Molecular and functional characterisation of mild MCAD deficiency

Abstract

Molecular and functional characterisation of mild MCAD deficiencyZschocke, J.; Schulze, A.; Lindner, M.; Fiesel, S.; Olgemöller, K.; Hoffmann, G.F.; Penzien, J.; Ruiter, J.P.N.; Wanders, R.J.A.; Mayatepek, E. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 08 May 2018Abstract We report a novel mild variant of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) diagnosed in four infants who, in neonatal screening, showed abnormal acylcarnitine profiles indicative of MCADD. Three patients showed completely normal urinary organic acids and phenylpropionic acid loading tests were normal in all four patients. Enzyme studies showed residual MCAD activities between "classical" MCADD and heterozygotes. ACADM gene analysis revealed compound heterozygosity for the common mutation K329E and a novel mutation, Y67H, in two cases, and homozygosity for mutation G267R and the novel mutation S245L, respectively, in two children of consanguineous parents. As in other metabolic disorders, the distinction between "normal" and "disease" in MCAD deficiency is blurring into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing.

Relevance of Expanded Neonatal Screening of Medium-Chain Acyl Co-A Dehydrogenase Deficiency: Outcome of a Decade in Galicia (Spain)

“…This mutation has never been identified in patients with a clinical phenotype, but in several newborns identified by neonatal screening in the United States, Australia, and Germany Smith et al 2010;Zschocke et al 2001). These newborns had a relatively mild acylcarnitine profile, like our patient 8, that was compound heterozygous for this and for the common mutation and only presented a slight elevation of metabolites.…”

“…The c.799G>A (p.G267R) mutation has been previously reported in symptomatic patients (Yokota et al 1991;Andresen et al 1997;Zschocke et al 2001). Glycine 267 is highly conserved in humans and other organisms and are found at the equivalent positions in human short-chain and branched-chain acylCoA dehydrogenases (Zschocke et al 2001). Expression studies in Escherichia coli revealed a decrease of the enzyme activity that could be increased by co-overexpression of the GroESL chaperonins (Andresen et al 1997).…”

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

“…All exons and parts of the neighbouring intron regions of the ACADM gene (NM_000016.4) were analysed by direct sequencing (Zschocke et al 2001). Mutations are described according to the recommendations of HGVS (http://www.hgvs.org/ mutnomen/).…”

“…Both our patients carried a known disease-causing mutation on the second allele (patient 17 c.199T>C and c.799G>A; patient 21 c.199T>C and c.985A>G). The mutation c.799G>A has been found in patients detected asymptomatically by newborn screening (Zschocke et al 2001), as well as in symptomatic patients (Yokota et al 1991;Andresen et al 1997). This mutation has been classified as severe (Smith et al 2010;Sturm et al 2012).…”

Quantitative Acylcarnitine Profiling in Peripheral Blood Mononuclear Cells Using In Vitro Loading With Palmitic and 2-Oxoadipic Acids: Biochemical Confirmation of Fatty Acid Oxidation and Organic Acid Disorders

“…Classical OAD, such as methylmalonic aciduria (MMA), propionic aciduria (PA), and isovaleric aciduria (IVA), characteristically present with metabolic acidosis, hypoglycemia, hyperketosis, elevated lactate, and hyperammonia during catabolic state, whereas cerebral OAD, such as glutaric aciduria type I (GA-I), predominantly exhibit neurologic symptoms (dystonia, ataxia, encephalopathy, seizures) (2,10,11,13-16,18 -21). At present, genotype phenotype correlation in the majority of these diseases is poorly understood and remarkable variations in the disease course have been described, ranging from asymptomatic patients to fatal course after neonatal onset (10,15,(22)(23)(24)(25)(26)(27).…”