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

Francjan J Van Spronsen,Maaike De Vries,Terry G J Derks,Margot F Mulder,Monique Williams,Hans R Waterham,Gepke Visser,Myrthe M Kuijpers,Peter C J I Schielen,Emmalie A Jager,Annet M Bosch,Estela R Gozalbo

doi:10.1002/jimd.12102

Abstract

To evaluate the Dutch newborn screening (NBS) for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency since 2007, a nationwide retrospective, observational study was performed of clinical, laboratory and epidemiological parameters of patients with MCAD deficiency born between 2007 and 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%. The prevalence of MCAD deficiency was 1/8300 (95% CI: 1/7300-1/9600). 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. 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.

Highlights

Medium-chain acyl-CoA dehydrogenase (MCAD, EC 1.3.8.7) facilitates the first step in the mitochondrial β-oxidation of CoA-esters of medium-chain fatty acids.[1]
For medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the primary screening marker, on which referral is solely based, is the dried blood spots (DBS) concentration of octanoylcarnitine (C8 cut off ≥0.5 μmol/L), derived from a conservative estimate based on literature[24,25] and adapted after a prospective pilot screening in the northern part of the Netherlands.[10]
The prevalence of MCAD deficiency is 1/8300 (CI 95%: 1/7300-1/9600), in agreement with the estimate based on the ACADM c.985A>G carrier frequency in the general population and the assumption of a 94% allele frequency for this common mutation in clinically ascertained cases.[14,32]

Summary

| INTRODUCTION

Medium-chain acyl-CoA dehydrogenase (MCAD, EC 1.3.8.7) facilitates the first step in the mitochondrial β-oxidation of CoA-esters of medium-chain fatty acids.[1]. Testing for MCAD deficiency has been implemented in population newborn bloodspot screening (NBS) programs in many countries from the late 1990s.7. NBS protocols vary with respect to the day of blood collection, analytical aspects, screening parameters, cut-off values, the use of post-analytical diagnostic algorithms based on multivariate pattern recognition and follow-up protocols to establish the definitive diagnosis.[7,8,9] In the Netherlands, MCAD deficiency was introduced in the national NBS program in 2007, after nationwide studies on the natural history,[10] the epidemiology,[11] a prospective pilot NBS study in the northern part of the country[12] and an economic evaluation.[13]. To evaluate the Dutch population NBS for MCAD deficiency since 2007, we performed a nationwide retrospective, observational study of clinical, laboratory and epidemiological parameters

| Ethics approval

| RESULTS

Findings

| DISCUSSION