Severe phenotype of an Iranian patient with methemoglobinemia type II due to a novel mutation in the CYB5R3 gene

Methemoglobinemia is a rare autosomal recessive genetic disease caused by disruptive mutations in the CYB5R3 gene (MIM: 250800). Herein, a novel mutation is reported in an Iranian patient affected with methemoglobinemia type II. In this case study, the patient is precisely described according to the thoroughly carried-out examinations and workups. In so doing, the peripheral blood sample was collected to evaluate the methemoglobin level and NADH-CYB5R3 activity test. Moreover, whole-exome sequencing (WES) was recruited to identify the mutation leading to this disorder. Subsequently, Sanger sequencing was employed to confirm the detected mutation. Magnetic Resonance Imaging was also performed to explore the structure of the brain. As identified by the blood test, the methemoglobin level increased up to 25%, and the NADH-CYB5R3 enzyme activity showed to be 13.8 IU/g of Hb. A novel homozygous mutation in CYB5R3 (NM_001171661: g.23435C>T, c.181C>T, p.R61X, rs1210302322) was identified as the cause of the Methemoglobinemia type II in the proband. This nonsense mutation alters arginine to the stop codon at position 61 of protein in the FAD-binding domain that results in a truncated protein. The MRI revealed brain atrophy and corpus calusom hypoplasticity. It was established that this variation can lead to Methemoglobinemia. The proband demonstrates Methemoglobinemia type II phenotype such as cyanosis, severe mental retardation, microcephaly, as well as developmental delay. The brain MRI revealed brain atrophy and corpus calusom hypoplasticity.The cyanosis symptom is managed by daily ascorbic acid uptake.