MCADD

Description

Other Names

Medium-chain acyl-CoA dehydrogenase deficiency; medium-chain acyl-coenzyme A dehydrogenase deficiency; carnitine deficiency secondary to medium-chain acyl-CoA dehydrogenase deficiency; MCAD deficiency; ACADM deficiency; MCADH deficiency

Diagnosis Coding

ICD-10

E71.311, medium-chain acyl-CoA dehydrogenase deficiency

ICD-10 for Medium-Chain Acyl-CoA Dehydrogenase Deficiency provides further coding details.

Description

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a condition that involves a defect in the catabolism of medium-chain fatty acids. It is the most prevalent inherited fatty acid oxidation disorder. [Therrell: 2014] During times of fasting, the body uses fat as a source of energy. Fats are catabolized through the beta-oxidation process, which involves several enzymes that break down long-chain fats to medium-chain fats, medium-chain fats to short-chain fats, and short-chain fats to ketone bodies and acetyl-CoA. The former are used directly for energy, and the latter enter the Kreb cycle to generate ATP and reducing equivalents. Medium-chain fatty acids are broken down through a cycle using the enzyme medium chain acyl-CoA dehydrogenase. People with an absent or decreased level of enzyme activity have MCADD.

Individuals with MCADD are usually diagnosed through newborn screening or after showing symptoms, which can occur at any age. Symptoms are variable, but may include lethargy, clamminess, irritability, fever, diarrhea, and vomiting. Acute decompensation is thought to be more common during rapid growth, acute illness, fasting, or other times of high metabolic requirements. Management revolves around fasting avoidance, fat restriction, and prompt treatment of acute episodes with intravenous (IV) glucose. [Feillet: 2012] [Potter: 2012]

Prevalence

Prevalence has been estimated at 1:17,759 live births; it is most common in northern Europeans and US Caucasians. [Therrell: 2014]

Genetics

MCADD is associated with mutations in the ACADM gene and is inherited in an autosomal recessive fashion. More than 50% of affected individuals are homozygous for the common c.985A>G (K304E) mutation. [Carpenter: 2001] [Zytkovicz: 2001] [Maier: 2005] The allele frequency for this mutation, considered to be a “severe” mutation, is about 71%. Severity of a mutation is defined by its association with an adverse clinical phenotype and more pronounced elevations of biochemical markers. [Waddell: 2006] The carrier frequency for the K304E mutation is between 1:40 and 1:100. [Tanaka: 1997] More pronounced elevations of biochemical markers are seen with homozygosity for this mutation. Rarer mutations tend to have a less severe biochemical phenotype and compound heterozygosity is the rule. [Andresen: 1997] [Maier: 2005] [Tajima: 2005] This interpretation has recently been challenged as several variants in trans with the c.985A>G have been described with biochemical phenotypes consistent with severe MCADD. [Smith: 2010] Severity is difficult to ascertain as individuals homozygous for the C.985A>G mutation may be asymptomatic. Those with rarer mutations should probably be considered at risk for clinical symptoms.

Parents of a child with MCADD are counseled that they have a 25% chance of having an affected baby, a 50% chance of having a baby who is a carrier, and a 25% chance of having a baby who is neither affected nor a carrier. Unaffected siblings have a 67% chance of being carriers for the disorder. All of the children of an affected individual will be, at the least, carriers. The probability of having an affected child depends on the carrier status of the spouse.

Prognosis

Prognosis is excellent when treatment for MCADD is initiated prior to the first decompensation, fasting is avoided, and intercurrent illness or metabolic crisis is managed appropriately. Prior to identification by expanded newborn screening, up to 29% of undiagnosed patients died during the first decompensation. [Lang: 2009] Those who survive an acute episode of decompensation may develop mild to severe sequelae.

Roles Of The Medical Home

If notified of a positive newborn test result for MCADD, the medical home should collaborate with a metabolic geneticist who will help verify the test result and follow through with appropriate care and education for the patient and the family. For the child with MCADD, it is important that the medical home provide prompt evaluations during times of illness or increased metabolic stress. There should be a lower threshold for evaluation and less reliance on telephone medicine for these patients. Special attention should be given to clinical symptoms of decreased oral intake, vomiting, diarrhea, fever, and level of alertness. [Walter: 2009] Routine developmental screening and close monitoring for sequelae following any crises are important. Home glucose monitors should not be encouraged as hypoglycemia is generally a late finding and normal glucose levels may instill a false sense of security. [Leonard: 2009]

Practice Guidelines

No published guidelines exist for the diagnosis or management of MCADD.

Helpful Articles

PubMed search for articles about medium-chain acyl-CoA dehydrogenase deficiency (MCADD), last 5 years.

Gartner V, McGuire PJ, Lee PR.
Child Neurology: medium-chain acyl-coenzyme A dehydrogenase deficiency.
Neurology. 2015;85(4):e37-40. PubMed abstract / Full Text

Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, Burgard P, Lindner M.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening.
JIMD Rep. 2015;23:101-12. PubMed abstract / Full Text

Rice GM, Steiner RD.
Inborn Errors of Metabolism (Metabolic Disorders).
Pediatr Rev. 2016;37(1):3-15; quiz 16-7, 47. PubMed abstract

Schatz UA, Ensenauer R.
The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population.
J Inherit Metab Dis. 2010. PubMed abstract

Feillet F, Ogier H, Cheillan D, Aquaviva C, Labarthe F, Baruteau J, Chabrol B, de Lonlay P, Valayanopoulos V, Garnotel R, Dobbelaere D, Briand G, Jeannesson E, Vassault A, Vianey-Saban C.
[Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management].
Arch Pediatr. 2012;19(2):184-93. PubMed abstract

Clinical Assessment

Screening

For The Condition

MCADD is included in the expanded newborn screening panel of all US states.

Of Family Members

If a child is identified as having MCADD, then it is assumed that both parents are carriers; however, only some recommend testing for parents because "asymptomatic" parents who are homozygous for ACADM gene mutations have been described. Testing of asymptomatic siblings, regardless of age, is recommended. [Leonard: 2009] [Duran: 1986] [Andresen: 1997] [Bodman: 2001] Siblings and parents can be screened either by acylcarnitine profile or by mutation analyses looking for the mutations identified in the presenting child.

Prenatal diagnosis by either molecular genetic or biochemical testing is possible; however, this must be done by either amniocentesis or chorionic villus sampling (CVS). It is felt that there is no advantage to prenatal testing if prompt postnatal testing by measurement of plasma acylcarnitines and urine acylglycines is obtained in at-risk pregnancies. [Onunaku: 2005]

For Complications

Routine developmental and educational screenings, and close monitoring for sequelae following any crises, are important. The Developmental Screening section of the Portal lists screening tools and provides surveillance tips.

Presentations

Individuals with MCADD can present at any age, although acute decompensation is thought to be more common between 3 to 15 months of age when rapid growth and high energy requirements occur. Frequency of decompensation decreases after 4 years of age, although adolescent and adult presentation might be more common than previously thought. [Lang: 2009] [Schatz: 2010]

There is no "typical" presentation. Affected individuals may be asymptomatic throughout their lifetime, may have intermittent symptoms of sleepiness or irritability after periods of fasting, or may have acute symptoms of irritability, somnolence, nausea, and/or vomiting that can quickly progress to coma after periods of fasting or during times of catabolic stress, such as intercurrent illness. Decreased level of consciousness and hepatomegaly may be the presenting features, accompanied by hypoketotic hypoglycemia. Seizures may be present. Common morbidities of MCADD include obesity, fatigue, muscle pain, and reduced exercise tolerance.

Diagnostic Criteria

The essential features of diagnosis are:
  • Positive findings on expanded newborn screening
  • Nonketotic hypoglycemia
  • Elevations of C8, C6, C10, C10:1 acylcarnitines
  • Elevations of urinary dicarboxylic acids, hexanoylglycine, suberylglycine, and cis-4-decenoic acid
  • DNA testing identifying the common A985G mutation and/or other pathogenic mutations
If clinical and biochemical findings are consistent with the diagnosis and no mutation is identified, then sequencing of the entire coding sequence or fatty acid oxidation studies in fibroblasts may be necessary to confirm the diagnosis.

Clinical Classification

MCADD is typically classified as classic or mild; regardless of classification, treatment is essentially the same.

Children with classic MCADD:
  • If undiagnosed, have up to 25% mortality with the first metabolic crisis
  • Have hepatomegaly accompanied by hypoketotic hypoglycemia, hyperuricemia, elevated LFTs, mild hyperammonemia, elevated anion gap
  • May have developmental regression, aphasia, ADHD, chronic muscle weakness
  • May have family members without symptoms or with varying degrees of the disorder (suggesting environmental factors may also play a role in the natural history of the disorder)
  • Are most commonly homozygous for the K304E (985A>G) mutation
Children with mild MCAD deficiency:
  • Have milder abnormalities on acylcarnitine profile
  • Should be considered at risk for developing clinical symptoms
  • Are either compound heterozygotes for K304E and another mutation, or homozygous for other mutations [Albers: 2001] [Zschocke: 2001]

Differential Diagnosis

Other fatty acid oxidation disorders - Important clinical features that might help differentiate MCADD from the other fatty acid oxidation disorders (e.g., very long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxylacyl-CoA dehydrogenase deficiency, carnitine palmitoyl transferase I/II deficiencies, carnitine transporter defect, and carnitine translocase deficiency) include absence of cardiomyopathy and/or rhabdomyolysis, seen in several but not all of the disorders, and different metabolites in acylcarnitine and urine organic acid profiles.

Ketogenesis defects - The ketogenesis defects often present within the first few days of life. The pattern of presentation in later childhood and some presenting symptoms, such as vomiting, decreased sensorium, and hepatomegaly, may be very similar to MCADD. Although hypoketotic hypoglycemia and sometimes hyperammonemia are biochemical features, severe ketoacidosis is the rule.

Organic acidurias - The majority of organic acidurias present with hyperketotic hypoglycemia rather than hypoketotic hypoglycemia.
  • An exception to this is 3-hydroxy-3-methylglutarica aciduria, a deficiency of 3-hydroxy-3methylglutaryl-CoA-lyase (HMG-CoA lyase deficiency). This enzyme is a key component in leucine metabolism and ketogenesis, and episodes may be triggered by fasting or illness. Acylcarnitine profiles and urine organic acid profiles differ from MCADD in that C5OH and C6DC-acylcarnitines are elevated in the plasma while 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids are elevated in the urine.
  • Malonic aciduria, a deficiency of malonyl-CoA decarboxylase activity can also be confused with fatty acid oxidation disorders because of its role as an important regulator of cytoplasmic malonyl-CoA levels, mitochondrial fatty acid uptake, and fatty acid oxidation. In this condition, however, malonic and methylmalonic acid are identified on urine organic acid profile and dicarboxylic aciduria ketonuria, rather than hypoketosis, is seen during periods of catabolic stress.
Urea cycle disorders - Urea cycle disorders may present during the neonatal period, during late infancy, or at puberty. The most acute presentation is in the neonatal period when infants with normal birth weight and health develop poor feeding, vomiting, lethargy, irritability, and tachypnea; health deteriorates rapidly. A transient metabolic alkalosis may be present. Plasma ammonia levels are generally greater than 150 umol/L at the time of presentation. Urinary orotic acid and abnormalities on plasma amino acid profiles are present in a number of the urea cycle disorders.

Respiratory chain defects - Respiratory chain defects are variable in their presentation. Biochemically affected individuals have lactic acidosis and ketonemia (often paradoxically, there are increased ketones after eating). Diagnosis is difficult and enzyme assay in skin or muscle is often necessary.

Carbohydrate metabolism defects - Carbohydrate metabolism defects may present with hypoglycemia, significant lactic acidosis, +/- ketosis, and hepatomegaly. Acylcarnitine profile and urine organic acid profile will be helpful in differentiating these disorders from MCADD.

Reye-like syndrome (acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) - Reye-like syndrome is generally a diagnosis of exclusion. Signs and symptoms that would suggest this diagnosis are listlessness, decreased energy level, drowsiness, irritability, aggressive behavior, disorientation or confusion, delirium, or seizures that occur several days after the onset of a viral illness (varicella, influenza). Patients are usually afebrile. Reye-like syndrome does not recur, whereas symptoms from MCADD can. The Portal's page on Reye Syndrome contains further details.

Comorbid Conditions

Those who survive an acute episode of decompensation may develop mild to severe sequelae such as developmental and behavioral problems, attention deficit disorder, cerebral palsy, chronic muscle weakness, failure to thrive, hemiplegia, and speech delays. [Derks: 2006]

Pearls & Alerts

Acute attacks can progress rapidly

If untreated, acute attacks can progress to coma within 1-2 hours after onset of symptoms (vomiting, nausea, lethargy). If an attack is undiagnosed, up to 25% of individuals die during their first attack. [Stanley: 2006]

Physical exam is often normal

In most children with MCADD, chronic cardiac and skeletal muscle involvement is not observed despite possibly devastating consequences.

Atypical ketones are found in some individuals

Although nonketotic hypoglycemia is a hallmark presentation, some affected individuals can generate some ketones.

Early evaluation for illness

Children with MCAADD who are ill require early evaluation and intervention.

History & Examination

Unless acutely ill, affected individuals generally have normal physical examinations without features that would lead a provider to consider the diagnosis.

Family History

In a clinical review of 94 families with MCADD, 20% had a positive family history of one or more unexplained childhood deaths. [Ding: 1991] Ask about a history of early childhood death and fasting intolerance.

Pregnancy Or Perinatal History

Maternal pregnancy complications such as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and acute fatty liver of pregnancy (AFLP) may be more frequent. [Nelson: 2000] [Browning: 2006]

Current & Past Medical History

Ask about interim health problems. Although medical history may be uninformative, undiagnosed children and adolescents may have had recurrent episodes of nausea, vomiting, or listlessness after long periods of fasting. Ensure that the immunization schedule is current.

Developmental & Educational Progress

Ask about developmental milestones and school performance. Developmental and educational progress should be monitored closely.

Maturational Progress

Although growth deficiency and pubertal delay are not generally components of this disorder, failure to thrive has been reported in some who have survived acute metabolic decompensations. [Iafolla: 1994] (Obesity may be more of a problem than failure to thrive.)

Social & Family Functioning

Discuss compliance with dietary restrictions and medication use; a hurdle may be costs.

Physical Exam

General

Vomiting, decreased level of consciousness, somnolence, and hepatomegaly may be noted during acute episodes.

Growth Parameters

Children with MCADD should follow a normal growth curve pattern.

Testing

Laboratory Testing

If a child is ill, obtain a basic metabolic panel, including a glucose level and liver function tests. At tertiary care facilities, acylcarnitine profiles and urine organic acid/acylglycine profiles are often obtained during acute episodes. Upon presentation, glucose levels may be low and ketone levels in the urine may be moderate, low, or nonexistent. [Roe: 2001] Urine organic acid profile, urine acylglycines, basic metabolic panel, plasma acylcarnitine profile, total and free carnitine levels, plasma ammonia levels, and plasma lactic acid levels should be measured. Recent studies have suggested that initial levels of C8, the C8/C10 ratio, and urinary hexanoylglycines may be predictive of severity of disease. [Smith: 2010]

With expanded newborn screening, the diagnosis is suspected when elevations of C8, C6, and C10:1 is seen on tandem mass spectrometry. Confirmatory testing includes elevations of C8 and C10 acylcarnitines, elevated urine dicarboxylic acids, urine hexanoylglycine and suberylglycine, and urine cis-4-decenoic acid.

Genetic Testing

DNA sequence analysis for the common A985G mutation should be performed. Full gene sequencing should be completed if the common mutation is not identified and the diagnosis is suspected on clinical grounds. This testing would typically be done by the metabolic geneticist.

Other Testing

Analysis of fatty acid beta-oxidation in cultured fibroblasts or MCAD enzyme activity in leukocytes, fibroblasts, liver, heart, or skeletal muscle can be used to confirm a diagnosis that remains in question. [Roe: 1999] [Hale: 1990] This testing would usually be ordered by a metabolic geneticist. Fatty acid levels in the blood are sometimes monitored by the metabolic geneticist and nutritionist to guide dietary management.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Refer to a metabolic geneticist who, along with a metabolic nutritionist, will educate the family about the disorder and its treatment. If the diagnosis has not been made but is suspected, refer for testing. Periodic visits are important to support families, monitor for problems, and provide needed education.

Pediatric Genetic Counseling (see Services below for relevant providers)

Refer for assistance with genetic testing, interpretation of results, and help discussing inheritance patterns, recurrence risks, and reproductive options for the individual with MCADD and their family.

Pediatric Neurology (see Services below for relevant providers)

Refer if indicated by clinical presentation, especially if seizures are part of the initial presentation or persistent.

Developmental Pediatrics (see Services below for relevant providers)

Referral should be made if there is concern about sequelae after an acute presentation or concern about specific developmental deficits.

Treatment & Management

How should common problems be managed differently in children with MCADD?

Growth Or Weight Gain

Children with MCADD should follow a normal growth curve pattern. Proper daily nutrition and healthy exercise should be encouraged. Appropriate guidance can be given to avoid underfeeding and over-restricting dietary fat intake. At each clinic visit, the patient’s diet records and eating habits should be reviewed.

Viral Infections

There is no predilection to specific viral or bacterial illnesses in MCADD; however, these illnesses can trigger emesis, lethargy, and hypoketotic hypoglycemia that can progress to coma and death if left unmanaged. A precipitous clinical deterioration in an otherwise healthy individual should raise the suspicion of MCADD or another fatty acid B-oxidation disorder if not already diagnosed.

Other

If the patient is well and eating normally, glucose supplementation is usually not necessary. Some advocate using high-carbohydrate supplements, such as cornstarch or polycose, as a glucose source in children before bedtime; a hearty bedtime snack also can suffice.

Pearls & Alerts

Infant formulas often use MCT oil and medium-chain triglycerides

Avoid MCT oil and medium-chain triglycerides. Because many infant formulas are supplemented with MCT oil, consultation with a metabolic nutritionist is vital.

Administer IV fluids

To avoid complications of fasting, children should be admitted to the hospital the night before planned surgeries for administration of appropriate IV fluids. If the patient is older and is not admitted for IV fluids prior to the procedure, then intraoperative IV fluids containing D10 should be given. Admission for provision of IV fluids containing D10 should be considered for pregnant teens with MCADD during labor and delivery.

Avoid alcohol consumption

Adolescents with MCADD should be counseled about the possible risks of excessive consumption of alcohol, which may include encephalopathy, rhabdomyolysis, and cardiac failure. [Lang: 2009]

Emergency treatment letter needed

All families who have a child with MCADD should have an emergency treatment letter that can be presented at the emergency room in case of illness. A medical alert bracelet or necklace also can be worn to let providers know that the the child has MCADD, but it is not a substitution for the emergency letter. See Sample Letter for Emergency Care (Medical Home Portal) (Word Document 14 KB).

Home glucose monitoring is unreliable

Hypoglycemia occurs after the onset of clinical symptoms and is an unreliable marker for early decompensation or encephalopathy; therefore, the use of home glucose monitoring is not encouraged. [Leonard: 2009]

Fasting at any age can lead to acute attacks

Although fasting tolerance improves with age, prolonged fasting in an affected individual can lead to coma and death at any age. Patients should be counseled to remain hydrated and eat carbohydrate-containing snacks during strenuous exercise.

Systems

Endocrine/Metabolism

Management of MCADD consists of avoiding fasting; maintaining a diet with less than 30% of the calories coming from fats; and avoiding medium-chain triglycerides, which are present in many infant formulas. The child with MCADD and their family will be educated about diet during their consultation with a metabolic geneticist.

General fasting guidelines are:
  • Infants should be fed frequently; fasting should not exceed 3 to 4 hours.
  • Between 6 months and 1 year of age, fasting should not exceed 8 hours.
  • Between 1 to 2 years of age, fasting should not exceed 10 hours and for individuals older than 2 years, fasting should not exceed 12 hours.
The addition of 1 to 3 tablespoons of food grade cornstarch mixed in liquid at bedtime has been described as helping to decrease the frequency of morning hypoglycemia in some infants. [California: 2005] With prolonged fasting, lipolysis and hepatic fatty acid oxidation become activated. Plasma levels of free fatty acids rise, but ketones remain inappropriately low. Patients then become hypoglycemic with severe symptoms of lethargy, nausea, and vomiting. Hepatomegaly is sometimes noted. Without rapid intervention with IV glucose, patients can progress to coma within 1-2 hours. Seizures may occur; without appropriate treatment sudden death from acute cardiorespiratory arrest may follow.

Special attention should be given to clinical symptoms of decreased oral intake, vomiting, diarrhea, fever, and level of alertness. Laboratory evaluations may be within reference ranges, but if a patient is unable to tolerate oral sugar-containing fluids, then IV fluid therapy should be given promptly, even with normal labs.

Treatment of ill children with MCADD involves:
  • IV fluid therapy, preferably with D10 1/4NS at 1.5-2 x maintenance (10 mg/kg/min), should be given to maintain plasma glucose concentrations above 100 mg/dl.
  • If D10 is not immediately available, D5 should be infused at a high rate until D10 becomes available.
  • If a patient becomes ill, prompt administration of IV glucose is mandatory. Delay in treatment may lead to sudden death or permanent neurologic sequelae. Under no circumstances should administration of IV glucose be delayed.
An emergency letter should be supplied to the family explaining this treatment. See Sample Letter for Emergency Care (Medical Home Portal) (Word Document 14 KB).

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Consult for management of diet and if child becomes ill.

Nutrition, Metabolic (see Services below for relevant providers)

The nutritionist will play a critical role in formulating a low-fat diet that still has the necessary fats, carbohydrates, proteins, vitamins, minerals, and cofactors to allow for appropriate growth and development.

Pharmacy & Medications

The use of carnitine is controversial, but indicated when there is a secondary carnitine deficiency. [Lee: 2005] Supplementation with carnitine should be initiated under the guidance of the metabolic specialist, if deemed necessary. It had been recommended that the dose of L-carnitine be 50-100 mg/kg.

L-carnitine is synthesized endogenously, but in patients with MCADD, levels may become depleted as it remains conjugated to accumulated medium chain fatty acids and subsequently excreted as acylcarnitine. There is some evidence that carnitine plus riboflavin enhances superoxide dismutase activity and decrease oxidative damage. [Skagen: 2016] [Derks: 2014] Some studies have shown that carnitine may improve exercise tolerance in affected adolescents and adults. Recent concerns about effects of exogenous carnitine on gut flora and cardiac health have led to re-evaluation of its effectiveness.

To prevent secondary carnitine deficiency, plasma-free carnitine concentration should be monitored and supplementation should be adjusted accordingly. A goal of 25-35 micromolar plasma free carnitine is typically recommended.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Refer if supplementation with carnitine is being considered.

Learning/Education/Schools

Individuals with MCADD do not have cognitive impairment directly related to the deficiency. Unless indicated for another reason, no individualized educational programs are recommended, and other than potentially needing a snack during school or extracurricular activities to prevent hypoglycemia, no interventions are typically recommended. However, it is important that school staff be aware that children have MCADD, in the event that the child becomes acutely ill.

Frequently Asked Questions

What is the typical clinical presentation of a patient with MCADD during an acute illness?

Presentation usually includes clamminess, irritability, lethargy, fever, diarrhea, vomiting, and +/- hypoglycemia. Low blood sugars may not occur until later in the illness; emergency care should be initiated with no delay if clinical symptoms are present.

What is the recommended diet and medication during a minor acute illness?

During minor illness, increase fluid intake (e.g., juice, Gatorade, and Powerade). Raw cornstarch at bedtime (1-1½ grams/kg mixed in a cool, sugar-free liquid to ensure a proper absorption) may be considered for infants and young children who experience symptomatic hypoglycemia. Carnitor® (100 mg/ml) solution given at 50 mg/kg/day and divided in 3-4 doses is recommended.

What should the bloodwork for evaluation include during an acute febrile illness associated with significant emesis or diarrhea?

Bloodwork should include a CBC with differential, complete metabolic profile, carnitine levels, dry bloodspot card for acylcarnitine profile, urine organic acid analysis, and acylglycines.

What treatment should be initiated during a significant acute illness?

During acute illness when adequate oral carbohydrates and fluid intake cannot be maintained, Carnitor® (100 mg/ml) solution, given at an inpatient medical facility at 100 mg/kg/day divided in 3 to 4 doses, is recommended. If this is not tolerated, switch to IV Carnitor® with a loading dose IV Carnitor® (1000 mg/5 ml), given 50 mg/kg slowly over 2 to 5 minutes, followed by 50 mg/kg over each subsequent 24 hours until the child is able to resume the normal oral diet. Administer IV D10 1/4 NS @ 1 ¼-1 ½ to maintain normal glycemia. Once the patient can tolerate oral intake to maintain normal blood glucose levels, discharge from a medical facility may be considered.

Issues Related to MCADD

Clinical Assessment

Reye Syndrome

Resources

Information for Clinicians

MCADD (OMIM)
Provides information about diagnosis, management, and studies related to MCADD; Online Mendelian Inheritance in Man, hosted by Johns Hopkins University.

MCADD (GeneReviews)
Excellent review of MCADD that includes a clinical description, differential diagnoses, management information, and molecular genetic information; by Detrich Matern, MD and Piero Rinaldo, MD, PhD - sponsored by the U.S. National Library of Medicine.

Guidelines for MCADD (Genetic Metabolic Dietitians International)
Extensive clinical information about nutrition therapy for MCADD. Topics include background, signs and symptoms, laboratory findings, biochemical basis of MCADD, chronic and acute management, monitoring, and special circumstances; edited by Dianne M. Frazier, PhD, MPH, RD.

Emergency Protocol Information & Letter Samples (FOD)
Links to emergency care sample letters for MCADD, VLCADD, LCHADD, and unclassified FOD; International Fatty Oxidation Disorders Support Group.

Helpful Articles

PubMed search for articles about medium-chain acyl-CoA dehydrogenase deficiency (MCADD), last 5 years.

Feillet F, Ogier H, Cheillan D, Aquaviva C, Labarthe F, Baruteau J, Chabrol B, de Lonlay P, Valayanopoulos V, Garnotel R, Dobbelaere D, Briand G, Jeannesson E, Vassault A, Vianey-Saban C.
[Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management].
Arch Pediatr. 2012;19(2):184-93. PubMed abstract

Gartner V, McGuire PJ, Lee PR.
Child Neurology: medium-chain acyl-coenzyme A dehydrogenase deficiency.
Neurology. 2015;85(4):e37-40. PubMed abstract / Full Text

Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, Burgard P, Lindner M.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening.
JIMD Rep. 2015;23:101-12. PubMed abstract / Full Text

Rice GM, Steiner RD.
Inborn Errors of Metabolism (Metabolic Disorders).
Pediatr Rev. 2016;37(1):3-15; quiz 16-7, 47. PubMed abstract

Schatz UA, Ensenauer R.
The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population.
J Inherit Metab Dis. 2010. PubMed abstract

Clinical Tools

Algorithms/Care Processes

MCADD Acute Illness Protocol (NECMP) (PDF Document 17 KB)
Guideline for clinicians treating the sick infant or child who has MCADD; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs. Click pdf to view the complete protocol.

Sample Letter for Emergency Care (Medical Home Portal) (Word Document 14 KB)
A sample letter with emergency treatment details that can be provided to families who have a child with MCADD.

ACT Sheet for MCADD (ACMG) (PDF Document 348 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for MCADD (ACMG) (PDF Document 63 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Information & Support for Families

Family Diagnosis Page

Information on the Web

MCADD - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

MCADD (Genetics Home Reference)
Excellent, detailed review of MCADD for patients and families; sponsored by the U.S. National Library of Medicine.

MCADD: A Guide for Parents (PacNoRGG) (PDF Document 618 KB)
Eight-page guide that includes an overview, social concerns, sample treatment plan, glossary, regional resources, and references; sponsored by the Pacific Northwest Regional Genetics Group.

MCADD: A Guide for Parents (PacNoRGG) (Spanish) (PDF Document 202 KB)
Spanish translation of an 8-page guide that includes an overview, social concerns, sample treatment plan, glossary, regional resources, and references; sponsored by the Pacific Northwest Regional Genetics Group.

Support National & Local

Fatty Oxidation Disorders (FOD) Family Support Group
Information for families about fatty acid oxidation disorders, support groups, coping, finances, and links to other sites.

Studies/Registries

MCADD (clinicaltrials.gov)

Services for Patients & Families

CSHCN Clinics

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Developmental Pediatrics

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Genetics Laboratories

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Newborn Screening Programs

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Nutrition, Metabolic

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Pediatric Genetic Counseling

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Pediatric Metabolic Genetics

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Pediatric Neurology

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For other services related to this condition, browse our Services categories or search our database.

Authors

Lead Author: Laurie Smith, MD, PhD - 6/2016
Reviewing Author: Natario Couser, MD, MS - 6/2016
Content Last Updated: 6/2016

Bibliography

Albers S, Levy HL, Irons M, Strauss AW, Marsden D.
Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency.
J Inherit Metab Dis. 2001;24(3):417-8. PubMed abstract

Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kølvraa S, Gregersen N.
The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?.
Hum Mol Genet. 1997;6(5):695-707. PubMed abstract

Bodman M, Smith D, Nyhan WL, Naviaux RK.
Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.
Arch Neurol. 2001;58(5):811-4. PubMed abstract

Browning MF, Levy HL, Wilkins-Haug LE, Larson C, Shih VE.
Fetal fatty acid oxidation defects and maternal liver disease in pregnancy.
Obstet Gynecol. 2006;107(1):115-20. PubMed abstract

California Department of Health Services.
Parents' Guide to MCADD.
2005; 22. Newborn Screening Program; http://www.cdph.ca.gov/programs/nbs/Documents/NBS-mcadd0605.pdf

Carpenter K, Wiley V, Sim KG, Heath D, Wilcken B.
Evaluation of newborn screening for medium chain acyl-CoA dehydrogenase deficiency in 275 000 babies.
Arch Dis Child Fetal Neonatal Ed. 2001;85(2):F105-9. PubMed abstract / Full Text

Derks TG, Reijngoud DJ, Waterham HR, Gerver WJ, van den Berg MP, Sauer PJ, Smit GP.
The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome.
J Pediatr. 2006;148(5):665-670. PubMed abstract

Derks TG, Touw CM, Ribas GS, Biancini GB, Vanzin CS, Negretto G, Mescka CP, Reijngoud DJ, Smit GP, Wajner M, Vargas CR.
Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-CoA dehydrogenase deficiency.
J Inherit Metab Dis. 2014;37(5):783-9. PubMed abstract

Ding JH, Roe CR, Iafolla AK, Chen YT.
Medium-chain acyl-coenzyme A dehydrogenase deficiency and sudden infant death.
N Engl J Med. 1991;325(1):61-2. PubMed abstract

Duran M, Hofkamp M, Rhead WJ, Saudubray JM, Wadman SK.
Sudden child death and 'healthy' affected family members with medium-chain acyl-coenzyme A dehydrogenase deficiency.
Pediatrics. 1986;78(6):1052-7. PubMed abstract

Feillet F, Ogier H, Cheillan D, Aquaviva C, Labarthe F, Baruteau J, Chabrol B, de Lonlay P, Valayanopoulos V, Garnotel R, Dobbelaere D, Briand G, Jeannesson E, Vassault A, Vianey-Saban C.
[Medium-chain acyl-CoA-dehydrogenase (MCAD) deficiency: French consensus for neonatal screening, diagnosis, and management].
Arch Pediatr. 2012;19(2):184-93. PubMed abstract

Gartner V, McGuire PJ, Lee PR.
Child Neurology: medium-chain acyl-coenzyme A dehydrogenase deficiency.
Neurology. 2015;85(4):e37-40. PubMed abstract / Full Text

Gramer G, Haege G, Fang-Hoffmann J, Hoffmann GF, Bartram CR, Hinderhofer K, Burgard P, Lindner M.
Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening.
JIMD Rep. 2015;23:101-12. PubMed abstract / Full Text

Hale DE, Stanley CA, Coates PM.
Genetic defects of acyl-CoA dehydrogenases: studies using an electron transfer flavoprotein reduction assay.
Prog Clin Biol Res. 1990;321:333-48. PubMed abstract

Iafolla AK, Thompson RJ Jr, Roe CR.
Medium-chain acyl-coenzyme A dehydrogenase deficiency: clinical course in 120 affected children.
J Pediatr. 1994;124(3):409-15. PubMed abstract

Lang TF.
Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).
J Inherit Metab Dis. 2009;32(6):675-83. PubMed abstract

Lee PJ, Harrison EL, Jones MG, Jones S, Leonard JV, Chalmers RA.
L-carnitine and exercise tolerance in medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency: a pilot study.
J Inherit Metab Dis. 2005;28(2):141-52. PubMed abstract

Leonard JV, Dezateux C.
Newborn screening for medium chain acyl CoA dehydrogenase deficiency.
Arch Dis Child. 2009;94(3):235-8. PubMed abstract

Maier EM, Liebl B, Röschinger W, Nennstiel-Ratzel U, Fingerhut R, Olgemöller B, Busch U, Krone N, v Kries R, Roscher AA.
Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency.
Hum Mutat. 2005;25(5):443-52. PubMed abstract

Nelson J, Lewis B, Walters B.
The HELLP syndrome associated wiht fetal medium-chain acyl-CoA dehydrogenase deficiency.
J Inherit Metab Dis. 2000;23(5):518-9. PubMed abstract

Onunaku, Ngozi.
Improving maternal and infant mental health: Focus on maternal depression.
National Center for Infant and Early Childhood Health Policy at UCLA. July. / http://main.zerotothree.org/site/DocServer/maternaldep.pdf
Discusses the impact of maternal depression on the social and emotional health of young children. Recommends specific steps that early childhood program and public health administrators can take to address the unmet mental health needs of mothers ultimately promoting the social and emotional health, school readiness, and future functioning of very young children.

Potter BK, Little J, Chakraborty P, Kronick JB, Evans J, Frei J, Sutherland SC, Wilson K, Wilson BJ.
Variability in the clinical management of fatty acid oxidation disorders: results of a survey of Canadian metabolic physicians.
J Inherit Metab Dis. 2012;35(1):115-23. PubMed abstract

Rice GM, Steiner RD.
Inborn Errors of Metabolism (Metabolic Disorders).
Pediatr Rev. 2016;37(1):3-15; quiz 16-7, 47. PubMed abstract

Roe CR and Ding J.
The metabolic and molecular basis of inherited disease.
8 th ed. ed. New York, NY: McGraw-Hill; 2001. 0079130356
Genetic perspectives, basic concepts, and diagnostic approaches to specific inherited syndromes.

Roe CR, Roe DS.
Recent developments in the investigation of inherited metabolic disorders using cultured human cells.
Mol Genet Metab. 1999;68(2):243-57. PubMed abstract

Schatz UA, Ensenauer R.
The clinical manifestation of MCAD deficiency: challenges towards adulthood in the screened population.
J Inherit Metab Dis. 2010. PubMed abstract

Skagen K, Trøseid M, Ueland T, Holm S, Abbas A, Gregersen I, Kummen M, Bjerkeli V, Reier-Nilsen F, Russell D, Svardal A, Karlsen TH, Aukrust P, Berge RK, Hov JE, Halvorsen B, Skjelland M.
The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis.
Atherosclerosis. 2016;247:64-9. PubMed abstract

Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.
Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing.
Mol Genet Metab. 2010;100(3):241-50. PubMed abstract

Stanley, CA, Editors: Fernandes J, Saudubray JM, vand den Berghe G, Walter JH .
Disorders of fatty acid oxidation.
Inborn Metabolic Diseases: Diagnosis and Treatment. 2006; 4th Edition:175-190.. Heidelberg: Springer Medizin Verlag

Tajima G, Sakura N, Yofune H, Nishimura Y, Ono H, Hasegawa Y, Hata I, Kimura M, Yamaguchi S, Shigematsu Y, Kobayashi M.
Enzymatic diagnosis of medium-chain acyl-CoA dehydrogenase deficiency by detecting 2-octenoyl-CoA production using high-performance liquid chromatography: a practical confirmatory test for tandem mass spectrometry newborn screening in Japan.
J Chromatogr B Analyt Technol Biomed Life Sci. 2005;823(2):122-30. PubMed abstract

Tanaka K, Gregersen N, Ribes A, Kim J, Kølvraa S, Winter V, Eiberg H, Martinez G, Deufel T, Leifert B, Santer R, François B, Pronicka E, László A, Kmoch S, Kremensky I, Kalaydjicva L, Ozalp I, Ito M.
A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.
Pediatr Res. 1997;41(2):201-9. PubMed abstract

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text

Waddell L, Wiley V, Carpenter K, Bennetts B, Angel L, Andresen BS, Wilcken B.
Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.
Mol Genet Metab. 2006;87(1):32-9. PubMed abstract

Walter JH.
Tolerance to fast: rational and practical evaluation in children with hypoketonaemia.
J Inherit Metab Dis. 2009;32(2):214-7. PubMed abstract

Zschocke J, Schulze A, Lindner M, Fiesel S, Olgemöller K, Hoffmann GF, Penzien J, Ruiter JP, Wanders RJ, Mayatepek E.
Molecular and functional characterisation of mild MCAD deficiency.
Hum Genet. 2001;108(5):404-8. PubMed abstract

Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, Strauss AW, Comeau AM, Eaton RB, Grady GF.
Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program.
Clin Chem. 2001;47(11):1945-55. PubMed abstract