A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an alpha2 globin gene variant (Hb Conakry).
A Guinean woman, heterozygous 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 [alpha80(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 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 heterozygous patient with an artificial in vitro increase of 2,3-DPG concentration.
Cohen-Solal
M
M
INSERM U474, Hôpital Henri Mondor, Créteil, France.
Préhu
C
C
Wajcman
H
H
Poyart
C
C
Bardakdjian-Michau
J
J
Kister
J
J
Promé
D
D
Valentin
C
C
Bachir
D
D
Galactéros
F
F
D000328:Adult; D000755:Anemia, Sickle Cell / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005914:Globins / Q000235:genetics*; D006451:Hemoglobin, Sickle / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011770:Pyruvate Kinase / Q000172:deficiency* / Q000235:genetics
D006451:Hemoglobin, Sickle; D005914:Globins; D011770:Pyruvate Kinase; D010100:Oxygen