Newborn screening for medium chain acyl-CoA dehydrogenase deficiency in England: Prevalence, predictive value and test validity based on 1.5 million screened babies

Abstract

BackgroundMedium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare, life-threatening condition. Early diagnosis by screening asymptomatic newborns may improve outcome, but the benefit to newborns identified with variants not encountered clinically is uncertain.ObjectiveTo estimate, overall and by ethnic group: screen-positive prevalence and predictive value (PPV); MCADD prevalence; proportion MCADD variants detected of predicted definite or uncertain clinical importance.SettingAll births in areas of high ethnic minority prevalence in England.MethodsProspective multicentre pilot screening service; testing at age five to eight days; standardized screening, diagnostic and management protocols; independent expert review of screen-positive cases to assign MCADD diagnosis and predicted clinical importance (definite or uncertain).ResultsApproximately 1.5 million babies (79% white; 10% Asian) were screened. MCADD was confirmed in 147 of 190 babies with a positive screening result (screen-positive prevalence: 1.20 per 10,000; MCADD prevalence: 0.94 per 10,000; PPV 77% [95% CI 71–83]), comprising 103 (70%) with MCADD variants of definite clinical importance (95 white [95%]; 2 Asian [2%]) and 44 (30%) with variants of uncertain clinical importance (29 white [67%]; 12 Asian [28%]).ConclusionOne baby in every 10,000 born in England is diagnosed with MCADD by newborn screening; around 60 babies each year. While the majority of MCADD variants detected are predicted to be of definite clinical importance, this varies according to ethnic group, with variants of uncertain importance most commonly found in Asian babies. These findings provide support for MCADD screening but highlight the need to take account of the ethnic diversity of the population tested at implementation.

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

“…Importantly, it has been shown that the proportion of newborns with the prevalent c.985A>G homozygous genotype is approximately 50% in a screened population (Andresen et al 2012) as compared with 80% in a clinically presenting population (Tanaka et al 1992), supporting the notion that c.985A>G homozygous MCADD has a higher penetrance than most other MCADD genotypes. This is also reflected in the biochemical phenotype, where c.985A>G homozygous newborns have higher mean and median C8 carnitine levels than newborns with other ACADM genotypes (Andresen et al 2012;Oerton et al 2011).…”

“…MCADD presents with a characteristic acylcarnitine pattern that can easily be identified in dried blood spot samples by tandem mass spectrometry (Oerton et al 2011), and taken together with the excellent prognosis upon early treatment, MCADD is therefore part of the newborn screening (NBS) program in several countries. In Denmark, MCADD has been part of the NBS program since 2002 .…”

Neonatal Screening for Medium-Chain Acyl-CoA Dehydrogenase Deficiency—Alternative Approaches

“…This contrasts with 42% of cases with two ACADM mutations and a genotype of "uncertain" significance ( Figure 1). [1]. The 'cut-off' shown for hexanoylglycine is empirical; the upper limit of normal by the method used was 1.1 micromol/mmol creatinine [5].…”

“…Sensitivity is high but specificity low. Homozygosity for the c.985A>G mutation is the most common genotype in MCADD in North-West Europe, constituting 80% of clinically-diagnosed cases in England but only 53% of screening-detected cases [1]. In a wider survey [2] only six of the 36 ACADM gene variants detected in screening-positive cases had also been identified in the clinically-presenting disorder making the presence of two variant alleles unsuitable as the sole diagnostic criterion.…”

“…Quantitative analysis by stable-isotope dilution gas chromatography-mass spectrometry is a better discriminant [5]. In the English pilot study [1] only one of 93 screening-positive babies with a genotype previously reported from clinically-affected cases had urinary hexanoylglycine <8 micromol/mmol creatinine. This contrasts with 42% of cases with two ACADM mutations and a genotype of "uncertain" significance ( Figure 1).…”