A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an alpha 2 globin gene variant (Hb Conakry)

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 HbS trait with a severe pyruvate kinase deficiency leading to a 2,3-DPG co ncentration of twice normal levels. Sequence of the PK-R gene revealed an u ndescribed mutation in the homozygous or hemizygous state within exon 5 (nu cleotide 2670 C-->A), leading to the interchange of Ser 130 into Tyr (PK Co nakry). In addition, the patient carried a new haemoglobin variant, Hb Cona kry [alpha 80(F1) Leu --> Val], which seemed to have a mild effect. The hig h intraerythrocytic 2,3-DPG concentration induced by the PK deficiency resu lted in a decreased oxygen affinity which favoured sickling to a level almo st similar to that of Hb S/C compound heterozygous patients. This was confi rmed by oxygen binding measurements of Hb A/Hb S erythrocytes in which 2,3- DPG content was modified in vitro. Hysteresis between deoxy- and reoxygenat ion curves, as well as increase in the n(max) 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 heterozygo us patient with an artificial in vitro increase of 2,3-DPG concentration.