MCADD - Initial Diagnosis

Page Contents

• Overview
• Presentations
• Diagnostic Criteria
• Pearls And Alerts
• Practice Guidelines
• Differential Diagnosis
• History And Examination
• Resources

Overview

Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is an inborn error of fatty acid metabolism. Unless acutely ill, affected individuals generally have normal physical examinations without features that would lead a provider to consider the diagnosis. Affected individuals may be completely 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 which can quickly progress to coma after periods of fasting or during times of catabolic stress, such as intercurrent illness.

Individuals may be identified as having MCADD either by presentation or by expanded newborn screening. If the child is identified by newborn screening, the child's primary care provider will be notified of a positive test result for MCAD deficiency and will need to collaborate with the family, the Newborn Screening Program, and a metabolic geneticist to confirm (or not) the test result and follow through with appropriate care and education for the patient and the family. The family can be prepared by indicating that laboratory tests suggest that the child may have some trouble using certain fats and that they will be seeing someone to help confirm the diagnosis and to help with the long-term management. During visits to metabolic genetics, the family will also meet with a specialized metabolic nutritionist and the disorder, diet, and management will be explained. If the diagnosis has not previously been made but is suspected, testing will be performed to rule in/out the diagnosis. This testing includes a basic metabolic panel, plasma ammonia level, plasma acylcarnitine profile, urine organic acid profile, urine acylglycine analysis, and carnitine levels. Many of these tests are highly specialized and may be difficult to obtain at smaller hospitals.

Presentations

Although no presentation is "typical," an individual with classic MCAD deficiency, prior to the introduction of expanded newborn screening and early identification, was a normal appearing infant at birth who, between 3 months and two years of age, would develop vomiting and lethargy that would quickly progress to coma and death. The initial episode was often accompanied by prolonged fasting, such as when nighttime feedings were decreased, or during intercurrent illness, such as viral respiratory or gastrointestinal infections. Although the physical exam is often normal except for findings associated with illness, hepatomegaly may be noted during an acute event. Laboratory studies at the time of illness or presentation reveal hypoketotic hypoglycemia, elevated uric acid, increased anion gap, and elevated transaminases. A mild elevation in ammonia levels is also seen. Many individuals, however, remain asymptomatic throughout their lifetimes. Presentation in adulthood has been reported. Recent reports suggest that adult presentation may be precipitated by participation in strenuous sports, prolonged fasting associated with surgery, illness or labor, or excessive consumption of alcohol and may have a higher mortality rate and be underdiagnosed. [Lang: 2009] [Schatz: 2010]

With the advent of expanded newborn screening, the diagnosis is suspected when elevations of C8, C6 and C10:1 are 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, and DNA analysis for the common A985G mutation with further sequencing if no mutation or heterozygosity for the A985G mutation is identified.

Diagnostic Criteria

What are the essential features of diagnosis?

• Positive findings on expanded newborn screening
• Nonketotic hypoglycemia
• Elevations of C8, C6, C10, C10:1 acylcarnitines
• Elevations on urinary dicarboxylic acids, hexanoylglycine, suberylglycine and cis-4-decenoic acid
• DNA testing identifying the common A985G mutation (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)

Pearls And Alerts

Acute attacks can rapidly progress to coma within 1-2 hours after onset of symptoms (vomiting, nausea, lethargy) if untreated, and if an attack is undiagnosed, up to 25% of deficient individuals die during their first attack.

In most children with MCADD, the physical exam is often completely normal, despite possibly devastating consequences. Specifically, chronic cardiac and skeletal muscle involvement, for all intents and purposes, is not observed.

Adults may present with acute encephalopathy, rhabdomyolysis and/or cardiac failure after prolonged fasting, strenuous exercise or excessive alcohol consumption.

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

Practice Guidelines

Differential Diagnosis

The differential diagnosis for hypoketotic hypoglycemia includes:

1. Other fatty acid oxidation disorders (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);
   • Important clinical features that might help differentiate MCADD from the other fatty acid oxidation disorders include absence of cardiomyopathy and/or rhabdomyolysis, seen in several but not all of the other disorders, and different metabolites in acylcarnitine and urine organic acid profiles.
2. Ketogenesis defects;
   • The ketogenesis defects often present within the first few days of life, although the pattern of presentation in later childhood may be very similar to MCADD. Vomiting, decreased sensorium, and hepatomegaly are also presenting symptoms. Although hypoketotic hypoglycemia and sometimes hyperammonemia are biochemical features, severe ketoacidosis is the rule.
3. Organic acidurias;
4. 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. Infants have normal birth weight and are initially healthy but soon develop poor feeding, vomiting, lethargy, irritability, and tachypnea. A transient metabolic alkalosis may be present. There is a rapid deterioration. Plasma ammonia levels are generally greater than 150 umol/l at the time of presentation. Urinary orotic acid is present in a number of the urea cycle disorders as well as abnormalities on plasma amino acid profile.
5. Respiratory chain defects;
   • Respiratory chain defects are variable in their presentation with a variety of symptoms. Biochemically, affected individuals have lactic acidosis and ketonemia (often paradoxical--increased ketones after eating). Diagnosis is difficult and enzyme assay in skin or muscle is often necessary.
6. Carbohydrate metabolism defects; and
   • 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.
7. 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, delirum, 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. Also see Reye syndrome and Reye syndrome information from the NIH.

History And Examination

Resources

Authors

Funding/Support

This module was developed in partnership with the Heartland Regional Genetics and Newborn Screening Collaborative and was funded in part by a Health Resources Services Administration (HRSA) cooperative agreement (U22MC03962).

Page Bibliography

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Smith EH, Thomas C, McHugh D, Gavrilov D, Raymond K, Rinaldo P, Tortorelli S, Matern D, Highsmith WE, Oglesbee D.
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