Positive Newborn Screen for MCAD -- Now What?

Stephanie L. Austin, MS, MA; Laura A. Stokowski, RN, MS


July 10, 2014

Editorial Collaboration

Medscape &

Genetic Diagnosis and Counseling

MCAD deficiency, like other inborn errors of metabolism, is increasingly recognized not as a dichotomous condition but rather as a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene.[23] More than 90 mutations in the ACADM gene have been identified.[9] For clinical genetic testing to confirm a diagnosis of MCAD deficiency, GeneReviews® recommends targeted mutation analysis for the 2 most common mutations in the ACADM gene: p.Lys304Glu (985A>G), the mutation prevalent in individuals of northern European heritage, and p.Tyr42His (c.199T>C). If neither or only one mutation is found, sequence analysis is recommended to identify other sequence variants.[9] Compound heterozygotes for c.985A>G/c.199T>C can have abnormal acylcarnitine profiles, but the clinical consequences of this genotype are unknown. Other genotypes conferring mild disease have been reported as well.

MCAD deficiency is an autosomal recessive condition, so any children of this couple have a 25% risk of being affected and a 50% risk of being carriers. If either of the parents is affected, the risk in future offspring is 50%. Future children of this couple will be presumed to have MCAD deficiency until the results of newborn screening are known.[20] Siblings and parents of a proband should be tested, either biochemically or with DNA-based mutation analysis. Such testing has occasionally found family members with asymptomatic MCAD deficiency who benefited from preventive management.

Social support is also important for families as they navigate this road. Families will benefit from explanations about differences between screening and testing, and a meeting with a genetic counselor should be arranged to discuss and answer their questions about the significance of the diagnosis for other family members and future children of the parents. It may be useful to share reputable support resources if the family is interested in reading more about the condition, such as the National Library of Medicine Genetics Home Reference, the Fatty Oxidation Disorder Family Support Group, the Organic Acidemia Association, or the United Mitochondrial Disease Foundation.

The risks for severe metabolic crisis and death have not been entirely eliminated in MCAD deficiency, even in the era of universal newborn screening.[22] The risk for sudden death in MCAD deficiency is highest in the first 2 years of life but does not completely wane, even in adulthood.[22] Known risk factors for sudden death include a C8 level of 6 µmol/L or higher on the newborn screen specimen, and a genotype other than homozygosity for the c.985A>G mutation. Vomiting frequently precedes sudden death. Fortunately, social support and medical follow-up can reduce the occurrence of sudden death in children with MCAD deficiency.[22] Therefore, it is important to assess the family's ability to understand the nature of the child's disorder and comply with the necessary preventive measures and treatment.[22]


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