MCAD deficiency in Denmark

Area of Science:

• Biochemistry
• Genetics
• Public Health

Background:

• Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited disorder of fatty acid oxidation.
• Newborn screening programs utilize tandem mass spectrometry (MS/MS) to detect MCADD due to its frequency and the benefits of early intervention.

Purpose of the Study:

• To determine the incidence of MCADD in Denmark via newborn screening.
• To compare screening-detected incidence with clinically presenting cases.
• To investigate the mutation spectrum and penetrance in MCADD.

Main Methods:

• Screening of 519,350 newborns using MS/MS for MCADD.
• Confirmation of diagnosis through mutation analysis.
• Analysis of mutation spectrum and carrier frequency.

Main Results:

• Newborn screening identified MCADD in 1 in 8,954 infants, a fourfold increase compared to the 1 in 39,691 incidence of clinically presenting cases.
• The mutation spectrum in screened newborns differed, with fewer homozygous cases for the common c.985A>G mutation and novel mutations observed.
• Reduced penetrance of the c.985A>G mutation was suggested, with potentially only 50% of homozygotes manifesting symptoms.

Conclusions:

• MCADD is significantly more frequent than previously estimated from clinical data.
• Reduced penetrance and a broader spectrum of mutations contribute to the discrepancy between screened and clinical incidence.
• Rapid genotyping from newborn blood spots is crucial for accurate MCADD diagnosis and genetic counseling.