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Hemoglobin M disease is an autosomal dominant congenital methemoglobinemia caused by alpha-globin variants that stabilize the oxidized (Fe3+) state of heme, leading to lifelong cyanosis despite normal arterial oxygen saturation. The HBA2 gene encodes the α2-globin chain, and missense substitutions at the heme-binding E7 histidine residue disrupt electron transfer and enhance methemoglobin formation, consistent with the clinical phenotype of Hemoglobin M Disease.
A single unrelated newborn male presented with central cyanosis from birth, had normal blood gas measurements but persistent low pulse oximetry unresponsive to 100% oxygen, and required no treatment beyond observation. Sequencing revealed HBA2:c.175C>T (p.His59Tyr) causing Hb M Boston (PMID:31269924). No affected relatives were identified, and methemoglobin levels measured by co-oximetry remained within normal limits despite the phenotype.
Gene–Disease AssociationLimitedSingle unrelated proband with HBA2:c.175C>T (p.His59Tyr) causing Hb M Boston; no familial segregation Genetic EvidenceLimitedOne proband reported; no additional familial segregation or multiple unrelated cases Functional EvidenceLimitedBiochemical and simulation studies support oxidized heme stabilization but limited direct functional assays |