Abstract
BackgroundSince the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes.MethodsWe performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 2007–2010. Clinical, molecular, and enzymatic data were integrated.ResultsEighty-four patients from 76 families were identified. Twenty-two percent of the subjects had a variant ACADM genotype. In patients with classical ACADM genotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 0-8%) when compared to subjects with variant ACADM genotypes (range 0-63%; 4 cases with 0%, remainder 20-63%). Patients with (fatal) neonatal presentations before diagnosis displayed residual MCAD enzyme activities <1%. After diagnosis and initiation of treatment, residual MCAD enzyme activities <10% were associated with an increased risk of hypoglycaemia and carnitine supplementation. The prevalence of MCAD deficiency upon screening was 1/8,750 (95% CI 1/7,210–1/11,130).ConclusionsDetermination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification. Subjects with variant ACADM genotypes and residual MCAD enzyme activities <10% should be considered to have the same risks as patients with classical ACADM genotypes. Parental instructions and an emergency regimen will remain principles of the treatment in any type of MCAD deficiency, as the effect of intercurrent illness on residual MCAD enzyme activity remains uncertain. There are, however, arguments in favour of abandoning the general advice to avoid prolonged fasting in subjects with variant ACADM genotypes and >10% residual MCAD enzyme activity.
Highlights
Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant Gene encoding medium-chain acyl-CoA dehydrogenase (ACADM) genotypes that have never been identified in clinically ascertained patients
Determination of residual MCAD enzyme activity improves our understanding of variant ACADM genotypes and may contribute to risk stratification
Subjects with variant ACADM genotypes and residual MCAD enzyme activities
Summary
Since the introduction of medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variant ACADM (gene encoding MCAD enzyme) genotypes that have never been identified in clinically ascertained patients. Medium-chain acyl-Coenzyme A dehydrogenase (MCAD [E.C.1.3.99.3]) deficiency (OMIM 201450) is the most common inherited disorder of mitochondrial fatty acid oxidation. The MCAD enzyme is responsible for the first step in the mitochondrial β-oxidation of CoA esters of medium-chain length fatty acids [1]. Before the introduction of population newborn bloodspot screening (NBS) for MCAD deficiency, patients presented clinically during periods of catabolic stress, precipitating acute symptoms [2,3]. Approximately 80% of clinically presenting patients were homozygous for the c.985A>G missense mutation in the ACADM gene encoding the MCAD enzyme [5]. Secondary free carnitine (C0) deficiency in blood may be corrected by carnitine supplementation in some patients, but evidence for this treatment is limited [7]
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