Medium Chain Acyl-CoA Dehydrogenase (ACADM) 2 Mutations

Content Review: October 2021 Last Update:
  • Preferred initial molecular test to confirm a diagnosis or identify carriers of MCAD deficiency in individuals with suggestive clinical and/or biochemical findings such as:
    • Abnormal newborn screen for MCAD
    • Reye-like syndrome (in infants)
  • Test for family members of a proband with the c.985A>G or c.199T>C variants
  • Carrier test for reproductive partner of an affected individual or a carrier of MCAD deficiency

For additional biochemical and genetic test options, refer to the Laboratory Test Directory.

Medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism and is the most frequently diagnosed fatty acid β-oxidation disorder.  Symptoms generally present between 3 and 24 months of age  and may include hypoketotic hypoglycemia, lethargy, seizure, coma, hepatomegaly, encephalopathy, Reye-like syndrome, or sudden death. These episodes may be triggered by prolonged fasting, infection, or surgery. Once diagnosed, patients generally have a good prognosis.  Genetic testing is typically indicated by a positive newborn screen or after positive biochemical tests in a newly symptomatic individual. 

Testing Strategy

Biochemical tests are necessary for the initial diagnosis of MCAD deficiency and may include the following:

  • Acylcarnitine Quantitative Profile, Plasma
  • Carnitine Panel
  • Acylglycines, Quantitative, Urine
  • Organic Acids, Urine

Refer to the Laboratory Test Directory for available test options.

Genetics

Gene

ACADM

Pathogenic Variants

c.985A>G; p.K329E

  • Most common pathogenic variant in individuals with MCAD deficiency

c.199T>C; p.Y67H

  • Mild pathogenic variant associated with residual MCAD enzymatic activity
  • Individuals heterozygous for this variant and another pathogenic variant on the opposite chromosome may have reduced acylcarnitine levels and may be at risk for metabolic crisis. 

Inheritance

Autosomal recessive

Test Interpretation

Clinical Sensitivity

Approximately 75% in White individuals  

Results

Result Clinical Significance

Homozygosity for c.985A>G

Predicts MCAD deficiency

Heterozygosity for c.985A>G

Indicates individual is at least a carrier for classic MCAD deficiency

Compound heterozygosity for c.985A>G variant and the mild c.199T>C variant

May have reduced acylcarnitine levels and may be at risk for metabolic crisis

Heterozygosity for c.199T>C

Indicates individual is at least a carrier for mild MCAD deficiency

Homozygosity for c.199T>C

Predicts mild MCAD deficiency

No variants detected

Indicates likelihood of MCAD deficiency or carrier state is reduced

Limitations

  • Diagnostic errors can occur due to rare sequence variations.
  • ACADM variants other than c.985A>G and c.199T>C will not be detected.

References

Related Information
Fatty Acid Oxidation Disorders Panel, Sequencing