Hereditary erythrocyte adenylate kinase deficiency: a defect of multiple phosphotransferases?

Abstract

Adenylate kinase (AK) modulates the interconversion of adenine nucleotides (AMP + adenosine triphosphate----2 ADP). We evaluated the fifth kindred with hereditary erythrocyte (RBC) AK deficiency. The proband had chronic hemolytic anemia. Her RBC had undetectable AK activity when measured spectrophotometrically, whereas those of her parents had half-normal AK activity. AK electrophoresis showed only AK- 1 in the parents. The activities of pyruvate kinase and phosphoribosylpyrophosphate synthetase were decreased given the young age of the proband's RBC. Despite the absence of spectrophotometric AK activity, the proband's RBC were able to incorporate 14C-adenine into 14C-adenine nucleotides at 50% of the rate expected for her young RBC population, suggesting the possibility of an alternative pathway for the formation of ADP from AMP. Normal hemolysate had AMP:guanosine triphosphate (GTP) phosphotransferase activity, which produced ADP at 8% to 9% of the rate of AK (6.8 +/- 0.8 IU/mL RBC). AMP:GTP phosphotransferase activity was not detectable in the proband's or parent's hemolysates. These additional biochemical defects in the AK- deficient RBC further support the concept that AK deficiency per se may not cause hemolytic anemia. We propose that defects occur in multiple phosphotransferases in the AK-deficient RBC and that these other biochemical defects may produce deleterious lesions that promote the shortened RBC survival in AK deficiency.

A case of complete adenylate kinase deficiency due to a nonsense mutation in AK-1 gene (Arg 107 Stop, CGA TGA) associated with chronic haemolytic anaemia

“…Following this observation, the cause-effect relationship between AK deficiency and hyperhaemolysis has been questioned. Some authors claimed that the shortened survival of AK-deficient RBC was caused, or at least enhanced, by the coexistence of defects of other enzymes such as phosphorybosil pyrophosphate synthetase, pyruvate kinase and AMP:GTP phosphotransferase (Lachant et al, 1991), G6PD (Szeinberg et al, 1969;Toren et al, 1994), or other unidentified factors (Matsuura et al, 1989).…”

“…In the present case no red cell abnormalities other than AK deficiency were detected, in spite of extensive membrane and metabolic studies. The slightly decreased PFK activity is probably the consequence of the increased 2,3-DPG levels (Mentzner & Glader, 1989) that are almost constantly found in AK deficiency (Beutler et al, 1983;Lachant et al, 1991). The remote possibility that a PK dysfunction could account for the increased 2,3-DPG was ruled out by the normal results of PK biochemical characterization.…”

“…Six AK1-deficient families have been reported (Szeinberg et al, 1969;Boivin et al, 1971;Kende et al, 1982;Beutler et al, 1983;Miwa et al, 1983;Lachant et al, 1991;Toren et al, 1994;Qualtieri et al 1997), but only in two was the molecular defect identified as missense mutations CGG-TGG Arg128-Trp and TAT-TGT Tyr164-Cys (Matsuura et al, 1989;Qualtieri et al, 1997). From a clinical point of view, erythrocyte AK deficiency is associated with chronic nonspherocytic haemolytic anaemia in all cases but one (Beutler et al, 1983), and with psychomotor impairment in some patients only (Boivin et al, 1971;Toren et al, 1994).…”

“…From a clinical point of view, erythrocyte AK deficiency is associated with chronic nonspherocytic haemolytic anaemia in all cases but one (Beutler et al, 1983), and with psychomotor impairment in some patients only (Boivin et al, 1971;Toren et al, 1994). However, the direct relationship between the reduced erythrocyte survival and the enzyme defect has been questioned by some authors and other concomitant causes of haemolysis have been hypothesized (Beutler et al, 1983;Lachant et al, 1991;Toren et al, 1994).…”