Medium-Chain Acyl-CoA Dehydrogenase Deficiency

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Continuing Education Activity

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common fatty acid ß-oxidation disorders. It is an autosomal recessive disorder that has a good prognosis if management is started early. If not managed correctly, a metabolic crisis may result. This activity reviews the evaluation and treatment of MCAD deficiency and highlights the role of the interprofessional team in the care of patients with this condition.


  • Describe the pathophysiology of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

  • Identify common presenting symptoms of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

  • Outline the management of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

  • Summarize the importance of communication and coordination amongst the interprofessional team to enhance the care of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.


Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD or MCAD deficiency) is one of the most common mitochondrial fatty acid β-oxidation disorders and is typically caused by a mutation in the ACADM gene.[1] The MCAD enzyme converts medium-chain fatty acyl-CoA into short-chain fatty acyl-CoA and acetyl CoA to provide the body with energy via ketones during times of fasting.[2] During these periods of fasting, gluconeogenesis is utilized via medium-chain acyl-CoA dehydrogenase to maintain blood glucose levels via the production of ketone bodies as acetyl-CoA accumulates.

The inability to provide energy to tissue when glycogen stores are depleted secondary to MCADD, particularly in neonates, may present with various symptoms due to hypoketotic hypoglycemia, including jaundice, cardiomyopathy, hepatopathy, altered mental status, seizure, and even death. Newborn screening has improved diagnosis before dangerous sequelae, but one study finds that it has not completely stopped the metabolic crisis or death.[3] Although recognition of this condition and the time to diagnosis have improved, continued close follow-up and education are required for these patients.[4]


Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an autosomal recessive disorder that is primarily caused by a homozygous mutation of 985A→G in the ACADM gene in roughly 80% of clinically symptomatic patients. Other gene mutations result in MCAD deficiency, but nearly 18% of affected patients will carry at least one allele with 985A→G mutation.[5][6][7] Mutation in this gene results in insufficient MCAD enzyme production and subsequent accumulation of medium-chain fatty acids in the blood.


The frequency of medium-chain acyl-CoA dehydrogenase deficiency can vary, with different studies publishing frequencies based on location. In North America and northern Europe, studies have shown an estimated prevalence of 1:5,000 to 1:20,000.[8][9][10] One study showed a prevalence ranging from 1:10,000 to 1:27,000 in the countries around France.[11] Another study found that the carrier frequency in the general population may be high as 1:70.[12] Males and females are equally affected.[13]


Affected patients are unable to synthesize ketone bodies for energy during times of fasting or acute stress; therefore will present in metabolic crisis due to hypoketotic hypoglycemia. Although widespread use of newborn screens has decreased the acute crisis, these patients continue to present to the emergency department.[6] Presenting symptoms can include altered mental status, lethargy, seizures, emesis, and even death in about 20% of patients with an initial crisis. On physical exam, hepatomegaly may be noted. Age of presentation can range from newborns, toddlers, to even adulthood in some patients depending on the phenotype.[14]

History and Physical

Patients usually present in the neonatal period between 3 and 15 months after a period of fasting, acute illness, or a combination of the two. Altered mental status, emesis, dehydration, drowsiness, and poor feeding may all be presenting symptoms. On exam, hepatomegaly may be identified, and neurologic exam may be abnormal if encephalopathy is present. Breastfeeding infants are particularly high risk in the first 72 hours, depending on maternal breastmilk supply. If supply and milk let down has not occurred, then neonates may experience prolonged periods of fasting resulting in an early presentation of metabolic crisis.[15]


Evaluation of MCAD deficiency is typically prompted after positive newborn blood screening showing elevated acylcarnitines.[12] If screened positive, children will be referred for further diagnostic testing, including formal urine organic acid analysis, plasma acylcarnitine profiling, and testing for mutations in the ACADM gene.[8][13] Diagnosis is confirmed via genotype finding homozygous 985A→G mutation or heterozygous with another known mutation and/or abnormal plasma acylcarnitines showing elevated concentrations of C6, C8, and C10:1 acylcarnitines with an increased C8/C10:1 ratio (ration must exceed 5:1).[11] Those with homozygous 985A→G genotype typically have higher C8 levels than heterozygotes.[3] Additionally, urine organic acid analysis may show an elevation in hexanoglycine, proprionoglycine, and suberylglycine.[12][13]

Treatment / Management

Early diagnosis of MCAD deficiency has been shown to reduce nearly half of medical care costs.[16] Additionally, early diagnosis can avoid possible deadly sequelae. Approximately 20% to 25% of patients who are not diagnosed via newborn screening may experience death or disability.[10] Management is centered around reducing times of fasting and ensuring nutrition intake to meet metabolic demands. Younger children are only allowed to fast for shorter periods versus older children who may fast for longer periods. Additionally, during times of stress such as acute illness, patients will likely require even shorter times of fasting with a maximum of 3 hours.[17] Diets should be high in carbohydrates and low in fat, particularly avoiding medium-chain triglycerides. Some patients may benefit from carnitine supplementation in those with carnitine transport deficiency to enhance fatty acid beta-oxidation, although some studies do not support this benefit.[1][18][19][20]

Management of children with MCAD deficiency who require anesthesia can pose additional risks. Patients who require a surgical procedure will need to be fasting and would benefit from overnight admission prior to the procedure to administer glucose-containing maintenance fluids. Providing intravenous fluids with glucose and close perioperative monitoring of blood glucose levels reduces the risk of metabolic crisis typically seen with fasting periods in this population.[21] Care coordination is essential between the anesthesiologist and primary clinician in managing the patient's MCAD deficiency to ensure safety.

Differential Diagnosis

The initial presentation of lethargy, emesis, and encephalopathy in patients with MCAD deficiency may be concerning for other etiologies like Reye syndrome, sudden infant death syndrome, or other metabolic diseases.[22][23] History of presentation helps discern MCAD deficiency from other illnesses. Reye syndrome may have similar symptoms but typically presents in older children with known aspirin ingestion. Additionally, laboratory values in Reye's syndrome will reveal much higher transaminases, and histology will reveal distinct changes.[23]

Other fatty acid oxidation disorders such as short-chain and long-chain fatty acid β-oxidation disorders may have similar presenting symptoms but may also have cardiomyopathy, developmental delays, and muscle involvement. Furthermore, other fatty acid oxidation disorders can be definitively differentiated based on mutation analysis and specific enzyme activity.[1][24] Sudden infant death syndrome may be considered after ruling out the previous diseases discussed.


Prognosis is generally good for patients with MCAD deficiency if diagnosed early in life. Early management via specialty centers has reduced mortality and morbidity to nearly zero.[25] Unfortunately, if intervention is not started early, up to 25% percent of initial presentations may result in death.[15][26][27][28] It is imperative for all newborns to receive newborn screens and appropriate follow-ups for early diagnosis and to reduce the risk of death in this population.


Complications of MCAD deficiency can vary in severity from drowsiness to death. Complications unrelated to cardiac functions include muscle weakness, fatigue, and poor exercise tolerance. Other complications include long-term neurologic sequelae (e.g., learning and behavior issues) caused by encephalopathy. Arrhythmias have has been reported.[10][15][25][26][29]

Deterrence and Patient Education

Although the prognosis of MCAD deficiency is good, the diagnosis requires patients to live a lifestyle different from their peers, which can add increased stress to the patient and family. One study reported that nearly 75% of parents felt a substantial burden due to metabolic disorders and treatments.[30] Parental stressors for the management of MCAD deficiency usually involve two main issues- safe fasting intervals and times of illness. These management strategies and stressors should decrease as their child ages, and over time these individuals can adhere to management recommendations autonomously.[17] Additionally, patients with MCAD deficiency experience higher emergency department visits and inpatient hospitalizations from the age of 6 to 12 months.[13] During this period, families may feel additional stressors given the frequency of hospital visits. Metabolic specialists can provide an emergency regimen for families to have in place before times of illness, which will not only reduce the risk of dangerous sequelae to this vulnerable population but also can help decrease family stress.

Enhancing Healthcare Team Outcomes

MCAD deficiency may be a difficult disease to manage, but with early diagnosis and intervention, this population may avoid life-threatening sequelae during times of illness. Newborn blood screening is highly sensitive and specific for the initial assessment of MCAD deficiency and is an essential screening tool. [Level 3] Further diagnostics using genetic tests (assessing for severe mutations i.e., 985A→G) and biochemical tests (elevation of C8/C10:1) are used to confirm the diagnosis. [Level 3][3] Interprofessional team management between pediatric metabolic specialists, primary care providers, anesthesiologists, surgeons, and other healthcare professionals is essential for patient safety and improved outcomes. Primarily, a metabolic specialist will provide emergency plans for patients during times of illness and fasting to avoid a metabolic crisis. Families should be thoroughly educated about reducing fasting times, especially during times of illness. Emergency plans should be given to emergency medicine clinicians upon presentation to ensure early intervention. Management is centralized around providing a steady glucose supply during times of illness and fasting. Close inpatient management is recommended particularly for younger patients, for times where perioperative fasting is needed, and times of illness to ensure adequate glucose supply. Although mortality may be high on the initial presentation without previous screening or diagnosis, early intervention has decreased mortality to near zero. Furthermore, interprofessional discussion and management are recommended to improve outcomes in this population.[31]



Tsega Temtem


7/10/2023 2:36:16 PM



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Level 2 (mid-level) evidence