Clinical characteristics.

Individuals with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency typically appear normal at birth, and many are diagnosed through newborn screening programs. Symptomatic individuals experience hypoketotic hypoglycemia in response to either prolonged fasting (e.g., weaning the infant from nighttime feedings) or during 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. Untreated severe hypoglycemic episodes can be accompanied by seizures, vomiting, lethargy, coma, and death. Metabolic decompensation during these episodes can result in elevated liver transaminases and hyperammonemia. Individuals with MCAD deficiency who have experienced the effects of uncontrolled metabolic decompensation are also at risk for chronic myopathy. Early identification and avoidance of prolonged fasting can ameliorate these findings. However, children with MCAD deficiency are at risk for obesity after initiation of treatment due to the frequency of feeding.

Diagnosis/testing.

The diagnosis of MCAD deficiency is established in a proband through biochemical testing (prominent accumulation of C8-acylcarnitine (octanoylcarnitine) with lesser elevations of C6-, C10-, and C10:1-acylcarnitines and elevated C8/C2 and C8/C10 ratios) AND/OR by identification of biallelic pathogenic variants in ACADM by molecular genetic testing OR by significantly reduced activity of MCAD activity in blood or cultured skin fibroblasts. Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers.

Management.

Treatment of manifestations: For routine daily treatment, fasting should be avoided and may require frequent feeding (every 2-3 hours) in infancy, overnight feeding, a bedtime snack, or 2 g/kg of uncooked cornstarch to maintain blood glucose levels during sleep. A normal, healthy diet containing no more than 30% of total energy from fat is recommended. All individuals with MCAD deficiency should avoid skipping meals and weight loss diets that recommend fasting. Prolonged or intense exercise should be covered by adequate carbohydrate intake and hydration. Intravenous glucose is recommended for surgical procedures that require several hours of fasting. Weight control measures such as regular education about proper nutrition and recommended physical exercise should be discussed to help avoid obesity. Standard treatment for developmental delay / aphasia, attention-deficit/hyperactivity disorder, and muscle weakness. For acute inpatient treatment, IV administration of glucose should be initiated immediately with 10% dextrose with appropriate electrolytes at a rate of 1.5 times maintenance rate or at 10-12 mg glucose/kg/minute to achieve and maintain a blood glucose level higher than 5 mmol/L, or between 120 and 170 mg/dL. Address electrolyte and pH imbalances with intravenous fluid management and initiate appropriate treatment for what triggered the metabolic stress.

Surveillance: Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician should be involved to ensure proper nutrition in terms of quality and quantity. Affected infants should be seen in team clinic in two to three months, then every six to 12 months if otherwise clinically well; however, the frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers. Routine assessments for growth, acquisition of developmental milestones, neurobehavioral issues, and secondary carnitine deficiency are recommended.

Agents/circumstances to avoid: Hypoglycemia; infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat; popular high-fat/low-carbohydrate diets; alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), which can elicit metabolic decompensation; aspirin.

Pregnancy management: Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency.

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. Because of the high carrier frequency for the ACADM c.985A>G pathogenic variant in individuals of northern European origin, carrier testing should be discussed with reproductive partners of individuals with MCAD deficiency. Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of MCAD deficiency is established in a proband by confirmatory biochemical testing AND/OR by identification of biallelic pathogenic (or likely pathogenic) variants in ACADM by molecular genetic testing (see Table 1) OR by significantly reduced medium-chain acyl-CoA dehydrogenase enzyme activity in blood or cultured skin fibroblasts. Because of its relatively high sensitivity, ACADM molecular genetic testing can obviate the need for enzymatic testing, which is available only in limited academic centers.

Note: (1) Confirmatory postmortem testing is possible in the individual with sudden and unexpected death if MCAD deficiency is suspected. (2) Biochemical and molecular diagnostic methods for MCAD deficiency are sensitive enough to identify asymptomatic affected individuals without using provocative tests. (3) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (4) Identification of biallelic ACADM variants of uncertain significance (or of one known ACADM pathogenic variant and one ACADM variant of uncertain significance) does not establish or rule out the diagnosis.

Clinical Description

Fatty acid beta-oxidation generates cellular energy in all tissues and fuels hepatic ketogenesis, a major source of energy for peripheral tissues once glycogen stores become depleted during prolonged fasting and/or periods of higher energy demands (see Molecular Genetics). The frequent feeding schedule of infants typically precludes the need for alternative energy sources, but as the interval between feeds increases, reliance on fatty acid catabolism commensurately increases. This can manifest in preprandial hypoglycemia symptoms such as lethargy, irritability, jitteriness, seizures, or hypoglycemic crisis. Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a known cause of sudden infant death syndrome (SIDS).

Genotype-Phenotype Correlations

A collaborative retrospective analysis of a cohort of 221 affected individuals identified by NBS in the United States showed that C8 level and genotype were significant predictors of neonatal symptoms. Individuals with neonatal symptoms had significantly higher C8 values [Bentler et al 2016]. While it appears that residual enzyme activity levels better correlate with phenotype [Touw et al 2013], it is reasonable to assume that environmental factors (e.g., diet, stress, or intercurrent illnesses) are critical in determining the natural history of this condition.

Several other genotype-phenotype correlations have been described:

• c.199T>C (p.Tyr67His) (previously known as Tyr42His). This pathogenic variant has an allele frequency of approximately 6% in MCAD-deficient newborns [Andresen et al 2001, Maier et al 2005, Waddell et al 2006, Nichols et al 2008] and is associated with some residual MCAD enzymatic activity [Andresen et al 2001]. People homozygous for this pathogenic variant, however, are probably not at risk to develop disease. Individuals who are heterozygous for the c.199T>C pathogenic variant and another pathogenic variant have lower acylcarnitine levels and are at risk for metabolic crisis [Gramer et al 2015].
• c.600-18G>A (IVS7 as G-A -18). Individuals with the compound heterozygous pathogenic variants c.600-18G>A and c.985A>G have a mild phenotype and may not be detected by NBS due to residual MCAD enzyme activity [Grünert et al 2015].
• c.985A>G (p.Lys329Glu) (previously known as p.Lys304Glu)
  • Individuals homozygous for the common European ACADM c.985A>G (p.Lys329Glu) pathogenic variant have the highest C8 NBS values and are most likely to have neonatal symptoms [Arnold et al 2010, Bentler et al 2016].
  • Those with less pronounced abnormalities in their acylcarnitine profiles are more likely to be compound heterozygotes either for the common pathogenic variant c.985A>G (p.Lys329Glu) and another pathogenic variant, or for two non-c.985A>G pathogenic variants [Maier et al 2005, Smith et al 2010].
  • Individuals homozygous for c.985A>G (p.Lys329Glu) had a mean C8 level of 13.8 µmol/L (range: 9-22 µmol/L), and compound heterozygotes had a mean C8 level of 2.6 µmol/L (range: 1.9-3.2 µmol/L) [Zytkovicz et al 2001, Blois et al 2005, Weiss et al 2023]. In another study, individuals homozygous for c.985A>G had higher NBS C8-carnitine (23.4 ± 19.6 vs 6.6 ± 3.0 μmol/L) and lifetime plasma C8-carnitine levels (6.2 ± 5 vs 3.6 ± 1.9 μmol/L) compared to those with at least one other pathogenic variant (p<0.001 for both calculations) [Anderson et al 2020].

Note: Historically, variant nomenclature designated the first amino acid at p.1 of the mature protein, whereas current nomenclature designates the first amino acid at p.1 of the pro-protein.

Nomenclature

MCAD deficiency was first described in individuals presenting with a Reye-like phenotype 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, Roe et al 1986, Bzduch et al 2001]. Accordingly, it is likely that prior to MCAD deficiency having been delineated, affected individuals were misdiagnosed as having Reye syndrome.

Prevalence

The overall prevalence of MCAD deficiency is 5.3 (range: 4.1-6.7; 99% CI) in 100,000 births across a variety of populations [Feuchtbaum et al 2012] and one in 17,759 in the United States [Therrell et al 2014, Maier 2015]. MCAD deficiency is prevalent in individuals of (especially northern) European ancestry. The carrier frequency for the c.985A>G pathogenic variant in ACADM is between 1:40 and 1:100 in those of northern European ancestry, suggestive of a founder effect [Gregersen et al 1993, Tanaka et al 1997]. A similar prevalence has been observed among Portuguese individuals with Roma ancestry [Rocha et al 2014] and Native Americans of California [Feuchtbaum et al 2012].

The number of newborns detected with MCAD deficiency through NBS programs exceeds that expected based on the population frequency of the common c.985A>G pathogenic variant [Andresen et al 2001, Maier et al 2005, Wilcken et al 2009, Vilarinho et al 2010, Andresen et al 2012, Touw et al 2012].

The ACADM c.449_452delCTGA deletion is more prevalent in Asian (i.e., Taiwanese, Japanese, and Korean) populations [Woo et al 2011, Chien et al 2013, Hara et al 2016, Tajima et al 2016].

Based on NBS programs or pilot studies worldwide, the incidence of MCAD deficiency has been determined as follows:

• Asia
  • Japan. One in 51,000 live births [Shigematsu et al 2002]. There has also been a significant increase in the diagnosis of MCAD deficiency in Japanese individuals, with most having at least one novel pathogenic variant [Hara et al 2016, Tajima et al 2016].
  • Saudi Arabia. One in 18,000 live births [Al-Hassnan et al 2010]
  • Taiwan. One in 263,500 live births [Chien et al 2013]
• Australia. One in 19,000 live births (New South Wales) [Wilcken et al 2009]
• Europe. The prevalence of MCAD deficiency in Europe has ranged from a high of 1:4,900 live births in northern Germany [Sander et al 2001] to a low of 1:24,900 in Austria [Kasper et al 2010] and 1:23,000 in central Italy.
• North America. Prevalence has ranged from 1:23,400 live births in Canada [Prasad et al 2012] to a range of 1:13,000-19,000 in various states aross the United States [Chace et al 2002, Frazier et al 2006, Hsu et al 2008, Nichols et al 2008, Anderson et al 2012, Feuchtbaum et al 2012, Therrell et al 2014, Maier 2015].

Historically, MCAD deficiency was considered less common in the Hispanic, African American, and Native American populations in the US. More recent analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans. Prevalences are similar among newborns of Hispanic, Black, and Middle Eastern origin (1:23,000 live births) [Feuchtbaum et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MCAD deficiency, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for MCAD deficiency. However, routine dietary therapy (see Table 4) can ameliorate and/or prevent symptoms of this condition.

An acute illness places the infant with MCAD deficiency at high risk for metabolic crisis. Metabolic crisis should be considered a medical emergency and implementation of treatment is essential (see Table 6). Consultation with a biochemical geneticist should be obtained as soon as possible.

Transitional care from pediatric to adult-centered multidisciplinary care settings. As a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for MCAD deficiency due to the absence of multidisciplinary outpatient departments.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with MCAD deficiency together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.

Prevention of Primary Manifestations

Avoidance of fasting remains the cornerstone of MCAD deficiency treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission. An emergency management protocol should be in place and parents or caregivers should be given an emergency letter.

A clinical geneticist or clinical biochemical geneticist or similarly qualified metabolic specialist should be consulted immediately during concurrent illness, especially when it involves fever and/or poor caloric intake.

Prevention of Secondary Complications

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also Tables 5 and 6).

Individuals with MCAD deficiency are at risk for a secondary free carnitine deficiency, as accumulated acylcarnitine species cause depletion of carnitine stores by renal excretion. Accumulated acylcarnitine species are also thought to inhibit organic cation/carnitine transporter 2 (OCTN2), which lowers the renal excretion threshold for free carnitine and further depletes carnitine stores in the body [Jager et al 2022]. However, controversy exists whether free carnitine level should be monitored routinely and if L-carnitine supplementation is necessary or clinically beneficial.

Surveillance

Infants should establish care with a biochemical genetics clinic including a metabolic dietitian as soon as possible following a positive newborn screen. A metabolic dietician (see gmdi.org) should be involved to ensure proper nutrition in terms of quality and quantity. After the baseline visit and confirmatory testing, affected infants should be seen in team clinic in two to three months, then every six to 12 months if otherwise clinically well. Affected individuals can be seen more frequently by a metabolic dietitian or in clinic as needed to ensure that families understand and are comfortable with treatment while the infant is otherwise well.

The frequency of routine follow-up visits is individualized based on comfort level of the affected persons, their families, and health care providers.

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 8 are recommended to monitor existing manifestations, the individual's response to care, and the emergence of new manifestations.

Agents/Circumstances to Avoid

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

Infant formulas, coconut oil, and other manufactured foods containing medium-chain triglycerides as the primary source of fat are not recommended in MCAD deficiency; however, ingesting small amounts is not contraindicated.

Popular high-fat/low-carbohydrate diets are not appropriate for individuals with MCAD deficiency.

Alcohol consumption, in particular acute alcohol intoxication (e.g., binge drinking), often elicits metabolic decompensation in individuals with MCAD deficiency [Lang 2009].

Aspirin has been demonstrated to exacerbate MCAD deficiency by increasing mitochondrial fatty acid oxidation and long-chain fatty acid flux and inhibiting peroxisomal fatty acid oxidation, which normally serves as a lipitoxic buffer [Uppala et al 2017].

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs and offspring of a proband in order to identify as early as possible those who would benefit from treatment and preventive measures.

• If the ACADM pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs and offspring of a proband.
• If the ACADM pathogenic variants in the family are not known, plasma acylcarnitine and urine acylglycine analysis can be used to clarify the disease status of at-risk sibs and offspring of a proband.

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

Pregnancy Management

Pregnant women who have MCAD deficiency must avoid catabolism. This is supported by several case reports describing carnitine deficiency, acute liver failure, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnant women with MCAD deficiency [Nelson et al 2000, Santos et al 2007, Leydiker et al 2011].

Therapies Under Investigation

A Phase II dose-escalating clinical trial examining the use of glycerol phenylbutyrate (Ravicti^®) in the prevention of hypoglycemia in affected individuals age ≥16 years is currently ongoing (NCT06067802).

A previous Phase I clinical trial for the use of glycerol phenylbutyrate at 2, 4, and 6 g/m²/day in four adults with MCAD deficiency who had at least one copy of the common ACADM c.985A>G (p.Lys329Glu) pathogenic variant was completed in 2017 (NCT01881984). The primary outcome was changes in the assessment of metabolic stress pre- and post-dosing with Ravicti^®. There were no serious adverse events. Other adverse events included gastrointestinal disorders (e.g., dry mouth, nausea, vomiting), elevated phenylbutyrate level, neck pain, decreased reflexes, and thromboembolic event. Previous molecular modeling has suggested that the MCAD enzyme may be able to utilize phenylbutyryl-coenzyme A as a substrate [Kormanik et al 2012].

A Phase II, open-label, fixed-dose study evaluating the use of sodium phenylbutyrate (ACER-001) in the treatment of adult and pediatric patients with MCAD deficiency due to the common ACADM c.985 A>G (p.Lys329Glu) pathogenic variant is ongoing as of June 2024 (NCT06069375).

A Phase II, escalating-dose, open-label study of triheptanoin to prevent hypoglycemia in individuals with MCAD deficiency is ongoing as of June 2024 (NCT06067802).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ACADM pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an ACADM pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ACADM pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Given that a clear genotype-phenotype correlation does not exist for MCAD deficiency and that individuals with biallelic ACADM pathogenic variants may remain asymptomatic until late adulthood, apparently unaffected sibs should be tested for MCAD deficiency (see Management, Evaluation of Relatives at Risk).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has MCAD deficiency or is a carrier (see Clinical Characteristics, Prevalence and Family planning), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ACADM.
• Given the high carrier frequency in the general population, it is appropriate to test the offspring of an individual with MCAD deficiency for the disorder (see Management, Evaluation of Relatives at Risk).

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

Carrier Detection

Molecular genetic testing to determine genetic status is possible if both ACADM pathogenic variants have been identified in an affected family member.

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

Related Genetic Counseling Issues

See Management, 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 and discussion of the availability of prenatal/preimplantation genetic 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.
• The carrier frequency for the ACADM c.985A>G pathogenic variant is between 1:40 and 1:100 in those of northern European ancestry. Analysis of data from California demonstrated that MCAD deficiency may be as prevalent in Native Americans (1:7,500 live births) as in northern Europeans (see Clinical Characteristics, Prevalence). Founder variants have been identified in the Mennonite and Amish populations (see Table 9).
• The ACMG includes MCAD deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [Gregg et al 2021]. Of note, because of the inherent detection limitations of ancestry-based targeted variant testing, sequence analysis (rather than targeted variant analysis) is recommended in the National Society of Genetic Counselors practice guidelines for expanded carrier screening [Sagaser et al 2023].

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Note: States store leftover dried blood spot samples for variable lengths of time following newborn screening (NBS) testing. These samples may be retrievable with parent/patient consent for retrospective biochemical or molecular genetic testing.

Prenatal Testing and Preimplantation Genetic Testing

Once both ACADM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for MCAD deficiency are possible.

Prompt postnatal testing by NBS, plasma acylcarnitines, and urine acylglycines and consultation with a biochemical geneticist are indicated.

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is a disorder of mitochondrial fatty acid beta-oxidation. Medium- and short-chain fatty acids passively diffuse across the mitochondrial membrane independent of carnitine transport and are activated to coenzyme A (CoA) esters in the mitochondrial matrix. Fatty acid beta-oxidation consists of four sequential reactions catalyzed by two sets of chain length-specific enzymes. Medium- and short-chain enzymes are located in the mitochondrial matrix. MCAD is responsible for the initial dehydrogenation of acyl-CoAs with a chain length between four and 12 carbon atoms. Each turn of the beta-oxidation spiral pathway shortens the acyl-CoA chain by two carbons and produces a molecule each of acetyl-CoA, FADH⁺, and NADH₂.

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.

Individuals with MCAD deficiency have reduced mitochondrial MCAD enzyme functioning and cannot convert medium-chain fatty acids (those with 6-10 carbons) into acetyl-CoA for ATP synthesis, ketogenesis, and Krebs (i.e., tricarboxylic acid) cycle use. MCAD deficiency impairs the energy supply to peripheral tissues through reduction of oxidative phosphorylation substrates and ketogenesis, thus increasing glucose dependency and utilization. This results in hypoketotic hypoglycemia, metabolic acidosis, liver disease, and lethargy, which progress to coma and death when glycogen stores are depleted. Metabolites detectable in body fluids (blood, urine, bile) include medium-chain fatty acids, corresponding fatty acylglycine and acylcarnitine esters, and dicarboxylic acids. Accumulation of these metabolites may cause oxidative damage [Derks et al 2014]. When well, individuals with MCAD deficiency are able to compensate for decreased energy production by using glycogen stores for free fatty acids. However, during times of illness and fasting, hepatic glycogen stores are rapidly depleted and affected individuals with MCAD deficiency are unable to utilize fatty acids for energy; therefore, they can rapidly progress to lethal hypoglycemia.

Mitochondrial complex I-III dysfunction in liver and skeletal muscles has also been postulated as a pathomechanism of disease in murine models of MCAD deficiency [Amaral & Wajner 2020].

Mechanism of disease causation. Loss of function

Author Notes

Dr Jerry Vockley (ude.cmpu@gyelkcov) is actively involved in clinical research regarding individuals with MCAD deficiency and other fatty acid oxidation disorders. He would be happy to communicate with persons who have any questions regarding diagnosis of MCAD deficiency or other considerations.

Author History

Irene J Chang, MD (2019-present)
Christina Lam, MD (2024-present)
Dietrich Matern, MD, PhD; Mayo Clinic College of Medicine (1999-2019)
J Lawrence Merritt 2nd, MD; University of Washington (2019-2024)
Piero Rinaldo, MD, PhD; Mayo Clinic College of Medicine (1999-2019)
Jerry Vockley, MD, PhD (2024-present)

Revision History

• 26 September 2024 (ma) Comprehensive update posted live
• 27 June 2019 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 19 January 2012 (me) Comprehensive update posted live
• 3 February 2005 (me) Comprehensive update posted live
• 27 January 2003 (me) Comprehensive update posted live
• 20 April 2000 (me) Review posted live
• 16 December 1999 (dm) Original submission

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