A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an α2 globin gene variant (Hb Conakry)

Abstract

A Guinean woman, hetererozygous for haemoglobin (Hb) S, was studied because of episodes of marked anaemia, repeated typical metaphyseal painful crises and haemosiderosis. Her sickling syndrome resulted from the association of Hb S trait with a severe pyruvate kinase deficiency leading to a 2,3‐DPG concentration of twice normal levels. Sequence of the PK‐R gene revealed an undescribed mutation in the homozygous or hemizygous state within exon 5 (nucleotide 2670 C → A), leading to the interchange of Ser 130 into Tyr (PK Conakry). In addition, the patient carried a new haemoglobin variant, Hb Conakry [α80(F1) Leu → Val], which seemed to have a mild effect. The high intraerythrocytic 2,3‐DPG concentration induced by the PK deficiency resulted in a decreased oxygen affinity which favoured sickling to a level almost similar to that of Hb S/C compound heterozygous patients. This was confirmed by oxygen binding measurements of Hb A/Hb S erythrocytes in which 2,3‐DPG content was modified in vitro. Hysteresis between deoxy‐ and reoxygenation curves, as well as increase in the nmax value, demonstrated that the extent of HbS polymerization in the propositus was almost the same as that of RBCs from a homozygous sickle cell patient or those of an A/S heterozygous patient with an artificial in vitro increase of 2,3‐DPG concentration.

Treating sickle cell disease by targeting HbS polymerization

“…Individuals with sickle trait (HbAS), which is normally a totally benign condition, have a clinical phenotype almost as severe as HbSS disease in which they also inherit a deficiency in red blood cell pyruvate kinase, which causes a marked increase in red cell 2,3-DPG. 84,85 Because 2,3-DPG plays such a critical role in potentiating HbS polymerization, there is a compelling rationale for the development of drugs that target the enzymatic pathway responsible for its remarkably high (5 mM) concentration in red cells. A number of anions stimulate the phosphatase activity of 2,3-DPG synthase, thereby lowering 2,3-DPG levels.…”

Discrepancies between genotype and phenotype in hematology: an important frontier

“…8 High levels of 2,3 diphosphoglycerate (2,3-DPG) promote sickling, [9][10][11][12] and the coinheritance of even sickle trait with pyruvate kinase deficiency, which increases 2,3-DPG levels, gave rise to a clinically significant sickling. 13 The inverse relationship between ␣-thalassemia and the severity of sickling has been known for nearly 20 years. 14 Its mechanism is presumably to decrease the hemoglobin concentration in red cells, a critical factor in sickling severity.…”

A Review of Clinical Profile in Sickle Cell Traits

“…4,6,20,21 Others may be the consequence of phenotypes with increased 2,3-DPG or with arterial desaturation which has increased the rate of polymerization of hemoglobin S sufficiently to convert a patient with sickle cell trait into phenotypic sickle cell disease. 6,18,22 …”