MCID: CNG223
MIFTS: 36

Congenital Methemoglobinemia

Categories: Blood diseases, Genetic diseases, Rare diseases

Aliases & Classifications for Congenital Methemoglobinemia

MalaCards integrated aliases for Congenital Methemoglobinemia:

Name: Congenital Methemoglobinemia 40 52 58 71
Hereditary Methemoglobinemia 52 58 6
Autosomal Recessive Methemoglobinemia 52 58
Methemoglobinemia Hereditary 54
Hemoglobin M Disease 71

Characteristics:

Orphanet epidemiological data:

58
hereditary methemoglobinemia
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal;

Classifications:

Orphanet: 58  
Rare haematological diseases


External Ids:

ICD10 via Orphanet 33 D74.0
UMLS via Orphanet 72 C0272087
Orphanet 58 ORPHA621
UMLS 71 C0272087 C3665425

Summaries for Congenital Methemoglobinemia

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 621 Definition A rare red cell disorder classified principally into two clinical phenotypes : autosomal recessive congenital (or hereditary) methemoglobinemia types I and II (RCM/RHM type 1; RCM/RHM type 2). Clinical description In RCM type 1, cyanosis from birth is the only symptom. It is well-tolerated and is associated with mild complaints of headaches, fatigue and shortness of breath upon exertion. RCM type 2 is much more severe; the cyanosis is accompanied by neurological dysfunction (with intellectual deficit, microcephaly , growth retardation, opisthotonus, strabismus and hypertonia), which usually becomes evident during the first four months of life. Two additional forms of RCM have also been reported. RCM type 3 was the term used to define a phenotype with cyanosis but without neurological abnormalities in which Cb5R deficiency was identified in leucocytes and platelets as well as erythrocytes . This distinction has been largely ignored in subsequent reports of other CYB5R3 variants, so the term RCM type 3 is rarely used. RCM type 4 is a very rare disease associated with chronic cyanosis caused by mutations in the CYB5A gene (18q23) encoding cytochrome b5. In addition, there have been two reports of NADPH reductase deficiency, but in one case (identified though an inability to metabolize methylene blue) methemoglobinemia was not present suggesting that this pathway has limited physiological importance. It is also possible that mutations of the substrate of NADPH reductase, which remains to be identified, could have a minor effect on the reduction of methemoglobin. Etiology RCM type 1 is caused by mutations of the CYB5R3 gene (22q13.31-qter) encoding the NADH-cytochrome b5 reductase (Cb5R) and Cb5R deficiency is limited to the erythrocytes. RCM type 2 is caused by global loss of Cb5R function. Over 40 different CYB5R3 mutations have been identified so far, some of which have been identified in both types. RCM type 1 is generally associated with missense mutations , whereas RCM type 2 is more commonly associated with truncating mutations, splicing errors or mutations that lead to disruption of the active site. Management and treatment Treatment of methemoglobinemia revolves around administration of methylene blue and/or ascorbic acid. Although ascorbic acid alone is sufficient to alleviate the cyanosis in milder cases, the reaction rate is slower than that of the combined treatment. However, these treatments have no effect on the neurological dysfunction in RCM type 2. Visit the Orphanet disease page for more resources.

MalaCards based summary : Congenital Methemoglobinemia, also known as hereditary methemoglobinemia, is related to hemoglobinopathy and methemoglobinemia. An important gene associated with Congenital Methemoglobinemia is CYB5R3 (Cytochrome B5 Reductase 3), and among its related pathways/superpathways is Methylene Blue Pathway, Pharmacodynamics. Affiliated tissues include brain, kidney and spleen, and related phenotypes are cyanosis and methemoglobinemia

Related Diseases for Congenital Methemoglobinemia

Diseases in the Methemoglobinemia family:

Methemoglobinemia, Beta Type Methemoglobinemia, Alpha Type
Congenital Methemoglobinemia Acquired Methemoglobinemia

Diseases related to Congenital Methemoglobinemia via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 41)
# Related Disease Score Top Affiliating Genes
1 hemoglobinopathy 29.3 G6PD CYB5R3
2 methemoglobinemia 29.2 SOD1 HBG2 G6PD CYB5R3 CYB5A
3 thalassemia 29.1 HBG2 G6PD
4 acquired methemoglobinemia 29.1 HBG2 G6PD CYB5R3
5 beta-thalassemia 28.9 HBG2 G6PD
6 methemoglobinemia due to deficiency of methemoglobin reductase 12.3
7 methemoglobinemia, beta-globin type 11.8
8 cyanosis, transient neonatal 10.6
9 methemoglobin reductase deficiency 10.3
10 autosomal recessive disease 10.1
11 microcephaly 10.1
12 methemoglobinemia and ambiguous genitalia 10.0
13 polycythemia vera 9.9
14 tricuspid atresia 9.9
15 leukodystrophy 9.9
16 patent foramen ovale 9.9
17 mitral valve stenosis 9.9
18 cerebral palsy 9.9
19 spondylosis 9.9
20 movement disease 9.9
21 dystonia 9.9
22 polycythemia 9.9
23 critical congenital heart disease 9.9
24 encephalopathy 9.9
25 hypertonia 9.9
26 meningococcal infection 9.7 SOD1 G6PD
27 glucosephosphate dehydrogenase deficiency 9.7 HBG2 G6PD
28 sickle cell disease 9.7 HBG2 G6PD
29 hyperphenylalaninemia 9.7 SOD1 G6PD
30 senile cataract 9.7 SOD1 G6PD
31 hemoglobin h disease 9.7 HBG2 G6PD
32 multinodular goiter 9.6 SOD1 G6PD
33 bilirubin metabolic disorder 9.6 HBG2 G6PD
34 iron deficiency anemia 9.6 HBG2 G6PD
35 sickle cell anemia 9.6 HBG2 G6PD
36 alpha-thalassemia 9.6 HBG2 G6PD
37 hereditary spherocytosis 9.5 HBG2 G6PD
38 neuronal ceroid lipofuscinosis 9.4 CYB5R3 CYB5A
39 chronic granulomatous disease 9.3 SOD1 HBG2 G6PD
40 deficiency anemia 9.3 SOD1 HBG2 G6PD
41 congenital hemolytic anemia 8.9 HBG2 G6PD CYB5R3 CYB5A

Graphical network of the top 20 diseases related to Congenital Methemoglobinemia:



Diseases related to Congenital Methemoglobinemia

Symptoms & Phenotypes for Congenital Methemoglobinemia

Human phenotypes related to Congenital Methemoglobinemia:

58 31 (show all 27)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 cyanosis 58 31 hallmark (90%) Very frequent (99-80%) HP:0000961
2 methemoglobinemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0012119
3 abnormality of the nail 58 31 frequent (33%) Frequent (79-30%) HP:0001597
4 exertional dyspnea 58 31 frequent (33%) Frequent (79-30%) HP:0002875
5 lip discoloration 58 31 frequent (33%) Frequent (79-30%) HP:0025118
6 microcephaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0000252
7 spastic tetraplegia 58 31 occasional (7.5%) Occasional (29-5%) HP:0002510
8 intellectual disability, severe 58 31 occasional (7.5%) Occasional (29-5%) HP:0010864
9 severe global developmental delay 58 31 occasional (7.5%) Occasional (29-5%) HP:0011344
10 blue sclerae 58 31 occasional (7.5%) Occasional (29-5%) HP:0000592
11 cerebellar atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0001272
12 athetosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0002305
13 frontal cortical atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0006913
14 limb dystonia 58 31 occasional (7.5%) Occasional (29-5%) HP:0002451
15 esotropia 58 31 occasional (7.5%) Occasional (29-5%) HP:0000565
16 cerebral hypomyelination 58 31 occasional (7.5%) Occasional (29-5%) HP:0006808
17 temporal cortical atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0007112
18 global brain atrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0002283
19 small for gestational age 58 31 very rare (1%) Very rare (<4-1%) HP:0001518
20 small basal ganglia 58 31 very rare (1%) Very rare (<4-1%) HP:0012697
21 delayed myelination 58 31 very rare (1%) Very rare (<4-1%) HP:0012448
22 seizure 31 very rare (1%) HP:0001250
23 global developmental delay 58 Occasional (29-5%)
24 seizures 58 Very rare (<4-1%)
25 hypertonia 58 Very rare (<4-1%)
26 spasticity 58 Occasional (29-5%)
27 abnormality of the nervous system 58 Frequent (79-30%)

Drugs & Therapeutics for Congenital Methemoglobinemia

Search Clinical Trials , NIH Clinical Center for Congenital Methemoglobinemia

Genetic Tests for Congenital Methemoglobinemia

Anatomical Context for Congenital Methemoglobinemia

MalaCards organs/tissues related to Congenital Methemoglobinemia:

40
Brain, Kidney, Spleen, Cerebellum, Heart, Liver, Placenta

Publications for Congenital Methemoglobinemia

Articles related to Congenital Methemoglobinemia:

(show top 50) (show all 247)
# Title Authors PMID Year
1
Congenital methemoglobinemia with a deficiency of cytochrome b5. 6 61
3951505 1986
2
A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency. 6
22170710 2012
3
Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. 6
20080843 2010
4
The human cytochrome b5 gene and two of its pseudogenes are located on chromosomes 18q23, 14q31-32.1 and 20p11.2, respectively. 6
8262522 1993
5
Recessive hereditary methemoglobinemia: two novel mutations in the NADH-cytochrome b5 reductase gene. 54 61
18343696 2008
6
A novel G143D mutation in the NADH-cytochrome b5 reductase gene in an Indian patient with type I recessive hereditary methemoglobinemia. 61 54
17964195 2008
7
NADH cytochrome b5 reductase and cytochrome b5 catalyze the microsomal reduction of xenobiotic hydroxylamines and amidoximes in humans. 61 54
15302896 2004
8
[A search for mutations in the DIA1 gene in case of hereditary methemoglobinemia type I in the iakut population]. 61 54
12884529 2003
9
Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene. 54 61
11295830 2001
10
A compound heterozygote in the NADH-cytochrome b5 reductase gene from a Chinese patient with hereditary methemoglobinemia type I. 61 54
10979206 2000
11
[Hereditary methemoglobinemias]. 61 54
10855391 2000
12
[Leu 72 Pro mutation in the NADH-cytochrome b5 reductase gene found in a Chinese hereditary methemoglobinemia patient]. 54 61
11243135 1998
13
Determination of concentration of cytosolic NADH-cytochrome b5 reductase in erythrocytes from normal Chinese adults, neonates and patients with hereditary methemoglobinemia by double-antibody sandwich ELISA. 61 54
9691146 1998
14
[Arginine-glutamine replacement at residue 57 of NADH-cytochrome b5 reductase in Chinese hereditary methemoglobinemia]. 54 61
15622768 1997
15
Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia. 61 54
8874222 1996
16
Establishment of monoclonal antibodies against human erythrocyte NADH-cytochrome b5 reductase. 54 61
8880217 1996
17
A novel point mutation in a 3' splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia. 54 61
7668255 1995
18
[Congenital methemoglobinemia]. 54 61
8657061 1995
19
An in-frame deletion of codon 298 of the NADH-cytochrome b5 reductase gene results in hereditary methemoglobinemia type II (generalized type). A functional implication for the role of the COOH-terminal region of the enzyme. 61 54
8119939 1994
20
Enzymatic instability of NADH-cytochrome b5 reductase as a cause of hereditary methemoglobinemia type I (red cell type). 54 61
1400360 1992
21
Exonic point mutations in NADH-cytochrome B5 reductase genes of homozygotes for hereditary methemoglobinemia, types I and III: putative mechanisms of tissue-dependent enzyme deficiency. 61 54
1707593 1991
22
Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type. 61 54
2107882 1990
23
[Molecular analysis of the structure of the mutant NADH-cytochrome b5 reductase gene causing methemoglobinemia]. 54 61
2323714 1990
24
Type I congenital methemoglobinemia in a Chinese family. 61
32556454 2020
25
Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia. 61
31898843 2020
26
A bolt from the blue; A case report of an unusual asthma exacerbation. 61
31908916 2020
27
Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats. 61
31650629 2019
28
Congenital methemoglobinemia: Rare presentation of cyanosis in newborns. 61
31754421 2019
29
Hereditary methemoglobinemia caused by Hb M-Hyde Park (Hb M-Akita) (HBB:c.277C > T; p.His93Tyr). 61
31267164 2019
30
Exon sequencing of the alpha-2-globin gene for the differential diagnosis of central cyanosis in newborns: a case report. 61
31269924 2019
31
Hereditary methemoglobinemia in a cyanotic cat presented for ovariohysterectomy. 61
31080263 2019
32
Recessive congenital methemoglobinemia type II: Hypoplastic basal ganglia in two siblings with a novel mutation of the cytochrome b5 reductase gene. 61
30614390 2019
33
Genetic cause for congenital methemoglobinemia in an Australian Pomeranian dog. 61
30767280 2019
34
Congenital Methemoglobinemia Identified by Pulse Oximetry Screening. 61
30733239 2019
35
Methemoglobin Modulation as an Intravascular Contrast Agent for Magnetic Resonance Imaging: Proof of Concept. 61
32039242 2019
36
'Acute leukemia in congenital methehemoglobinemia - an enigma to explore'. 61
30788079 2019
37
Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. 61
29482478 2018
38
[Cyanosis in 14-year-old patient. Methemoglobinemia: case report]. 61
29756717 2018
39
Failure of Pulse Oximetry and Cooximetry as Monitors in a Patient With Hemoglobin MIwate: A Case Report. 61
29293483 2018
40
The Acute Treatment of Methemoglobinemia in Pregnancy. 61
29627348 2018
41
A new mutation of congenital methemoglobinemia exacerbated after methylene blue treatment. 61
29657736 2018
42
Congenital methemoglobinemia misdiagnosed as polycythemia vera: Case report and review of literature. 61
29721250 2018
43
Congenital methemoglobinemia type II in a 5-year-old boy. 61
29375859 2018
44
Familial Congenital Methemoglobinemia in Pomeranian Dogs Caused by a Missense Variant in the NADH-Cytochrome B5 Reductase Gene. 61
29356095 2018
45
Congenital Methemoglobinemia: It is Time for National Level Registry System. 61
28991125 2017
46
Long-term Treatment with Methylene Blue in a Dog with Hereditary Methemoglobinemia Caused by Cytochrome b5 Reductase Deficiency. 61
28963729 2017
47
Anesthetic management of congenital methemoglobinemia in an emergency cesarean section. 61
29109650 2017
48
Patient with Persistent Low Oxygen Saturation for Emergency Cesarean Section. 61
28928588 2017
49
Methemoglobinemia: Living with Dormant Devil. 61
28428705 2017
50
A microplate reader-based method to quantify NADH-cytochrome b5 reductase activity for diagnosis of recessive congenital methaemoglobinemia. 61
27863456 2017

Variations for Congenital Methemoglobinemia

ClinVar genetic disease variations for Congenital Methemoglobinemia:

6 ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 CYB5R3 NM_000398.7(CYB5R3):c.757G>A (p.Val253Met)SNV Pathogenic 505719 rs144071404 22:43015928-43015928 22:42619922-42619922

Expression for Congenital Methemoglobinemia

Search GEO for disease gene expression data for Congenital Methemoglobinemia.

Pathways for Congenital Methemoglobinemia

Pathways related to Congenital Methemoglobinemia according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 9.4 G6PD CYB5R3 CYB5A

GO Terms for Congenital Methemoglobinemia

Cellular components related to Congenital Methemoglobinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial outer membrane GO:0005741 8.96 CYB5R3 CYB5A
2 hemoglobin complex GO:0005833 8.62 HBG2 CYB5R3

Biological processes related to Congenital Methemoglobinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 response to ethanol GO:0045471 9.37 SOD1 G6PD
2 cellular response to oxidative stress GO:0034599 9.32 SOD1 G6PD
3 glutathione metabolic process GO:0006749 9.26 SOD1 G6PD
4 oxidation-reduction process GO:0055114 9.26 SOD1 G6PD CYB5R3 CYB5A
5 cholesterol biosynthetic process GO:0006695 9.16 G6PD CYB5R3
6 L-ascorbic acid metabolic process GO:0019852 8.62 CYB5R3 CYB5A

Molecular functions related to Congenital Methemoglobinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 heme binding GO:0020037 8.96 HBG2 CYB5A
2 oxidoreductase activity GO:0016491 8.8 SOD1 G6PD CYB5R3

Sources for Congenital Methemoglobinemia

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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