Zur and colleagues have reported on the identification of a novel β-globin mutation that produced a hemoglobin with decreased oxygen affinity in a 4-year-old boy with poor physical resistance to stress. Mutations in both the α- and β-globin genes that produce low-affinity variants have been reported, although low-affinity hemoglobin variants are rare compared with high-affinity variants (1, 2). Mild anemia with decreased oxygen saturation and decreased erythropoietin is usually noted, and cyanosis may also be present in some cases. Homozygosity for low-affinity variants has not been reported, likely because of embryonic lethality. Detection of low–oxygen affinity hemoglobin should be in the differential diagnosis of patients with cyanosis. If a low-affinity hemoglobin is suspected after the common cardiovascular and pulmonary causes have been ruled out, diagnostic testing should make use of HPLC and determination of the full oxygen-dissociation curve [partial pressure of O2 at which hemoglobin is half-saturated (P50) and the Hill coefficient] by hemoximetry. Oxygen saturation and P50 calculated from the pH and the oxygen pressure (Po2) should be used with caution, owing to the assumptions used with these calculations regarding normal 2,3-diphosphoglycerate concentrations and no abnormal hemoglobin. Definitive diagnosis, however, will depend on globin (α and β) gene sequencing. Two distinct models have been proposed to describe the mechanism for the low-affinity (β-L68F) and high-affinity (β-L68H) hemoglobin variants discussed in the case report by Zur et al. We hypothesize that the larger bulkier phenylalanine side chain in the β-L68F variant is likely associated with steric hindrance in the relaxed (R) state, leading to stabilization of the tense (T) state and therefore a low-affinity hemoglobin. In contrast, the β-L68H substitution places histidine 68 within H-bond range of tryptophan 15, which now stabilizes the R state and thereby produces a high-affinity variant. Treatment is not needed for these patients; however, identification of the hemoglobin variant is important to avoid unnecessary workup and alleviate the concerns of the patient and family.
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Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication September 26, 2011.
- Accepted for publication October 3, 2011.
- © 2012 The American Association for Clinical Chemistry