Neurological and Neuroimaging Features of CYB5R3-Related Recessive Hereditary Methemoglobinemia Type II

Abstract

Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase deficiency is a rare disease caused by pathogenic variants in CYB5R3. Unlike type I, in RHM type II (RHM2), the enzymatic defect affects erythrocytes and all body tissues, thus resulting in cyanosis and neurological impairment. Although the first description of RHM2 dates back to the mid-1950s, detailed clinical and neuroimaging information are available for only a few patients. Here, we describe a new patient with RHM2 that harbors an unreported homozygous 31 Kb deletion involving part of CYB5R3, and showing a peculiar neuroimaging pattern resembling a ponto-cerebellar hypoplasia-like condition. A careful review of the available literature was performed with the aim of better delineating neurological and neuroimaging as well as the genotypic spectra of this extremely rare disease.

Familial Psychomotor Delay of an Uncommon Cause: Type II Congenital Methemoglobinemia

“…In contrast with detailed biochemical or genetic studies, the clinical features and long-term outcomes of patients are poorly documented. 8 The neurological phenotype is consistent with a severe neurodevelopmental disorder characterized by global developmental delay; congenital or acquired microcephaly; tetraparesis; spasticity; movement disorders (choreoathetosis and dystonia), and drug-resistant epilepsy in a smaller percentage of patients (16%). Life expectancy usually does not exceed 10 years.…”

“…Methemoglobinemia is due to a lack of reduction of methemoglobin to hemoglobin that is catalyzed by the enzyme cytochrome B 5 reductase 3, known as methemoglobin reductase. 8 , 9 There are 2 main systems: NADH-dependent methemoglobin reductase type I or diaphorase, which is the main system for converting methemoglobin to hemoglobin and ensures the stability of its levels in the body. The other is NADPH-dependent methemoglobin II, which does not play a physiological role but becomes functional in the presence of oxidizable compounds such as methylene blue, demonstrating its effectiveness in the treatment of methemoglobinemia.…”

“…Some of the agents responsible are not toxic in vitro, but become toxic in vivo through the formation of an oxidizing metabolite: this is the case of nitrates reduced to nitrite by intestinal microbial flora. 4 - 14 …”

“…Survival appears to depend on 2 factors: swallowing function, determining the risk of respiratory infections and failure to thrive; and medical, paramedical, and familial management. 8 , 9 …”

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

“…To date, approximately 70 different mutations in CYB5R3 have been identified that give rise to both type I and type II RCM [Gupta et al, 2020]. RCM type I seems associated with missense variants causing a production of an unstable enzyme purely in the red blood cells, increasing erythrocytic methemoglobin levels, limiting oxygen fixation and delivery to all the tissues; whereas RCM type II seems to be associated with nonsense, frameshift and splice-site mutations that lead to a truncated protein with low expression of the enzyme in all tissues and disruption of all metabolic processes involving CYB5R3, such as fatty acid desaturation and elongation and cholesterol biosynthesis, which are important for normal brain development [Kobayashi et al, 1990;Maran et al, 2005;Gupta et al, 2020;Nicita et al, 2022].…”