A nationwide retrospective observational study of population newborn screening for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency in the Netherlands

PURPOSE: To evaluate the Dutch newborn screening (NBS) for Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency since 2007.METHODS: A nationwide retrospective, observational study of clinical, laboratory and epidemiological parameters of patients with MCAD deficiency born between 2007-2015. Severe MCAD deficiency was defined by ACADM genotypes associated with clinical ascertainment, or variant ACADM genotypes with a residual MCAD enzyme activity < 10 %. Mild MCAD deficiency was defined by variant ACADM genotypes with a residual MCAD enzyme activity ≥ 10%.RESULTS: The prevalence of MCAD deficiency was 1 / 8,300 (95% CI: 1 / 7,300 - 1 / 9,600). Sensitivity of the Dutch NBS was 99% and specificity ~100%, with a positive predictive value of 86%. Thirteen newborns with MCAD deficiency suffered from neonatal symptoms, three of them died. Of the 189 identified neonates, 24% had mild MCAD deficiency. The acylcarnitine ratio octanoylcarnitine (C8)/decanoylcarnitine (C10) was superior to C8 in discriminating between mild and severe cases and more stable in the first days of life.CONCLUSION: NBS for MCAD deficiency has a high sensitivity, specificity, and positive predictive value. In the absence of a golden standard to confirm the diagnosis, the combination of acylcarnitine (ratios), molecular and enzymatic studies allows risk stratification. To improve evaluation of NBS protocols and clinical guidelines, additional use of acylcarnitine ratios and multivariate pattern-recognition software may be reappraised in the Dutch situation. Prospective recording of NBS and follow-up data is warranted covering the entire health care chain of preventive and curative medicine.TAKE-HOME MESSAGE: The acylcarnitine ratio octanoylcarnitine (C8)/decanoylcarnitine (C10) is stable in the first days of life in subjects with MCAD deficiency and may be reappraised in the Dutch NBS and clinical follow-up. The combination of acylcarnitine (ratios), molecular and enzymatic studies allows risk stratification; in the Netherlands, Approximately 25% of the neonates identified by the Dutch NBS have mild MCAD deficiency. This article is protected by copyright. All rights reserved.