MCID: HRD146
MIFTS: 31

Hereditary Methemoglobinemia

Categories: Rare diseases, Blood diseases, Genetic diseases

Aliases & Classifications for Hereditary Methemoglobinemia

MalaCards integrated aliases for Hereditary Methemoglobinemia:

Name: Hereditary Methemoglobinemia 53 59 6
Congenital Methemoglobinemia 53 59 73
Autosomal Recessive Methemoglobinemia 53 59
Methemoglobinemia Hereditary 55
Hemoglobin M Disease 73

Characteristics:

Orphanet epidemiological data:

59
hereditary methemoglobinemia
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal;

Classifications:



External Ids:

Orphanet 59 ORPHA621
UMLS via Orphanet 74 C0272087
ICD10 via Orphanet 34 D74.0

Summaries for Hereditary Methemoglobinemia

NIH Rare Diseases : 53 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 621Disease definitionHereditary methemoglobinemia (HM) is a rare red cell disorder classified principally into two clinical phenotypes: autosomal recessivecongenital (or hereditary) methemoglobinemia types I and II (RCM/RHM type 1; RCM/RHM type 2, see these terms). 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. It 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, with global loss of Cb5R function, 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. 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. 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 alsopossible that mutations of the substrate of NADPH reductase, which remains to be identified, could have a minor effect on the reduction of methemoglobin. 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 : Hereditary Methemoglobinemia, also known as congenital methemoglobinemia, is related to congenital methemoglobinemia and methemoglobinemia. An important gene associated with Hereditary Methemoglobinemia is CYB5R3 (Cytochrome B5 Reductase 3), and among its related pathways/superpathways are Metabolism of water-soluble vitamins and cofactors and Methylene Blue Pathway, Pharmacodynamics. The drugs Methylene blue and Pharmaceutical Solutions have been mentioned in the context of this disorder. Affiliated tissues include heart, testes and liver.

Related Diseases for Hereditary Methemoglobinemia

Diseases in the Methemoglobinemia family:

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

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

# Related Disease Score Top Affiliating Genes
1 congenital methemoglobinemia 31.2 CYB5A CYB5R3 HBG2
2 methemoglobinemia 28.5 CYB5A CYB5R3 HBG2
3 methemoglobinemia, beta-globin type 11.0
4 type i 10.1
5 methemoglobinemia due to deficiency of methemoglobin reductase 10.1
6 methemoglobin reductase deficiency 9.9
7 disease of mental health 9.8
8 acquired methemoglobinemia 9.0 CYB5R3 HBG2

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



Diseases related to Hereditary Methemoglobinemia

Symptoms & Phenotypes for Hereditary Methemoglobinemia

Drugs & Therapeutics for Hereditary Methemoglobinemia

Drugs for Hereditary Methemoglobinemia (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):


# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Methylene blue Approved, Investigational Phase 1 61-73-4
2 Pharmaceutical Solutions Phase 1

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Safety, Tolerability, and Pharmacokinetic Study of Methylene Blue Following a 1 mg/kg Intravenous Dose in Healthy Adults Completed NCT02478281 Phase 1 Methylene Blue
2 Study of Methemoglobin as a Biomarker of Tissue Hypoxia During Acute Hemodilution in Heart Surgery Patients Completed NCT01883713

Search NIH Clinical Center for Hereditary Methemoglobinemia

Genetic Tests for Hereditary Methemoglobinemia

Anatomical Context for Hereditary Methemoglobinemia

MalaCards organs/tissues related to Hereditary Methemoglobinemia:

41
Heart, Testes, Liver, Kidney, Spleen

Publications for Hereditary Methemoglobinemia

Articles related to Hereditary Methemoglobinemia:

(show top 50) (show all 114)
# Title Authors Year
1
A new mutation of congenital methemoglobinemia exacerbated after methylene blue treatment. ( 29657736 )
2018
2
Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I. ( 29482478 )
2018
3
Congenital methemoglobinemia misdiagnosed as polycythemia vera: Case report and review of literature. ( 29721250 )
2018
4
Congenital methemoglobinemia type II in a 5-year-old boy. ( 29375859 )
2018
5
Familial Congenital Methemoglobinemia in Pomeranian Dogs Caused by a Missense Variant in the NADH-Cytochrome B5 Reductase Gene. ( 29356095 )
2018
6
Long-term Treatment with Methylene Blue in a Dog with Hereditary Methemoglobinemia Caused by Cytochrome b5 Reductase Deficiency. ( 28963729 )
2017
7
Enzymopenic Congenital Methemoglobinemia in Children of the Republic of Sakha (Yakutia). ( 27879543 )
2017
8
Anesthetic management of congenital methemoglobinemia in an emergency cesarean section. ( 29109650 )
2017
9
Congenital Methemoglobinemia: It is Time for National Level Registry System. ( 28991125 )
2017
10
Recessive congenital methemoglobinemia in immediate generations. ( 27922248 )
2016
11
Congenital methemoglobinemia type 2 and cerebellar atrophy/hypoplasia. ( 26133947 )
2015
12
Congenital Methemoglobinemia Type II-Clinical Improvement with Short-Term Methylene Blue Treatment. ( 26574897 )
2015
13
A novel nine base deletion mutation in NADH-cytochrome b5 reductase gene in an Indian family with recessive congenital methemoglobinemia-type-II. ( 28649542 )
2015
14
Corneal epitheliopathy in congenital methemoglobinemia. ( 24503601 )
2014
15
The Role of Preoperative Evaluation for Congenital Methemoglobinemia. ( 27366424 )
2014
16
Congenital methemoglobinemia in a dog with a promoter deletion and a nonsynonymous coding variant in the gene encoding cytochrome ba88. ( 25145387 )
2014
17
Late Diagnosis of Congenital Methemoglobinemia in an Elderly Patient During Cardiac Surgery. ( 23725685 )
2013
18
[Population frequency and age of c.806C > T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia]. ( 23866629 )
2013
19
Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India. ( 24266649 )
2013
20
[Novel large deletion c.22-1320_633+1224del in the CYB5R3 gene from patients with hereditary methemoglobinemia]. ( 23297489 )
2012
21
Recessive congenital methemoglobinemia caused by a rare mechanism: maternal uniparental heterodisomy with segmental isodisomy of a chromosome 22. ( 22658170 )
2012
22
Recessive congenital methemoglobinemia due to NADH-cytochrome b5 reductase deficiency associated with recurrent early pregnancy loss (REPL) in an Indian family. ( 22797852 )
2012
23
Severe mental retardation and recessive congenital methemoglobinemia in three Indian patients: compound heterozygous for NADH-cytochrome b5 reductase gene mutations. ( 21328435 )
2011
24
Cerebellar atrophy in a child with hereditary methemoglobinemia type II. ( 20650578 )
2011
25
A rare cause of mental motor retardation: recessive congenital methemoglobinemia type II. ( 19480335 )
2009
26
Anesthetic management of a patient with congenital methemoglobinemia. ( 19762306 )
2009
27
A novel L218P mutation in NADH-cytochrome b5 reductase associated with type I recessive congenital methemoglobinemia. ( 19579085 )
2009
28
Recessive hereditary methemoglobinemia: two novel mutations in the NADH-cytochrome b5 reductase gene. ( 18343696 )
2008
29
A novel G143D mutation in the NADH-cytochrome b5 reductase gene in an Indian patient with type I recessive hereditary methemoglobinemia. ( 17964195 )
2008
30
Hemoglobin M variant and congenital methemoglobinemia: methylene blue will not be effective in the presence of hemoglobin M. ( 18566207 )
2008
31
Hemoglobin M variant and congenital methemoglobinemia: methylene blue will not be effective in the presence of hemoglobin M. ( 18245076 )
2008
32
Hereditary methemoglobinemia. ( 16499818 )
2006
33
Identification and characterization of the novel FAD-binding lobe G75S mutation in cytochrome b(5) reductase: an aid to determine recessive congenital methemoglobinemia status in an infant. ( 16310381 )
2006
34
Prophylactic methylene blue in a patient with congenital methemoglobinemia. ( 15753496 )
2005
35
Congenital methemoglobinemia caused by Hb-MRatnagiri (beta-63CAT-->TAT, His-->Tyr) in an Indian family. ( 15929117 )
2005
36
A case with quadriparetic cerebral palsy and cyanosis: congenital methemoglobinemia. ( 16087059 )
2005
37
Hereditary methemoglobinemia in an infant. ( 16269854 )
2005
38
Methylene blue in congenital methemoglobinemia: prophylactic or on demand? ( 16189344 )
2005
39
Cytochrome b5 reductase: the roles of the recessive congenital methemoglobinemia mutants P144L, L148P, and R159*. ( 15488472 )
2004
40
Anesthetic management of a patient with congenital methemoglobinemia. ( 15567652 )
2004
41
[A search for mutations in the DIA1 gene in case of hereditary methemoglobinemia type I in the iakut population]. ( 12884529 )
2003
42
Congenital methemoglobinemia: a rare cause of cyanosis in the newborn--a case report. ( 12897322 )
2003
43
Introduction: congenital methemoglobinemia revisited. ( 12411314 )
2002
44
Congenital methemoglobinemia due to NADH-methemoglobin reductase deficiency in three Indian families. ( 12803131 )
2002
45
Severe oxyhemoglobin desaturation during induction of anesthesia in a patient with congenital methemoglobinemia. ( 11685006 )
2001
46
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. ( 11295830 )
2001
47
Congenital methemoglobinemia. ( 10832246 )
2000
48
[Hereditary methemoglobinemias]. ( 10855391 )
2000
49
Comments on congenital methemoglobinemia. ( 11105433 )
2000
50
A compound heterozygote in the NADH-cytochrome b5 reductase gene from a Chinese patient with hereditary methemoglobinemia type I. ( 10979206 )
2000

Variations for Hereditary Methemoglobinemia

ClinVar genetic disease variations for Hereditary Methemoglobinemia:

6
# Gene Variation Type Significance SNP ID Assembly Location
1 CYB5R3 NM_000398.6(CYB5R3): c.757G> A (p.Val253Met) single nucleotide variant Pathogenic rs144071404 GRCh37 Chromosome 22, 43015928: 43015928
2 CYB5R3 NM_000398.6(CYB5R3): c.757G> A (p.Val253Met) single nucleotide variant Pathogenic rs144071404 GRCh38 Chromosome 22, 42619922: 42619922

Expression for Hereditary Methemoglobinemia

Search GEO for disease gene expression data for Hereditary Methemoglobinemia.

Pathways for Hereditary Methemoglobinemia

GO Terms for Hereditary Methemoglobinemia

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

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

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

# Name GO ID Score Top Affiliating Genes
1 L-ascorbic acid metabolic process GO:0019852 8.62 CYB5A CYB5R3

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

# Name GO ID Score Top Affiliating Genes
1 heme binding GO:0020037 8.62 CYB5A HBG2

Sources for Hereditary Methemoglobinemia

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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