Methemoglobin Reductase Deficiency

Percy, Melanie J.; Barnes, Chris; Crighton, Gemma; Leventer, Richard J.; Wynn, Robert F.; Lappin, Terence

doi:10.1097/mph.0b013e318257a492

Cited by 10 publications

(15 citation statements)

References 17 publications

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“…In most cases, type I methemoglobinemia can be corrected with methylene blue or ascorbic acid and riboflavin, and patients with type I are expected to have a normal life expectancy 7,13 . Type II is a more severe form of methemoglobinemia that affects all cells, resulting in developmental defects, neurological disabilities, and early mortality 13,14 . Studies have shown different genetic polymorphisms linked to type I and type II methemoglobinemia 12–14 .…”

Section: Discussionmentioning

confidence: 99%

“…Type II is a more severe form of methemoglobinemia that affects all cells, resulting in developmental defects, neurological disabilities, and early mortality 13,14 . Studies have shown different genetic polymorphisms linked to type I and type II methemoglobinemia 12–14 . Recent studies have also found genetic polymorphisms associated with atypical type II disease phenotypes 14,16 .…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown different genetic polymorphisms linked to type I and type II methemoglobinemia 12–14 . Recent studies have also found genetic polymorphisms associated with atypical type II disease phenotypes 14,16 . Thus, investigation of common polymorphisms present in these genes was expected to provide information regarding MetHb levels.…”

Section: Discussionmentioning

confidence: 99%

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Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy

et al. 2014

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Background In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. Methods A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. Analysis of variance was performed to identify genetic associations with MetHb levels. Results An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (p=0.01). This result remained significant after adjustment for the iNO dose (p=0.009), gender (p=0.03), multiple gestation (p=0.03), birth weight (p=0.02), and gestational age (p=0.02). No significant associations were found with the other SNPs. Conclusion We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy

et al. 2014

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“…Further, the same mutation p.Gly76Ser was associated with a type I RHM patient [ 11 ] and a type II RHM patient [ 12 ], thereby suggesting that genetic, metabolic, or environmental factors could determine the phenotype of each type of RHM. In fact, an atypical intermediate phenotype between types I and II RHM was also reported for several patients with milder neurological symptoms [ 9 , 13 ]. Two of these patients showed a novel mutation replacing arginine by proline (p.Arg58Pro) in the presence of either p.Gly76Ser or p.Leu188del mutations associated with a more severe phenotype that type I but milder than type II RHM [ 13 ].…”

Section: Introductionmentioning

confidence: 93%

“…Truncating mutations leading to the loss of enzymatic activity have been associated with type II RHM, while the missense mutations have been associated with type I RHM, probably because these mutations only induce the instability and the decrease of its concentration in erythrocytes due to the lack of a nucleus [ 10 ]. However, there is no a pattern for distinguishing between both types of RHM [ 8 , 9 , 10 , 11 , 12 , 13 ]. For example, the mutation replacing cysteine-204 by tyrosine (p.Cys204Tyr) produced type I RHM, whereas the replacement of the same cysteine by arginine (p.Cys204Arg) resulted in type II RHM [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II

Siendones

Ballesteros

Navas

2018

JCM

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Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD+/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.

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