METHB-CYB5R3
MCID: MTH026
MIFTS: 36

Methemoglobinemia Due to Deficiency of Methemoglobin Reductase (METHB-CYB5R3)

Categories: Blood diseases, Genetic diseases, Mental diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

MalaCards integrated aliases for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

Name: Methemoglobinemia Due to Deficiency of Methemoglobin Reductase 56 52 73
Methemoglobinemia, Type I 56 29 13 6
Nadh-Dependent Methemoglobin Reductase Deficiency 56 52 73
Nadh-Cytochrome B5 Reductase Deficiency 56 25 73
Deficiency of Cytochrome-B5 Reductase 25 29 6
Nadh Cytochrome B5 Reductase Deficiency 52 71
Methemoglobinemia Type 2 29 6
Diaphorase Deficiency 52 25
Congenital Methemoglobinemia Due to Nadh-Cytochrome B5 Reductase 3 Deficiency 25
Chronic Familial Methemoglobin Reductase Deficiency 25
Methemoglobinemia, Congenital, Autosomal Recessive 56
Congenital Nadh-Methemoglobin Reductase Deficiency 25
Autosomal Recessive Congenital Methemoglobinemia 25
Methemoglobinemia Congenital Autosomal Recessive 73
Nadh-Cytochrome B5 Reductase Deficiency Type Ii 73
Nadh-Cytochrome B5 Reductase Deficiency, Type I 29
Nadh-Cytochrome B5 Reductase Deficiency Type I 73
Nadh Methemoglobin Reductase Deficiency 52
Autosomal Recessive Methemoglobinemia 52
Cytochrome B5 Reductase Deficiency 25
Methemoglobinemia Cyb5r3-Related 73
Methemoglobinemia, Type Ii 56
Nadh Diaphorase Deficiency 52
Methemoglobinemia Type Ii 73
Methemoglobinemia Type I 73
Nadh-Cyb5r Deficiency 25
Methb-Cyb5r3 73

Characteristics:

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
most common form of congenital methemoglobinemia
two clinical forms - type i (deficiency of b5r is isolated to erythrocytes) and type ii (deficiency of b5r in all cell types)
type ii is progressive and leads to shortened lifespan
type i b5r endemic in athabascan indians, navajo indians, and yakutsk natives of siberia
heterozygotes at risk of developing acute, symptomatic methemoglobinemia after exposure to exogenous, methemoglobin-inducing agents


HPO:

31
methemoglobinemia due to deficiency of methemoglobin reductase:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Genetics Home Reference : 25 Autosomal recessive congenital methemoglobinemia is an inherited condition that mainly affects the function of red blood cells. Specifically, it alters a molecule within these cells called hemoglobin. Hemoglobin carries oxygen to cells and tissues throughout the body. In people with autosomal recessive congenital methemoglobinemia, some of the normal hemoglobin is replaced by an abnormal form called methemoglobin, which is unable to deliver oxygen to the body's tissues. As a result, tissues in the body become oxygen deprived, leading to a bluish appearance of the skin, lips, and nails (cyanosis). There are two forms of autosomal recessive congenital methemoglobinemia: types I and II. People with type I have cyanosis from birth and may experience weakness or shortness of breath related to the shortage of oxygen in their tissues. People with type II have cyanosis as well as severe neurological problems. After a few months of apparently normal development, children with type II develop severe brain dysfunction (encephalopathy), uncontrolled muscle tensing (dystonia), and involuntary limb movements (choreoathetosis); also, the size of their head remains small and does not grow in proportion with their body (microcephaly). People with type II have severe intellectual disability; they can recognize faces and usually babble but speak no words. They can sit unassisted and grip objects but have impaired motor skills that leave them unable to walk. In type II, growth is often slowed. Abnormal facial muscle movements can interfere with swallowing, which can lead to feeding difficulties and further slow growth. People with autosomal recessive congenital methemoglobinemia type I have a normal life expectancy, but people with type II often do not survive past early adulthood.

MalaCards based summary : Methemoglobinemia Due to Deficiency of Methemoglobin Reductase, also known as methemoglobinemia, type i, is related to methemoglobinemia and pyruvate dehydrogenase e3-binding protein deficiency, and has symptoms including seizures, ataxia and headache. An important gene associated with Methemoglobinemia Due to Deficiency of Methemoglobin Reductase is CYB5R3 (Cytochrome B5 Reductase 3). Affiliated tissues include brain, skin and liver, and related phenotypes are intellectual disability and global developmental delay

OMIM : 56 Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979). (250800)

UniProtKB/Swiss-Prot : 73 Methemoglobinemia CYB5R3-related: A form of methemoglobinemia, a hematologic disease characterized by the presence of excessive amounts of methemoglobin in blood cells, resulting in decreased oxygen carrying capacity of the blood, cyanosis and hypoxia. There are two types of methemoglobinemia CYB5R3-related. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms.

Related Diseases for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Diseases related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 16)
# Related Disease Score Top Affiliating Genes
1 methemoglobinemia 12.2
2 pyruvate dehydrogenase e3-binding protein deficiency 11.8
3 dihydrolipoamide dehydrogenase deficiency 11.8
4 maple syrup urine disease 11.8
5 methemoglobinemia and ambiguous genitalia 11.3
6 congenital methemoglobinemia 10.6
7 methemoglobin reductase deficiency 10.6
8 cyanosis, transient neonatal 10.3
9 microcephaly 10.2
10 spondylosis 10.2
11 athetosis 10.2
12 movement disease 10.1
13 leukodystrophy 9.9
14 dystonia 9.9
15 encephalopathy 9.9
16 hypertonia 9.9

Graphical network of the top 20 diseases related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:



Diseases related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Symptoms & Phenotypes for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Human phenotypes related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

31 (show all 12)
# Description HPO Frequency HPO Source Accession
1 intellectual disability 31 HP:0001249
2 global developmental delay 31 HP:0001263
3 microcephaly 31 HP:0000252
4 hypertonia 31 HP:0001276
5 strabismus 31 HP:0000486
6 growth delay 31 HP:0001510
7 headache 31 HP:0002315
8 polycythemia 31 HP:0001901
9 cyanosis 31 HP:0000961
10 exertional dyspnea 31 HP:0002875
11 opisthotonus 31 HP:0002179
12 methemoglobinemia 31 HP:0012119

Symptoms via clinical synopsis from OMIM:

56
Neurologic Central Nervous System:
headache
mental retardation (type i)
developmental delay (type ii)
opisthotonos (type ii)
hypertonia (type ii)
more
Skin Nails Hair Skin:
cyanosis

Head And Neck Head:
microcephaly (type ii)

Respiratory:
dyspnea, exertional

Hematology:
polycythemia
type i - methemoglobin concentration 10-35%

Growth Other:
growth retardation

Head And Neck Eyes:
strabismus (type ii)

Laboratory Abnormalities:
nadh-cytochrome b(5) reductase deficiency

Clinical features from OMIM:

250800

UMLS symptoms related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:


seizures, ataxia, headache, lethargy, cyanosis, dyspnea on exertion

Drugs & Therapeutics for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Search Clinical Trials , NIH Clinical Center for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Genetic Tests for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Genetic tests related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

# Genetic test Affiliating Genes
1 Methemoglobinemia Type 2 29
2 Methemoglobinemia, Type I 29
3 Deficiency of Cytochrome-B5 Reductase 29 CYB5R3
4 Nadh-Cytochrome B5 Reductase Deficiency, Type I 29

Anatomical Context for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

MalaCards organs/tissues related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

40
Brain, Skin, Liver

Publications for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Articles related to Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

(show top 50) (show all 68)
# Title Authors PMID Year
1
A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: determination of the molecular basis. 61 6 56
10874300 2000
2
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. 56 61 6
1707593 1991
3
Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency. 56 6
18318771 2008
4
Heterogeneity of the molecular biology of methemoglobinemia: a study of eight consecutive patients. 6 56
15921385 2005
5
Identification of a novel point mutation (Leu72Pro) in the NADH-cytochrome b5 reductase gene of a patient with hereditary methaemoglobinaemia type I. 6 56
9695975 1998
6
Recessive congenital methaemoglobinaemia type II a new mutation which causes incorrect splicing in the NADH-cytochrome b5 reductase gene. 6 56
9266404 1997
7
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. 6 56
7668255 1995
8
Four new mutations in the NADH-cytochrome b5 reductase gene from patients with recessive congenital methemoglobinemia type II. 6 56
7718898 1995
9
Analysis of mutant NADH-cytochrome b5 reductase: apparent "type III" methemoglobinemia can be explained as type I with an unstable reductase. 6 56
8427971 1993
10
Hereditary methemoglobinemia due to cytochrome b5 reductase deficiency in blood cells without associated neurologic and mental disorders. 6 56
4063522 1985
11
The reduction of methaemoglobin in red blood cells and studies on the cause of idiopathic methaemoglobinaemia. 56 6
16748235 1948
12
Enzymatic instability of NADH-cytochrome b5 reductase as a cause of hereditary methemoglobinemia type I (red cell type). 6 61
1400360 1992
13
Recessive congenital methaemoglobinaemia: functional characterization of the novel D239G mutation in the NADH-binding lobe of cytochrome b5 reductase. 6
15953014 2005
14
Familial idiopathic methemoglobinemia revisited: original cases reveal 2 novel mutations in NADH-cytochrome b5 reductase. 6
12393396 2002
15
Introduction: congenital methemoglobinemia revisited. 56
12411314 2002
16
Metoclopramide-induced methemoglobinemia in a patient with co-existing deficiency of glucose-6-phosphate dehydrogenase and NADH-cytochrome b5 reductase: failure of methylene blue treatment. 56
11418378 2001
17
A novel mutation in the NADH-cytochrome b5 reductase gene of a Chinese patient with recessive congenital methemoglobinemia. 6
10807796 2000
18
Methemoglobinemia: etiology, pharmacology, and clinical management. 56
10533013 1999
19
Erythrocyte enzyme activities in cord blood of extremely low-birth-weight infants. 56
10509002 1999
20
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. 6
8119939 1994
21
Historical note: methemoglobinemia--long ago and far away. 56
8416293 1993
22
Structural role of serine 127 in the NADH-binding site of human NADH-cytochrome b5 reductase. 6
1898726 1991
23
Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type. 6
2107882 1990
24
Fatal outcome of methemoglobinemia in an infant. 56
3573274 1987
25
Prenatal diagnosis of congenital methemoglobinemia with mental retardation. 56
3793441 1986
26
Enzymopenic hereditary methemoglobinemia: a clinical/biochemical classification. 56
3539237 1986
27
Characterization of weak alleles at the DIA1 locus (Mustapha 1, Mustapha 2, and Mustapha 3) in the Algerian population. 56
6885054 1983
28
NADH cytochrome b5 reductase activity in lymphoid cell lines. Expression of the defect in epstein Barr virus transformed lymphoblastoid cell lines from patients with recessive congenital methemoglobinemia. 56
6265499 1981
29
Congenital methaemoglobinaemia due to NADH methaemoglobin reductase deficiency: successful treatment with oral riboflavin. 56
6893937 1981
30
Methaemoglobinaemia resulting from heterozygosity for two NADH-methaemoglobin reductase variants: characterization as NADH-ferricyanide reductase. 56
6893938 1981
31
Membrane-bound cytochrome b5 reductase (methemoglobin reductase) in human erythrocytes. Study in normal and methemoglobinemic subjects. 56
7451647 1981
32
Quantitative variations of red-cell cytochrome b5 reductase (NADH-methemoglobin-reductase) in the Algerian population: evidence for defective alleles. 56
7327574 1981
33
Prenatal diagnosis of congenital enzymopenic methaemoglobinaemia with mental retardation due to generalized cytochrome b5 reductase deficiency: first report of two cases. 56
7346809 1981
34
NADH-cytochrome b5 reductase in platelets and leukocytes with special reference to normal levels and to levels in carriers of hereditary methemoglobinemia with or without neurological symptoms. 56
6768212 1980
35
[Clinical and biological forms of cytochrome b5 reductase deficiency]. 56
159760 1979
36
Heterogeneity of hereditary methaemoglobinaemia: a study of 4 Cuban families with NADH-Methaemoglobin reductase deficiency including a new variant (Santiago de Cuba variant). 56
663552 1978
37
Congenital methemoglobin-reductase (cytochrome b5 reductase) deficiency associated with mental retardation in a Spanish girl. 56
97893 1978
38
Leukocyte diaphorase deficiency in congenital methemoglobinemia: a valuable prognostic indicator. 56
603804 1977
39
Generalised deficiency of cytochrome b5 reductase in congenital methaemoglobinaemia with mental retardation. 56
1207738 1975
40
Unstable variant of NADH methemoglobin reductase in Puerto Ricans with hereditary methemoglobinemia. 56
4336945 1972
41
DPNH-methemoglobin reductase deficiency and hereditary methemoglobinemia. 56
4333562 1971
42
Electrophoretic and functional variants of NADH-methemoglobin reductase in hereditary methemoglobinemia. 56
5543874 1971
43
Inherited methemoglobinemia (enzyme deficiencies). 56
4393777 1970
44
Heterogeneity of the enzymatic defect in congenital methemoglobinemia. 56
4390269 1969
45
Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam. 56
5686480 1968
46
Electrophoresis of red cell NADH- and NADPH-diaphorases in normal subjects and patients with congenital methemoglobinemia. 56
16496543 1967
47
Demonstration of an enzyme variant in a case of congenital methaemoglobinaemia. 56
6061565 1967
48
Hereditary methemoglobinemic cyanosis due to diaphorase deficiency in three successive generations. 56
4963515 1967
49
Mental retardation in methemoglobinemia due to diaphorase deficiency. 56
4378489 1965
50
HEREDITARY METHEMOGLOBINEMIA DUE TO DIAPHORASE DEFICIENCY IN NAVAJO INDIANS. 56
14244100 1964

Variations for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

ClinVar genetic disease variations for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

6 (show all 23) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 CYB5R3 NM_000398.7(CYB5R3):c.310G>T (p.Gly104Cys)SNV Pathogenic 827634 22:43026911-43026911 22:42630905-42630905
2 CYB5R3 NM_000398.7(CYB5R3):c.190C>G (p.Leu64Val)SNV Pathogenic 827633 22:43027420-43027420 22:42631414-42631414
3 CYB5R3 NM_000398.7(CYB5R3):c.103A>C (p.Thr35Pro)SNV Pathogenic 827632 22:43032771-43032771 22:42636765-42636765
4 CYB5R3 NM_000398.7(CYB5R3):c.382T>C (p.Ser128Pro)SNV Pathogenic 234 rs121965006 22:43024239-43024239 22:42628233-42628233
5 CYB5R3 NM_000398.7(CYB5R3):c.173G>A (p.Arg58Gln)SNV Pathogenic 235 rs121965007 22:43027437-43027437 22:42631431-42631431
6 CYB5R3 NM_000398.7(CYB5R3):c.446T>C (p.Leu149Pro)SNV Pathogenic 236 rs121965008 22:43024175-43024175 22:42628169-42628169
7 CYB5R3 NM_000398.7(CYB5R3):c.316G>A (p.Val106Met)SNV Pathogenic 237 rs121965009 22:43026905-43026905 22:42630899-42630899
8 CYB5R3 NM_000398.7(CYB5R3):c.734-1G>TSNV Pathogenic 238 rs794728011 22:43015952-43015952 22:42619946-42619946
9 CYB5R3 NM_000398.7(CYB5R3):c.463+8G>CSNV Pathogenic 239 rs200872504 22:43024150-43024150 22:42628144-42628144
10 CYB5R3 NM_000398.7(CYB5R3):c.655C>T (p.Arg219Ter)SNV Pathogenic 240 rs121965010 22:43019873-43019873 22:42623867-42623867
11 CYB5R3 NM_000398.7(CYB5R3):c.610T>C (p.Cys204Arg)SNV Pathogenic 241 rs121965011 22:43023333-43023333 22:42627327-42627327
12 CYB5R3 NM_000398.7(CYB5R3):c.817_819del (p.Met273del)deletion Pathogenic 242 rs794728012 22:43015866-43015868 22:42619860-42619862
13 CYB5R3 NM_000398.7(CYB5R3):c.895_897del (p.Phe299del)deletion Pathogenic 243 rs121965012 22:43015788-43015790 22:42619782-42619784
14 CYB5R3 NM_000398.7(CYB5R3):c.464-2A>CSNV Pathogenic 245 rs794728013 22:43023696-43023696 22:42627690-42627690
15 CYB5R3 NM_000398.7(CYB5R3):c.218T>C (p.Leu73Pro)SNV Pathogenic 246 rs121965013 22:43027392-43027392 22:42631386-42631386
16 CYB5R3 NM_000398.7(CYB5R3):c.229C>T (p.Gln77Ter)SNV Pathogenic 247 rs121965014 22:43026992-43026992 22:42630986-42630986
17 CYB5R3 NM_000398.7(CYB5R3):c.478C>T (p.Arg160Ter)SNV Pathogenic 248 rs61732609 22:43023680-43023680 22:42627674-42627674
18 CYB5R3 NM_000398.7(CYB5R3):c.611G>A (p.Cys204Tyr)SNV Pathogenic 249 rs121965015 22:43023332-43023332 22:42627326-42627326
19 CYB5R3 NM_000398.7(CYB5R3):c.875G>A (p.Gly292Asp)SNV Pathogenic 250 rs121965016 22:43015810-43015810 22:42619804-42619804
20 CYB5R3 NM_000398.7(CYB5R3):c.763_765GAG[1] (p.Glu256del)short repeat Pathogenic 251 rs121965017 22:43015917-43015919 22:42619911-42619913
21 CYB5R3 NM_000398.7(CYB5R3):c.719A>G (p.Asp240Gly)SNV Pathogenic 252 rs121965018 22:43019809-43019809 22:42623803-42623803
22 CYB5R3 NM_000398.7(CYB5R3):c.226+2T>CSNV Pathogenic 801428 22:43027382-43027382 22:42631376-42631376
23 CYB5R3 NM_000398.7(CYB5R3):c.352C>T (p.His118Tyr)SNV Uncertain significance 809380 22:43024269-43024269 22:42628263-42628263

UniProtKB/Swiss-Prot genetic disease variations for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase:

73
# Symbol AA change Variation ID SNP ID
1 CYB5R3 p.Arg58Gln VAR_004619 rs121965007
2 CYB5R3 p.Val106Met VAR_004620 rs121965009
3 CYB5R3 p.Ser128Pro VAR_004621 rs121965006
4 CYB5R3 p.Leu149Pro VAR_004622 rs121965008
5 CYB5R3 p.Leu73Pro VAR_010750 rs121965013
6 CYB5R3 p.Ala179Val VAR_010752 rs201232518
7 CYB5R3 p.Cys204Arg VAR_010753 rs121965011
8 CYB5R3 p.Cys204Tyr VAR_010754 rs121965015
9 CYB5R3 p.Gly292Asp VAR_037316 rs121965016

Expression for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Search GEO for disease gene expression data for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase.

Pathways for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

GO Terms for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

Sources for Methemoglobinemia Due to Deficiency of Methemoglobin Reductase

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