Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum

Abstract

Type II recessive hereditary methaemoglobinaemia (RHM) is a rare disease due to generalized NADH-cytochrome b5 reductase (cytb5r) deficiency. It results in mild cyanosis and severe neurological impairment. The clinical features and long-term outcome are poorly documented, and there are no systematic reviews. We examined six cases of type II RHM, four of which were new, together with 45 previously published cases, in order to establish the range of phenotypic expression. The clinical picture was very similar in most cases, with severe encephalopathy, microcephaly, generalized dystonia, movement disorders and mild cyanosis. The neurological prognosis was poor; in particular, none of the patients walked or spoke. In addition, the possibility of an atypical and milder phenotype was considered. We concluded that children with unexplained severe encephalopathy associated with generalized dystonia should be examined for cyanosis and have a methaemoglobinaemia assay performed. The diagnosis can be confirmed by very low cytb5r activity in both red and white blood cells. Here we report three novel mutations in the NADH-cytochrome b5 reductase gene. Prenatal diagnosis of this extremely severe disease should be proposed to affected families.

Structure Guided Chemical Modifications of Propylthiouracil Reveal Novel Small Molecule Inhibitors of Cytochrome b5 Reductase 3 That Increase Nitric Oxide Bioavailability

“…In the human population, genetic mutations leading to deficient CYB5R3 activity causes recessive hereditary methemoglobinemia (7). Type I methemoglobinemia only affects erythrocytes, causing increased levels of methemoglobin in these cells (7), whereas Type II methemoglobinemia affects all somatic cells causing severe developmental neurological disorders (8). Recent evidence suggests that membrane-bound CYB5R3 expression and activity also contributes to metabolic homeostasis (9), stress protection (9), and nitric oxide (NO) bioavailability (10).…”

Biochemical and anatomical basis of brain dysfunctions caused by cytochrome b5 reductase deficiency or dysregulation

“…More than 50% of the mutations of the Cb 5 R reported in humans produce recessive congenital methemoglobinemia of type II, an inherited disease characterized by mild cyanosis, developmental delay, severe neurological impairment and reduced life expectancy [20][21][22][23] . In erythrocytes, methemoglobin is kept by two systems at levels below 1% of total hemoglobin 24 .…”

“…This pathway only affords in vivo a minor contribution to the reduction of methemoglobin, because its malfunction do not cause a methemoglobin reduction-deficient phenotype 24,25 . Clinical neurological dysfunctions of the humans affected by recessive congenital methemoglobinemia of type II include progressive microcephaly, generalized dystonia, movement disorders, failure to thrive, and cortical and subcortical atrophy [20][21][22][23] , including cerebellar atrophy 26 .…”

Characterization of a Novel Mutation in the NADH-Cytochrome b5 Reductase Gene Responsible for Rare Hereditary Methaemoglobinaemia Type I

“…In RCM type I, the cb5r deficiency is limited to erythrocytes, and cyanosis is the only clinical symptom. In RCM type II, cyanosis is associated with severe neurological impairment, because the cb5r deficiency is generalized to all tissues [2]. In general, mutations resulting in the synthesis of unstable cb5r lead to type I methaemoglobinaemia, while mutations associated with severe loss of enzyme activity are often linked to RCM type II.…”