Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study

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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. It could be hypothesised that residual MCAD enzyme activity can contribute in risk stratification of subjects with variant ACADM genotypes. Methods We 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. Results Eighty-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). Conclusions 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 <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.

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Publié le 01 janvier 2012
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Touwet al. Orphanet Journal of Rare Diseases2012,7:30 http://www.ojrd.com/content/7/1/30
R E S E A R C HOpen Access Risk stratification by residual enzyme activity after newborn screening for mediumchain acylCoA dehyrogenase deficiency: data from a cohort study 1,2,3* 1,34 56 Catharina M L Touw, G Peter A Smit, Maaike de Vries , Johannis B C de Klerk , Annet M Bosch , 7 89 102,3 Gepke Visser , Margot F Mulder , M Estela RubioGozalbo , Bert Elvers, Klary E NiezenKoning, 11 112,3 1,3 Ronald J A Wanders, Hans R Waterham, DirkJan Reijngoudand Terry G J Derks
Abstract Background:Since the introduction of mediumchain acyl coenzyme A dehydrogenase (MCAD) deficiency in population newborn bloodspot screening (NBS) programs, subjects have been identified with variantACADM(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 variantACADM genotypes. Methods:We performed a retrospective cohort study of all patients identified upon population NBS for MCAD deficiency in the Netherlands between 20072010. Clinical, molecular, and enzymatic data were integrated. Results:Eightyfour patients from 76 families were identified. Twentytwo percent of the subjects had a variant ACADMgenotype. In patients with classicalACADMgenotypes, residual MCAD enzyme activity was significantly lower (median 0%, range 08%) when compared to subjects with variantACADMgenotypes (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 1/7,2101/11,130). Conclusions:Determination of residual MCAD enzyme activity improves our understanding of variantACADM genotypes and may contribute to risk stratification. Subjects with variantACADMgenotypes and residual MCAD enzyme activities<10% should be considered to have the same risks as patients with classicalACADMgenotypes. 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 ACADMgenotypes and>10% residual MCAD enzyme activity. Keywords:Population newborn screening, Enzyme, Genotype, Prevalence
* Correspondence: n.touw@umcg.nl 1 Section of Metabolic Diseases, Beatrix Childrens Hospital, University of Groningen, University Medical Centre of Groningen, PO Box 30 001, CA84, 9700 RB, Groningen, The Netherlands 2 Laboratory of Metabolic Diseases, Department of Laboratory Medicine, University of Groningen, University Medical Centre of Groningen, PO Box 30 001, CA84, 9700 RB, Groningen, The Netherlands Full list of author information is available at the end of the article
© 2012 Touw et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.