Hereditary deficiency of phosphoglycerate kinase: a new variant in erythrocytes and leucocytes, not associated with haemolytic anaemia

Abstract

An X-chromosome linked phosphoglycerate kinase deficiency in erythrocytes and leucocytes was discovered in a large German kindred. Seven males of two generations were found to have only 21% of the normal enzyme activity in their erythrocytes, and twelve females of three generations showed various degrees of this defect. The differences in the expression of the deficiency in heterozygote females are explained by the Lyon hypothesis. The deficiency is caused by a variant enzyme, named phosphoglycerate kinase München. Although it differs from the normal enzyme electrophoretically, the two enzymes resemble one another closely in many respects. They have essentially the same Km for the substrates of the backward reaction, identical pH optima and similar rates of thermal inactivation. In contrast to the nine previously described phosphoglycerate kinase deficiencies, all of which are associated with haemolytic anaemia, the carriers of phosphoglycerate kinase München show no overt clinical symptoms. The erythrocyte concentrations of adenine nucleotides and 2,3-diphosphoglycerate are normal.

Phosphoglycerate kinase deficiency in two brothers with McArdle‐like clinical symptoms

“…To our knowledge all of these patients were one-off, sporadic cases. Familial-reduced PGK activity has been reported in a German family (Krietsch et al, 1977), however the affected males had no clinical manifestations.…”

A new variant of phosphoglycerate kinase deficiency (p.I371K) with multiple tissue involvement: Molecular and functional characterization

“…The mechanisms by which a reduction of PGK1 activity causes the clinical symptoms have not so far clearly understood. It has been proposed that the decrease of ATP levels and of the ATP/ADP ratio may induce hemolysis as observed in other hemolytic anemias due to glycolytic defects [27,28], although it seems that the PGK1 reaction is not rate limiting for ATP production in RBC, at least as long as the residual enzyme activity is above 20% [29]. Moreover, in cases of severe PGK deficiency, an increase of RBC 2,3-BPG levels could contribute to reducing ATP production through the inhibition of several glycolytic enzymes (such as hexokinase, phosphofructokinase, and pyruvate kinase) and the acidification of the intracellular medium [29][30][31][32][33].…”

PGK deficiency

“…While most of the remaining known mutations of the PGK1 gene were identified by investigating patients with clinical disease, there is one exception. PGK München was found by screening 3000 normal blood samples for decreased PGK activity (Krietsch et al , 1977). Presumably because the residual activity of this variant is 21% of normal, no clinical or biochemical abnormalities seem to result.…”