CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn

Herranz, David Molina; Escudero, Carmelo; Gracia, Segundo Rite; Red, Yurena Aguilar de la; Nieto, Jorge M.; Álvarez, Silvia Izquierdo; Gracia, M A Montañés; Recasens, Valle; Mata, C. F. Hernandez

doi:10.1016/j.clinbiochem.2022.01.008

Cited by 2 publications

(3 citation statements)

References 13 publications

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“…For the cases presented, diagnosis of sodium nitrite toxicity was based on a wide variety of information obtained from the decedent history, death scene, autopsy, toxicology, and biochemistry findings, often in the absence of a definitive, quantitative diagnostic test. While there are several other possible causes of methemoglobinemia, both congenital and acquired (including recessive congenital methemoglobinemia [43], mothball intoxication [44] and dapsone overdose [45], and several other substances [46]), all death investigations demonstrated evidence of sodium nitrite ingestion. Furthermore, use of the urinalysis dipstick for presumptive nitrite detection was applied in the latter eight cases, which all returned a positive result, raising suspicion of potential sodium nitrite toxicity and prompted further investigations.…”

Section: Discussionmentioning

confidence: 99%

Increasing use of sodium nitrite in suicides—an emerging trend

Stephenson

Wills

Heuvel

et al. 2022

Forensic Sci Med Pathol

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Sodium nitrite (NaNO2) is a compound with broad practical applications in food preservation, automotive maintenance, and animal control. Sodium nitrite is also potentially fatal when ingested, as it interferes with the ability of red blood cells to transport oxygen. While incidents of accidental consumption have been reported in the literature, case reports of sodium nitrite being used as a pharmacological suicide agent are becoming more frequent. Therefore, a study was undertaken to evaluate trends in sodium nitrite deaths in South Australia between 2000 and 2019. All cases of fatal sodium nitrite ingestion were identified in the Toxicology database and autopsy reports at Forensic Science SA (FSSA). Ten cases of fatal sodium nitrite ingestion were identified, with the rate of cases increasing significantly over the study period (p > .001). Of the ten deaths attributed to sodium nitrite toxicity, eight were male, and two were female. The age range of decedents was 22–74 years (mean 51.9, SD 21.1), 22–74 years for males (mean 58.4, SD 18.2) and 23–29 years for females (mean 26.0, SD 4.2). Males (80%) and those with a history of depression and/or suicidal ideation (70%) were over-represented within the study population. While autopsy findings were generally consistent with the literature, scene findings emphasized the accessibility of sodium nitrite to the general public. This study highlights both a significant increasing trend in the use of sodium nitrite in suicides and important analytical limitations in the evaluation of suspected cases.

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Section: Discussionmentioning

confidence: 99%

Increasing use of sodium nitrite in suicides—an emerging trend

Stephenson

Wills

Heuvel

et al. 2022

Forensic Sci Med Pathol

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“…The crystal water particle was removed and the 3D structure was subjected to loop modeling in order to correct the missing residues, followed by energy minimization with the MMFF94s force field implemented in molecular operating environment (MOE). The mutation was induced in the structure using the mutagenesis tool implemented in PyMol software [ 2 ]. The structure of heme was retrieved from PubChem database, and subjected to optimization using DFT/B3LYP/3-21G framework implemented in Gaussian 09 software package [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

“…Under normal conditions, the CYB5R3 enzyme in erythrocytes converts the methemoglobin to its ferrous state (Fe ++ ); however, due to genetic mutations in the CYB5R3 gene, it cannot be converted back into ferrous state (Fe ++ ) from ferric (Fe +++ ) state, resulting in methemoglobinemia. Furthermore, in this medical condition, the methemoglobin level is greater than 1% and ferrous iron (Fe ++ ) is oxidized to the ferric state (Fe +++ ), culminating in tissue hypoxia [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

et al. 2023

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Background and Objective: Mutations in the CYB5R3 gene cause reduced NADH-dependent cytochrome b5 reductase enzyme function and consequently lead to recessive congenital methemoglobinemia (RCM). RCM exists as RCM type I (RCM1) and RCM type II (RCM2). RCM1 leads to higher methemoglobin levels causing only cyanosis, while in RCM2, neurological complications are also present along with cyanosis. Materials and Methods: In the current study, a consanguineous Pakistani family with three individuals showing clinical manifestations of cyanosis, chest pain radiating to the left arm, dyspnea, orthopnea, and hemoptysis was studied. Following clinical assessment, a search for the causative gene was performed using whole exome sequencing (WES) and Sanger sequencing. Various variant effect prediction tools and ACMG criteria were applied to interpret the pathogenicity of the prioritized variants. Molecular dynamic simulation studies of wild and mutant systems were performed to determine the stability of the mutant CYB5R3 protein. Results: Data analysis of WES revealed a novel homozygous missense variant NM_001171660.2: c.670A > T: NP_001165131.1: p.(Ile224Phe) in exon 8 of the CYB5R3 gene located on chromosome 22q13.2. Sanger sequencing validated the segregation of the identified variant with the disease phenotype within the family. Bioinformatics prediction tools and ACMG guidelines predicted the identified variant p.(Ile224Phe) as disease-causing and likely pathogenic, respectively. Molecular dynamics study revealed that the variant p.(Ile224Phe) in the CYB5R3 resides in the NADH domain of the protein, the aberrant function of which is detrimental. Conclusions: The present study expanded the variant spectrum of the CYB5R3 gene. This will facilitate genetic counselling of the same and other similar families carrying mutations in the CYB5R3 gene.

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CYB5R3 homozygous pathogenic variant as a rare cause of cyanosis in the newborn

Cited by 2 publications

References 13 publications

Increasing use of sodium nitrite in suicides—an emerging trend

Increasing use of sodium nitrite in suicides—an emerging trend

Molecular Dynamic Simulation Analysis of a Novel Missense Variant in CYB5R3 Gene in Patients with Methemoglobinemia

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