Congenital methaemoglobinaemia Type I in a Turkish infant due to a novel mutation, Pro144Ser, in NADH-cytochrome b5 reductase

Abstract

A baby centrally cyanosed from birth was investigated for a congenital cardiac defect. Echocardiography and angiography revealed patent foramen ovale without any other cardiac abnormality. Congenital methaemoglobinaemia was considered as the methaemoglobin level was 27%, suggesting either Hb M or a deficiency of the NADH-cytochrome b5 reductase (cytb5r) enzyme. Measurement of the cytb5r enzyme activity of this patient indicated a reduced level of 7.3 IU/g Hb (normal range 11.5-26.9 IU/g Hb). Sequencing the DIA 1 gene that encodes cytb5r revealed a novel C403T base change, predicting a proline to serine change at codon 144. This amino-acid change is not located in the enzyme's active site and does not cause loss of function. Instead it results in reduced stability of the enzyme and development of the less severe or Type I form of recessive congenital methaemoglobinaemia. The infant was started on daily ascorbic acid treatment. She has very mild cyanosis and normal growth and developmental parameters on follow-up at 10 months of age.

Recessive congenital methaemoglobinaemia: cytochrome b5 reductase deficiency

“…To delineate the cause of the central cyanosis it is important to eliminate haemoglobin variants, such as the M group of haemoglobins. These variants cause structural alteration of the haem pocket due to amino acid substitution at the proximal or distal histidine of either the alpha or beta globin chain (Percy et al , 2004). This can lead to spontaneous oxidation of the Fe 2+ ion embedded in the haem resulting in methaemoglobinaemia.…”

Identification of High-Risk Single Nucleotide Polymorphisms in the Human CYB5R3 Gene Responsible for Recessive Congenital Methemoglobinemia: A Computational Approach

“…None of them are located in the enzyme's active site, and therefore they do not affect the protein function. Instead, they lead to an unstable enzyme [Davis et al, 2004;Percy et al, 2004;Kedar et al, 2008;Warang et al, 2015].…”

Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia

“…Bold and Green, mutation identified previously but specifically found in prenatal screening in this study. CYB5R, cytochrome b5 reductase; RCM, recessive congenital methemoglobinemia Kugler et al (2001) c.382T>C p.Ser128Pro II FAD Kobayashi et al (1990) c.431G>A p.Gly144Asp I FAD Kedar, Warang, Nadkarni, Colah, and Ghosh (2008) c.434C>T p.Pro145Leu I Hinge region Dekker et al (2001) c.433C>T p.Pro145Ser I Hinge region Percy, Oren, Savage, and Irken (2004) c.446T>C p.Leu149Pro III FAD Katsube et al (1991) c.464G>A p.Gly155Glu I Hinge region Warang et al (2015a) c.470T>G p.Phe157Cys I Hinge region Lorenzo et al (2011) c.479G>C p.Arg160Pro I Hinge region Warang et al (2015a) c.478C>T p.Arg160X II Hinge region Aalfs et al (2000) c.514G>C p.Val172Leu I NAD Rawa et al (2013)…”