Homozygous or compound heterozygous for Pyruvate Kinase (PK) deficiency are classical etiology for chronic non spherocytic hemolytic anemias while heterozygous carriers are free from disease. We report here 2 patients heterozygous for PK deficiency which displayed an unexpected marked chronic anemia. Enzymatic and molecular studies were performed to unravel the mechanism causing this phenotype. The first patient, a 60-year-old woman from Mali presented with Hb 10g/dL, MCV 98fL, and was free from any Hb abnormality. The second one was the first child of a healthy French Caucasian couple, and suffered since birth from a marked hemolytic anemia (Hb 7g/dL). We found that the first patient carried together an Arg569Met/Leu PK-R mutation (
Pissard et al. Brit J Haematol, 2006, 133, 683-9
) and the rare G6PD Santa Maria mutation (nt c.542 A>T, Asp181Val). The second patient had a PK splice site mutation (IVS4 + 10 G>T) and a new hexokinase mutation [c.1793_c.1836 +7(del 50)] which starts in exon 12 and ends in intron 12. It results in a protein troncated inside the glucose binding site. In this case, family study showed that the PK deficiency was inherited from the father and the HK deficiency from the mother. Enzymatic data are shown in the table. None of these enzymatic defects could alone, in the heterozygous state, be responsible for an hemolytic anemia. To explain why, in these two cases the combination of two defects resulted in a hemolytic disease, we hypothesized that the increase of the intra-erythrocytic 2,3-DPG level resulting from the PK-R deficiency might cause these disorders. It is well known that increase of the 2,3-DPG level dramatically change several properties of the RBCs such as a decrease in oxygen affinity and an inhibition of the G6PD activity (Tomoda A. Brit J Haematol, 1983, 54, 475 – 84
). It has been shown that, when associated to a sickle cell trait, PK-R deficiency by increasing 2,3-DPG leads to sickle cell anemia (Cohen.Solal M. et al, Brit J Haematol, 1998, 103, 950-6
). We propose that, in these two patients, the global mechanism leading to the disease results from the increased 2,3-DPG which cause a failure in the anti oxidant pathway. In the first case G6PD inhibition occurs along with a mutated enzyme and in the second one inhibition take place in a under supplied pentose phosphate pathway due to the hexokinase deficiency. Together with the diminished ATP supply of the cell, this decreased anti-oxidant activity might cause the hemolysis. Thus in any anemic heterozygous PK deficient patient, another RBC abnormality needs to be searched for.| patients
. | Pk activity (5.9–8.1)
. | g6pd activity (5.3–7.9)
. | hexokinase activity (0.74–1.14)
. | 2.3 DPG (11.7–15.3)
. |
|---|
| nd : not determined |
| 1 | 3.2 UI/g Hb | 4.5 UI/g Hb | nd | 21.2 μM /g Hb |
| 2 | 6.8 UI /g Hb | 9.2 UI /g Hb | 0.3 UI / g Hb | 36.8 μM /g Hb |
| patients
. | Pk activity (5.9–8.1)
. | g6pd activity (5.3–7.9)
. | hexokinase activity (0.74–1.14)
. | 2.3 DPG (11.7–15.3)
. |
|---|
| nd : not determined |
| 1 | 3.2 UI/g Hb | 4.5 UI/g Hb | nd | 21.2 μM /g Hb |
| 2 | 6.8 UI /g Hb | 9.2 UI /g Hb | 0.3 UI / g Hb | 36.8 μM /g Hb |
Disclosure: No relevant conflicts of interest to declare.
