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Twenty Years of Newborn Screening for MCADD in Portugal: genetic data
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Introduction: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive inherited metabolic disorder that affects fatty acid oxidation metabolism. Most cases present the most common c.985G>A mutation in ACADM gene, while a few patients carry other rare mutations. In Portugal, MCADD has been included in the newborn screening program since 2004 and is the most frequently diagnosed inborn error of metabolism detected through this program, with an incidence of 1 in 6,433.
Materials and Methods: Approximately 1,762,713 newborns were screened for MCAD deficiency between October 2004 and January 2025, using tandem mass spectrometry (MS/MS) to detect elevated octanoylcarnitine (C8) levels and an increased C8/C10 ratio. Tandem mass spectrometry (MS/MS) results and genetic testing data were analyzed.
Results: Over the 20 years period, a total of 274 newborns were identified with high values of C8 and C8/C10 ratios from dried blood spots. Biochemical and molecular follow up confirmed the MCADD diagnosis in 273 cases. Molecular characterization was not available for 90 cases. Of the remaining 183 cases, which were studied at our Newborn Screening, Metabolism and Genetics Unit, 162 (88%) were homozygous for the c.985G>A mutation, while 22 were compound heterozygotes. Of these, 13 carried the c.985G>A mutation along with a another mutation, whereas 8 had two distinct mutations. Additionally, seven novel mutations were identified in this cohort: c.94G>C, c.113G>C, c.214G>T, c.532A>T, c.974A>G, c.1133G>A, and c.708+1G>A.
Conclusion: Newborn screening has been crucial for identifying and managing of MCADD in Portugal. Our study confirms the c.985G>A mutation as the most frequent pathogenic variant, consistent with previous reports. The identification of seven novel mutations expands the spectrum of known variants, underscoring the importance of comprehensive genetic analysis. These findings reinforce the importance of newborn screening in early diagnosis and intervention, while also contributing to a deeper understanding of the genetic diversity of MCADD, with implications for genetic counseling and long-term management.
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((Abstract page 50))
Palavras-chave
Newborn Screening MCADD Doenças Genéticas Rastreio Neonatal Portugal