylglycine analysis to allow early diagnosis and treatment of those family members with MCAD deficiency who have previously been asymptomatic [Leydiker et al 2011].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The need for reduction of dietary fat to less than 20% of total calories and the need for L-carnitine supplementation or increase of the L-carnitine dose during metabolic stress are controversial.

  • Several authors recommend oral supplementation with 100 mg/kg/day of carnitine to correct the frequently observed secondary carnitine deficiency and to enhance the elimination of toxic metabolites [Roe & Ding 2001].
  • Two exercise studies of persons with MCAD deficiency before and after L-carnitine supplementation suggested improved exercise tolerance with supplementation of 100 mg/kg/day [Lee et al 2005] and statistically insignificant benefit with supplementation of 50 mg/kg/day [Huidekoper et al 2006].
  • Carnitine-mediated detoxification of medium-chain fatty acids, assessed by urinary excretion of medium-chain acylcarnitines, is quantitatively negligible in MCAD-deficient patients [Rinaldo et al 1993] and carnitine supplementation does not, under controlled circumstances, improve the response to a fasting challenge [Treem et al 1989].
  • Note: Although the cost of long-term supplementation with carnitine could be significant, no untoward effects of L-carnitine have been reported in individuals with MCAD deficiency [Potter et al 2012], in contrast to LCHAD deficiency, in which the formation of long-chain 3-hydroxy acylcarnitine species is believed by some authors to be detrimental [Rocchiccioli et al 1990, Ribes et al 1992].

Gene therapy has been suggested but aside from studies in fibroblast cultures of a patient with MCAD deficiency has not been attempted in vivo [Schowalter et al 2005].

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MCAD deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband

  • The offspring of an individual with MCAD deficiency inherit a disease-causing mutation in ACADM from their affected parent.
  • The risk that the reproductive partner of an individual with MCAD deficiency is heterozygous for an ACADM disease-causing allele may be as high as 1/40. Thus, the risk to the offspring of an affected individual and reproductive partner of northern European origin of having MCAD deficiency is about 1/80.
  • It is appropriate to test the offspring of an individual with MCAD deficiency for the disorder.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the two disease-causing mutations have been identified in an affected family member.

Carriers for MCAD deficiency can be detected by measurement of MCAD enzymatic activity in various tissues.

Biochemical screening tests such as acylcarnitine, organic acid, or acylglycine analyses are not useful in determining carrier status.

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Note: States store leftover dried blood spot samples for variable lengths of time following newborn screening testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing. See for state-by-state newborn screening laboratory contact information.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed [Rinaldo et al 2001].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical testing. Prenatal diagnosis for pregnancies at increased risk is also possible by assay of MCAD enzymatic activity in CVS or amniocyte cultures. Amniocyte cultures can also be used for analysis of fatty acid oxidation as it is done in fibroblast cultures (see Testing, Analysis of fatty acid β-oxidation in cultured fibroblasts).

Prenatal diagnosis, with its inherent risks, offers no advantage to timely postnatal measurement of plasma acylcarnitines and urine acylglycines. Prompt postnatal testing and consultation with a biochemical geneticist are indicated.

Requests for prenatal testing for conditions which (like MCAD deficiency) do not affect intellect and have effective treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • FOD Family Support Group (Fatty Oxidation Disorder)
    PO Box 54
    Okemos MI 48805-0054
    Phone: 517-381-1940
    Fax: 866-290-5206 (toll-free)
  • Organic Acidemia Association
    PO Box 1008
    Pinole CA 94564
    Phone: 510-672-2476
    Fax: 866-539-4060 (toll-free)
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (View All in OMIM)


Normal allelic variants. ACADM is a nuclear gene. It consists of 12 exons that span more than 44 kb and encode a precursor monomer of 421 amino acids.

Pathologic allelic variants. More than 90 mutations have been described to date [HGMD, Smith et al 2010]. Among the 92 mutations listed in the HGMD database are 65 missense and nonsense mutations, nine splicing mutations, 11 small deletions, four small insertions, one small indel mutation, and two large deletions. One mutation located in exon 11, 985A>G, which causes an amino acid change from lysine to glutamate at residue 304 (p.Lys304Glu) of the mature MCAD protein, is present in 70% of alleles in individuals with MCAD deficiency based on newborn screening and clinical testing results in diverse populations [Andresen et al 2001, Zytkovicz et al 2001, Maier et al 2005, Waddell et al 2006, Nichols et al 2008, Smith et al 2010]. The p.Lys304Glu mutation was independently described by four groups [Kelly et al 1990, Matsubara et al 1990, Yokota et al 1990, Gregersen et al 1991] and early estimates of the frequency of p.Lys304Glu, based on retrospective clinical studies, were close to 90% of all alleles investigated [Yokota et al 1992]. With the advent of newborn screening for MCAD deficiency, however, this frequency is continuously declining as additional mutations are identified [Ziadeh et al 1995, Smith et al 2010].

Normal gene product. The mature MCAD protein is a homotetramer encoded by a nuclear gene; it is active within the mitochondria. The leading 25 amino acids of the precursor protein are cleaved off once the MCAD protein has reached the mitochondria. Heat shock protein 60 (Hsp60) then aids in the folding of the monomer (42.5 kd). The assembled, mature homotetramer is flavin dependent, with each subunit containing one flavin adenine dinucleotide (FAD) molecule. Electron transfer flavoprotein (ETF) functions as the enzyme's electron acceptor, which explains why MCAD metabolites are also present in individuals with glutaric acidemia type II.

Abnormal gene product. The known pathologic mutations within ACADM represent primarily missense mutations, followed by deletions, nonsense mutations, and splicing mutations. The common mutation, p.Lys304Glu, is a missense mutation and leads to reduced production of an unstable protein, but does not impair the enzyme's active site.


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Suggested Reading

  1. Morris AAM, Spiekerkoetter U. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. In: Fernandes J, Saudubray J-M, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases – Diagnosis and Treatment. 5 ed. Heidelberg, Germany: Springer-Verlag; 2012:201-14.
  2. Strauss AW, Andresen BS, Bennett MJ. Mitochondrial fatty acid oxidation defects. In: Sarafoglou K, Hoffmann GF, Roth K, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. New York, NY: McGraw-Hill; 2008:17-32.

Chapter Notes

Revision History

  • 19 January 2012 (me) Comprehensive update posted live
  • 3 February 2005 (me) Comprehensive update posted to live Web site
  • 27 January 2003 (me) Comprehensive update posted to live Web site
  • 20 April 2000 (me) Review posted to live Web site
  • 16 December 1999 (dm) Original submission
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