Prevalence of the most common pathogenic variants in three genes for inborn errors of metabolism associated with sudden unexpected death in infancy: a population-based study in south Brazil

Randon, Dévora Natalia; Sperb‐Ludwig, Fernanda; Vianna, Fernanda S.L.; Becker, Ana Paula Pizzio; Vargas, Carmen Regla; Sitta, Ângela; Sant'Ana, Alexia Nedel; Schwartz, Ida Vanessa Döederlein; Bitencourt, Fernanda Hendges de

doi:10.1590/1678-4685-gmb-2019-0298

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…Rio Grande do Sul was largely colonized by Azoreans, Germans, and Italians, and its capital, Porto Alegre, was an important historical center of Azorean immigration [21,22] . In the sample included in the study, 63.9% of the individuals claimed to have European ancestry, with two of the three heterozygous individuals reporting German ancestry [16] . This finding is consistent with literature showing that approximately 77% of the population in Southern Brazil has European ancestry as a result of the aforementioned colonization patterns [19,20] .…”

Section: Discussionmentioning

confidence: 99%

“…The characteristics of the study population, with a mean age of 36.6 ± 12.1 years (range, 19 to 69 years), are shown in Table 1. [16] The dataset is available upon request.…”

Section: Methodsmentioning

confidence: 99%

“…There are 497 municipalities in the state, and Porto Alegre is the main city (13% of inhabitants of this state live in Porto Alegre) [15] . The characteristics of the study population, with a mean age of 36.6 ± 12.1 years (range, 19 to 69 years), are shown in Table 1 [16] . The dataset is available upon request.…”

Section: Methodsmentioning

confidence: 99%

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Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Santos

Randon

Bitencourt

et al. 2022

Reproductive and Developmental Medicine

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Objectives: To investigate the prevalence of ACADM pathogenic variants, c.985A>G and c.199T>C, for medium chain acyl CoA dehydrogenase deficiency (MCADD) in a healthy population in the southern region of Brazil.Methods: This was an observational cross-sectional study with a convenience sampling strategy. The participants were recruited from the blood bank of the Hospital de Clínicas of Porto Alegre, Brazil. A total of 1000 healthy individuals from the state of Rio Grande do Sul were included. Genotyping for the c.199T>C and c.985A>G variants was performed using real-time polymerase chain reaction (PCR) and the PCR-restriction fragment length polymorphism (RFLP) technique, respectively. Individuals considered heterozygous for c.985A>G were subjected to additional acylcarnitine profile analysis using tandem mass spectrometry. Carrier frequency was obtained by calculating the ratio of heterozygous individuals to the total number of individuals analyzed and reported with a 95% confidence interval. Allele and genotype frequencies were calculated based on the Hardy-Weinberg equilibrium.Results: The c.985A>G variant was detected as heterozygotes in three individuals (frequency of the heterozygous genotype = 1:333, allele frequency = 0.0015, minimum frequency of MCADD = 1:444,444) whose acylcarnitine profiles were within normal limits. The c.199T>C variant was not identified.Conclusions: Considering the small sample size and associated allelic heterogeneity with MCADD, these findings are believed to denote the rarity or underdiagnosis of MCADD in southern Brazil. This study provides evidence for the need for further investigation to ascertain the contribution of these diseases to child morbidity and mortality in the country.

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Section: Discussionmentioning

confidence: 99%

“…The characteristics of the study population, with a mean age of 36.6 ± 12.1 years (range, 19 to 69 years), are shown in Table 1. [16] The dataset is available upon request.…”

Section: Methodsmentioning

confidence: 99%

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Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Santos

Randon

Bitencourt

et al. 2022

Reproductive and Developmental Medicine

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“…However, in isolated MMA, mutation of the MUT gene is the most common, and the most common mutation in China is c.729_730insTT (p.D244LfsX39), accounting for 16.5% of cases ( Han et al, 2015 ). The most common mutations in Brazil and Spain are c.655A>T (p.N219Y) and 322C>T (p.R108C), respectively ( Worgan et al, 2006 ; Randon et al, 2020 ).…”

Section: Diagnosis Of Mmamentioning

confidence: 99%

Methylmalonic acidemia: Neurodevelopment and neuroimaging

et al. 2023

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Methylmalonic acidemia (MMA) is a genetic disease of abnormal organic acid metabolism, which is one of the important factors affecting the survival rate and quality of life of newborns or infants. Early detection and diagnosis are particularly important. The diagnosis of MMA mainly depends on clinical symptoms, newborn screening, biochemical detection, gene sequencing and neuroimaging diagnosis. The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction. Neuroimaging examination has important clinical significance in the diagnosis and prognosis of MMA. This review mainly reviews the etiology, pathogenesis, and nervous system development, especially the neuroimaging features of MMA.

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Improving the second-tier classification of methylmalonic acidemia patients using a machine learning ensemble method

Zhu,

Genchev,

Wang

et al. 2024

World J Pediatr

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Introduction Methylmalonic acidemia (MMA) is a disorder of autosomal recessive inheritance, with an estimated prevalence of 1:50,000. First-tier clinical diagnostic tests often return many false positives [five false positive (FP): one true positive (TP)]. In this work, our goal was to refine a classification model that can minimize the number of false positives, currently an unmet need in the upstream diagnostics of MMA. Methods We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction. We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients, followed by additional ratio feature construction. Feature selection strategies (selection by filter, recursive feature elimination, and learned vector quantization) were used to determine the input set for evaluating the performance of 14 classification models to identify a candidate model set for an ensemble model development. Results Our work identified computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity. The best results [area under the receiver operating characteristic curve (AUROC) of 97%, sensitivity of 92%, and specificity of 95%] were obtained utilizing an ensemble of the algorithms random forest, C5.0, sparse linear discriminant analysis, and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor. The model achieved a good performance trade-off for a screening application with 6% false-positive rate (FPR) at 95% sensitivity, 35% FPR at 99% sensitivity, and 39% FPR at 100% sensitivity. Conclusions The classification results and approach of this research can be utilized by clinicians globally, to improve the overall discovery of MMA in pediatric patients. The improved method, when adjusted to 100% precision, can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families. Graphical Abstract

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Prevalence of the most common pathogenic variants in three genes for inborn errors of metabolism associated with sudden unexpected death in infancy: a population-based study in south Brazil

Cited by 4 publications

References 25 publications

Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Medium-chain acyl-CoA dehydrogenase deficiency: prevalence of ACADM pathogenic variants c.985A>G and c.199T>C in a healthy population in Rio Grande do Sul, Brazil

Methylmalonic acidemia: Neurodevelopment and neuroimaging

Improving the second-tier classification of methylmalonic acidemia patients using a machine learning ensemble method

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