Genotype and residual enzyme activity in medium‐chain <scp>acyl‐CoA</scp> dehydrogenase (<scp>MCAD</scp>) deficiency: Are predictions possible?

Tucci, Sara; Wagner, Christine; Grünert, Sarah C.; Matysiak, Uta; Weinhold, Natalie; Klein, Jeannette; Porta, Francesco; Spada, Marco; Bordugo, Andrea; Rodella, Giulia; Furlan, Francesca; Sajeva, Anna; Menni, Francesca; Spiekerkoetter, Ute

doi:10.1002/jimd.12368

Cited by 8 publications

(9 citation statements)

References 32 publications

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“…Consequently, patients diagnosed within the screening generally show a lower proportion (30–71%) of that common variant 27,61 . In addition, a good correlation between genotype and enzyme function has recently been demonstrated 62 …”

Section: Discussionmentioning

confidence: 99%

“…27,61 In addition, a good correlation between genotype and enzyme function has recently been demonstrated. 62 In conclusion, in 9 years, 222 IEM have been detected with a large clinical, biochemical, and molecular heterogeneity. Most of the cases benefited from presymptomatic diagnosis but with quite notable differences among the different disorders and 27 novel variants have been reported.…”

Section: Conflict Of Interestmentioning

confidence: 95%

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Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region

et al. 2022

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We present the results of our experience in the diagnosis of inborn errors of metabolism (IEM) since the Expanded Newborn Screening was implemented in our Region. Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by mass spectrometry (MS)/MS. Newborns with alterations were referred to the clinical centers for follow-up.Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011 to 2019, 592 822 children were screened: 902 of them were referred for abnormal results. An IEM was confirmed in 222 (1/2670): aminoacidopathies: 89 hyperphenylalaninemia (HPA) (51 benign HPA, 32 phenylketonuria, 4 DNAJC12 defect, and 2 primapterinuria), 6 hypermethioninemia, 3 tyrosinemia type 1 (TYR-1), 1 TYR-3, 4 maple syrup urine disease (MSUD), 2 branched-chain amino acid transferase 2 deficiency, 2 homocystinuria, 1 cystinuria, 2 ornithine transcarbamylase (OTC) deficiency, 2 citrullinemia type I (CTLN1); FAO defects: 43 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 13 very long-chain acyl-CoA dehydrogenase deficiency, 2 long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), 1 multiple acyl-coA dehydrogenation deficiency, 11 systemic primary carnitine deficiency, 2 carnitine palmitoyltransferase type 2 (CPT-II) deficiency, 1 CPT-I deficiency; organic acidurias: 12 glutaric aciduria type 1 (GA-1), 4 methylmalonic acidemia (MMA), 7 MMA including combined cases with homocystinuria (MMAHC), 6 propionic acidemia (PA), 7 3-methylcrotonyl-CoA carboxylase, 1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency lyase deficiency. Only 19 infants (8.5%) were symptomatic at

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Section: Discussionmentioning

confidence: 99%

Section: Conflict Of Interestmentioning

confidence: 95%

Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region

et al. 2022

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“…All variants but one (c.626C > T) were previously described [ 16 , 22 ], although the pathogenity of some of them was not previously proven by functional studies. The nucleotide change c.626C > T is likely a missense mutation (p.Pro209Leu) and was classified as a VUS in ClinVar according to the AGMD rules and by the Varsome platform [ 20 ] as well as c.346T > G.…”

Section: Resultsmentioning

confidence: 99%

“…However, it remains often difficult to evaluate at which level of residual enzyme function there is a risk of a metabolic derangement. Despite the diagnosis, the clinical relevance of mild MCADD remains uncertain [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Medium-Chain Acyl-CoA Dehydrogenase Activity and Its Potential as a Diagnostic Confirmation Tool in Newborn Screening Cases

Alcaide

Ferrer-López

Gutierrez

et al. 2022

JCM

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The determination of acylcarnitines (AC) in dried blood spots (DBS) by tandem mass spectrometry in newborn screening (NBS) programs has enabled medium-chain acyl-coA dehydrogenase deficiency (MCADD) to be identified in presymptomatic newborns. Nevertheless, different confirmatory tests must be performed to confirm the diagnosis. In this work, we have collected and analyzed the NBS results and confirmatory test results (plasma AC, molecular findings, and lymphocyte MCAD activity) of forty individuals, correlating them with clinical outcomes and treatment, with the aim of obtaining useful diagnostic information that could be applied in the follow-up of the patients. Our results led us to classify patients into two groups. The first group (14 cases) had high increased octanoylcarnitine (C8) levels, biallelic pathogenic variants, and severe impaired enzyme activity (<10% of the intra-assay control (IAC)); all of these cases received nutritional therapy and required carnitine supplementation during follow-up, representing the most severe form of the disease. The second group (16 patients) was a heterogeneous group presenting moderate increases in C8, biallelic likely pathogenic/pathogenic variants, and intermediate activity (<41% IAC). All of them are currently asymptomatic and could be considered as having a milder form of the disease. Finally, eight cases presented a normal–mild increase in plasma C8, with only one pathogenic variant detected, and high–intermediate residual activity (15–100%). Based on our results, we confirm that combined evaluation of acylcarnitine profiles, genetic findings, and residual enzyme activities proves useful in predicting the risk of future metabolic decompensation, in making decisions regarding future treatment or follow-up, and also in confirming the clinical effects of unknown clinical variants.

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“…The ACADS protein is a flavoenzyme that is involved in fatty acid catabolism in the mitochondria [22]. A deficiency in ACADS production can inhibit some fats from being converted to energy [23].…”

Section: Plos Onementioning

confidence: 99%

Toward a methodology for evaluating DNA variants in nuclear families

2021

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The genetic underpinnings of most pediatric-cancer cases are unknown. Population-based studies use large sample sizes but have accounted for only a small proportion of the estimated heritability of pediatric cancers. Pedigree-based studies are infeasible for most human populations. One alternative is to collect genetic data from a single nuclear family and use inheritance patterns within the family to filter candidate variants. This approach can be applied to common and rare variants, including those that are private to a given family or to an affected individual. We evaluated this approach using genetic data from three nuclear families with 5, 4, and 7 children, respectively. Only one child in each nuclear family had been diagnosed with cancer, and neither parent had been affected. Diagnoses for the affected children were benign low-grade astrocytoma, Wilms tumor (stage 2), and Burkitt’s lymphoma, respectively. We used whole-genome sequencing to profile normal cells from each family member and a linked-read technology for genomic phasing. For initial variant filtering, we used global minor allele frequencies, deleteriousness scores, and functional-impact annotations. Next, we used genetic variation in the unaffected siblings as a guide to filter the remaining variants. As a way to evaluate our ability to detect variant(s) that may be relevant to disease status, the corresponding author blinded the primary author to affected status; the primary author then assigned a risk score to each child. Based on this evidence, the primary author predicted which child had been affected in each family. The primary author’s prediction was correct for the child who had been diagnosed with a Wilms tumor; the child with Burkitt’s lymphoma had the second-highest risk score among the seven children in that family. This study demonstrates a methodology for filtering and evaluating candidate genomic variants and genes within nuclear families that may merit further exploration.

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Genotype and residual enzyme activity in medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency: Are predictions possible?

Cited by 8 publications

References 32 publications

Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region

Diagnosis of inborn errors of metabolism within the expanded newborn screening in the Madrid region

Lymphocyte Medium-Chain Acyl-CoA Dehydrogenase Activity and Its Potential as a Diagnostic Confirmation Tool in Newborn Screening Cases

Toward a methodology for evaluating DNA variants in nuclear families

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