Medium-chain acyl-CoA dehydrogenase deficiency: Two novel ACADM mutations identified in a retrospective screening

Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible β-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients. Conclusions An expanded newborn screening programme would be beneficial because it would have detected MCAD deficiency in both patients before the development of clinical signs. Our study also provides one of the first descriptions of ACADM mutations in Southeast Europe.

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A nationwide retrospective observational study of population newborn screening for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency in the Netherlands

Journal of Inherited Metabolic Disease ◽

10.1002/jimd.12102 ◽

2019 ◽

Vol 42 (5) ◽

pp. 890-897 ◽

Cited By ~ 6

Author(s):

Emmalie A. Jager ◽

Myrthe M. Kuijpers ◽

Annet M. Bosch ◽

Margot F. Mulder ◽

Estela R. Gozalbo ◽

...

Keyword(s):

The Netherlands ◽

Observational Study ◽

Newborn Screening ◽

Retrospective Observational Study ◽

Mcad Deficiency ◽

Medium Chain ◽

Chain Acyl

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Next generation sequencing as a follow-up test in an expanded newborn screening programme

Clinical Biochemistry ◽

10.1016/j.clinbiochem.2017.10.016 ◽

2018 ◽

Vol 52 ◽

pp. 48-55 ◽

Cited By ~ 7

Author(s):

Andraz Smon ◽

Barbka Repic Lampret ◽

Urh Groselj ◽

Mojca Zerjav Tansek ◽

Jernej Kovac ◽

...

Keyword(s):

Next Generation Sequencing ◽

Newborn Screening ◽

Screening Programme ◽

Next Generation ◽

Newborn Screening Programme ◽

Expanded Newborn Screening ◽

Generation Sequencing

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Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

Frontiers in Genetics ◽

10.3389/fgene.2021.648493 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ziga I. Remec ◽

Urh Groselj ◽

Ana Drole Torkar ◽

Mojca Zerjav Tansek ◽

Vanja Cuk ◽

...

Keyword(s):

Enzyme Activity ◽

Pilot Study ◽

Genetic Analysis ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Screening Program ◽

Dried Blood Spots ◽

Expanded Newborn Screening ◽

Chain Acyl ◽

Long Chain

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.

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Reflection on the Expanded Newborn Screening Programme in Saudi Arabia: Incidence of Screened Disorders

Journal of Paediatrics and Child Health ◽

10.1111/jpc.13669 ◽

2017 ◽

Vol 53 (10) ◽

pp. 1034-1035 ◽

Cited By ~ 1

Author(s):

Sarar Mohamed

Keyword(s):

Saudi Arabia ◽

Newborn Screening ◽

Screening Programme ◽

Newborn Screening Programme ◽

Expanded Newborn Screening

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Diagnostic potential of stored dried blood spots for inborn errors of metabolism: a metabolic autopsy of medium-chain acyl-CoA dehydrogenase deficiency

Journal of Clinical Pathology ◽

10.1136/jclinpath-2017-204962 ◽

2018 ◽

Vol 71 (10) ◽

pp. 885-889 ◽

Cited By ~ 4

Author(s):

Noriyuki Kaku ◽

Kenji Ihara ◽

Yuichiro Hirata ◽

Kenji Yamada ◽

Sooyoung Lee ◽

...

Keyword(s):

Newborn Screening ◽

Inborn Errors Of Metabolism ◽

Dried Blood Spots ◽

Screening Tests ◽

Inborn Errors ◽

Mcad Deficiency ◽

Medium Chain ◽

Blood Spots ◽

Chain Acyl ◽

Biochemical Analyses

AimIt is estimated that 1–5% of sudden infant death syndrome (SIDS) cases might be caused by undiagnosed inborn errors of metabolism (IEMs); however, the postmortem identification of IEMs remains difficult. This study aimed to evaluate the usefulness of dried blood spots (DBSs) stored after newborn screening tests as a metabolic autopsy to determine the causes of death in infants and children who died suddenly and unexpectedly.MethodsInfants or toddlers who had suddenly died without a definite diagnosis between July 2008 and December 2012 at Kyushu University Hospital in Japan were enrolled in this study. Their Guthrie cards, which had been stored for several years at 4–8°C, were used for an acylcarnitine analysis by tandem mass spectrometry to identify inborn errors of metabolism.ResultsFifteen infants and children who died at less than 2 years of age and for whom the cause of death was unknown were enrolled for the study. After correcting the C0 and C8 values assuming the hydrolysation of acylcarnitine in the stored DBSs, the corrected C8 value of one case just exceeded the cut-off level for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency screening. Genetic and biochemical analyses confirmed this patient to have MCAD deficiency.ConclusionDBSs stored after newborn screening tests are a promising tool for metabolic autopsy. The appropriate compensation of acylcarnitine data and subsequent genetic and biochemical analyses are essential for the postmortem diagnosis of inborn errors of metabolism.

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Medium-Chain Acyl-CoA Deficiency: Outlines from Newborn Screening,In SilicoPredictions, and Molecular Studies

The Scientific World JOURNAL ◽

10.1155/2013/625824 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Serena Catarzi ◽

Anna Caciotti ◽

Janita Thusberg ◽

Rodolfo Tonin ◽

Sabrina Malvagia ◽

...

Keyword(s):

Newborn Screening ◽

Molecular Analysis ◽

Acid Oxidation ◽

Missense Mutations ◽

Screening Programs ◽

Medium Chain ◽

Expanded Newborn Screening ◽

Chain Acyl ◽

Liquid Chromatography Tandem Mass ◽

Rising Incidence

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disorder of fatty acid oxidation characterized by hypoglycemic crisis under fasting or during stress conditions, leading to lethargy, seizures, brain damage, or even death. Biochemical acylcarnitines data obtained through newborn screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were confirmed by molecular analysis of the medium-chain acyl-CoA dehydrogenase (ACADM) gene. Out of 324.000 newborns screened, we identified 14 MCADD patients, in whom, by molecular analysis, we found a new nonsense c.823G>T (p.Gly275*) and two new missense mutations: c.253G>C (p.Gly85Arg) and c.356T>A (p.Val119Asp). Bioinformatics predictions based on both phylogenetic conservation and functional/structural software were used to characterize the new identified variants. Our findings confirm the rising incidence of MCADD whose existence is increasingly recognized due to the efficacy of an expanded newborn screening panel by LC-MS/MS making possible early specific therapies that can prevent possible crises in at-risk infants. We noticed that the “common” p.Lys329Glu mutation only accounted for 32% of the defective alleles, while, in clinically diagnosed patients, this mutation accounted for 90% of defective alleles. Unclassified variants (UVs or VUSs) are especially critical when considering screening programs. The functional and pathogenic characterization of genetic variants presented here is required to predict their medical consequences in newborns.

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