Congenital Recessive Methemoglobinemia Revealed in Adulthood: Description of a New Mutation in Cytochrome b5 Reductase Gene

Abstract

Methemoglobinemia can be acquired (oxidizing drugs or chemicals products) or inherited either by mutations affecting globin chains [M hemoglobins (M Hbs)] or by defects in the enzymatic system involved in the reduction of spontaneous Hb oxidation: nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. It is encoded by the CYB5R3 gene: there are two phenotypes of autosomal recessive congenital methemoglobinemia, in type II CYB5R deficiency is generalized and affects all cells, leading to an early onset, whereas in type I, the enzyme deficiency is restricted to erythrocytes, usually discovered in infancy but not exclusively. We report a new case of methemoglobinemia discovered in a patient from Bahrain who exhibited an unknown dyspnea at the age of 37 years without trigger events or oxidizing products. We discovered a new mutation in the CYB5R3 gene: exon 9, codon 266 (delGAG) (GLU) (CYB5R3: c.726_729delGAG) in the homozygous state. Appearance of methemoglobinemia in an adult usually suggests an acquired cause but our case illustrated that it could also reveal a type I mutation of cytochrome b5 reductase.

Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs

“…Based upon owner completed QOL questionnaires, clinical signs were variable and generally mild including decreased activity and exercise tolerance, and occasionally exertional syncope. These clinical manifestations are similar to previous case reports in dogs [6][7][8][9][10] as well as humans with CYB5R deficiency 19,22,25,[27][28][29][30][31][32] .…”

Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I

“…Previously described mutations in this region affected two residues only: Arg160 and Ala179. Of those, only p.Arg160X combined with p.Gln77X results in methemoglobinemia type II, and this phenotype can be related to very low catalytic activity or to a loss of protein expression of both mutated protein chains [18,19]. Other mutations in exon 6, homozygous or compound heterozygous with the mutations outside exon 6, cause RCM type I.…”

Fast hyperbaric decompression after heliox saturation altered the brain proteome in rats

“…Furthermore, the mitochondrial fission 1 protein which might induce cytochrome c release from mitochondria ultimately leading to apoptosis was upregulated. NADH-cytochrome b5 reductase 3 was downregulated in rats exposed to fast decompression, and defects in this protein has been associated with methemoglobinemia and tissue hypoxia [ 33 ].…”