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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 621
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).
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.
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.
Source: GARD Last updated on 05-01-20
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