Medium-chain acyl-CoA dehydrogenase deficiency

genotype-biochemical phenotype correlations

Leigh Waddell, Veronica Wiley, Kevin Carpenter, Bruce Bennetts, Lyn Angel, Brage S Andresen, Bridget Wilcken

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.

OriginalsprogEngelsk
TidsskriftMolecular Genetics and Metabolism
Vol/bind87
Udgave nummer1
Sider (fra-til)32-9
Antal sider8
ISSN1096-7192
DOI
StatusUdgivet - jan. 2006

Fingeraftryk

Acyl-CoA Dehydrogenase
Genetic Association Studies
Screening
Mutation
Newborn Infant
Mass spectrometry
Exons
Fatty Acids
Plasmas
Oxidation
Defects
Heterozygote
Tandem Mass Spectrometry
Parents
octanoylcarnitine

Citer dette

Waddell, Leigh ; Wiley, Veronica ; Carpenter, Kevin ; Bennetts, Bruce ; Angel, Lyn ; Andresen, Brage S ; Wilcken, Bridget. / Medium-chain acyl-CoA dehydrogenase deficiency : genotype-biochemical phenotype correlations. I: Molecular Genetics and Metabolism. 2006 ; Bind 87, Nr. 1. s. 32-9.
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abstract = "The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80{\%} are homozygous for the common mutation, c.985A > G and 18{\%} heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.",
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Medium-chain acyl-CoA dehydrogenase deficiency : genotype-biochemical phenotype correlations. / Waddell, Leigh; Wiley, Veronica; Carpenter, Kevin; Bennetts, Bruce; Angel, Lyn; Andresen, Brage S; Wilcken, Bridget.

I: Molecular Genetics and Metabolism, Bind 87, Nr. 1, 01.2006, s. 32-9.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Medium-chain acyl-CoA dehydrogenase deficiency

T2 - genotype-biochemical phenotype correlations

AU - Waddell, Leigh

AU - Wiley, Veronica

AU - Carpenter, Kevin

AU - Bennetts, Bruce

AU - Angel, Lyn

AU - Andresen, Brage S

AU - Wilcken, Bridget

PY - 2006/1

Y1 - 2006/1

N2 - The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.

AB - The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.

KW - Acyl-CoA Dehydrogenase

KW - Carnitine

KW - DNA Mutational Analysis

KW - Fibroblasts

KW - Genetic Testing

KW - Genetic Variation

KW - Genotype

KW - Glycine

KW - Homozygote

KW - Humans

KW - Infant, Newborn

KW - Mass Spectrometry

KW - Phenotype

KW - Statistics as Topic

U2 - 10.1016/j.ymgme.2005.09.020

DO - 10.1016/j.ymgme.2005.09.020

M3 - Journal article

VL - 87

SP - 32

EP - 39

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 1

ER -