Severe mental retardation and recessive congenital methemoglobinemia in three Indian patients: Compound heterozygous for NADH‐cytochrome b5 reductase gene mutations

Abstract

The diagnosis of Type II congenital methemoglobinemia has been established in three Indian patients in a single family based on persistent cyanosis and neurological manifestations with severe enzyme deficiency in erythrocytes. Clinical evaluation showed very severe encephalopathy, microcephaly, generalized dystonia, and mild cyanosis. Molecular studies demonstrated compound heterozygosity for two mutations in the reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) gene. One was a novel mutation 705G→A, which leads to the substitution of a Trp by a stop codon at residue 235 within exon 8 and the other was a previously reported missense mutation 608G→A leading to a replacement of Cys-203 (TGC) by Try (TAC) in exon 7. Although both amino acid substitutions are located in the NADH-binding domain, the whole protein structure, especially the region between the flavin adenine dinucleotide and NADH-binding domains, is disturbed. The presence of a premature stop codon results in the production of truncated b5R and should explain the severe enzyme deficiency seen in these cases.