Metabolic compensation for profound erythrocyte adenylate kinase deficiency. A hereditary enzyme defect without hemolytic anemia.

Abstract

A B S T R A C T A child with hemolytic anemia was found to have severe erythrocyte adenylate kinase (AK) deficiency, but an equally enzyme-deficient sibling had no evidence of hemolysis. No residual enzyme activity was found in erythrocytes by spectrophotometric methods that could easily have detected 0.1% of normal activity. However, concentrated hemolysates were shown to have the capacity to generate small amounts of ATP and AMP from ADP after prolonged incubation. Hemolysates could also catalyze the transfer of labeled -y-phosphate from ATP to ADP. Intact erythrocytes were able to transfer phosphate from the "y-position of ATP to the ,B-position, albeit at a rate substantially slower than normal. They could also incorporate 4CG-labeled adenine into ADP and ATP. Thus, a small amount of residual AK-like activity representing about 1/2,000 of the activity normally present could be documented in the deficient erythrocytes. The residual activity was not inhibited by N-ethylmaleimide, which completely abolishes the activity of the normal AK1 isozyme of erythrocytes. The minute amount of residual activity in erythrocytes could represent a small amount of the AK2 isozyme, which has not been thought to be present in erythrocytes, or the activity of erythrocyte guanylate kinase with AMP substituting as substrate for GMP.Peripheral blood leukocytes, cultured skin fibroblasts, and transformed lymphoblasts from the deficient subject manifested about 17, 24, and 74%, respectively, of the activity of the concurrent controls. This residual activity is consistent with the existence of genetically independent AK isozyme, AK2, which is known to exist in these tissues.

Use of Mathematical Models for Predicting the Metabolic Effect of Large-Scale Enzyme Activity Alterations. Application to Enzyme Deficiencies of Red Blood Cells

“…Generally, the results of the models for these enzymes fit better with observations found in those probationers equipped with the lowest activities reported. For example, Beutler et al (1983) describes one case of AK deficiency, where two siblings had activities less than 0.05%. The girl had periodical hemolytic episodes whereas her brother was free of symptomes.…”

Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia

“…[1][2][3][4][5][6][7][8][9] Moderate to severe chronic nonspherocytic hemolytic anemia (CNSHA) occurred in all patients except one of black ancestry. 4 Therefore, the direct relationship between the reduced erythrocyte survival and the enzyme defect has been questioned by some authors, and other concomitant causes of hemolysis have been hypothesized. 4,6,7 Psychomotor impairment has been also observed in about 50% of the reported cases.…”

“…4 Therefore, the direct relationship between the reduced erythrocyte survival and the enzyme defect has been questioned by some authors, and other concomitant causes of hemolysis have been hypothesized. 4,6,7 Psychomotor impairment has been also observed in about 50% of the reported cases. 2,7,9 We report here for the first time 2 cases of moderate red cell AK deficiency associated with CNSHA; 1 of them represents the first description of this enzymopathy in Spain.…”

Severe erythrocyte adenylate kinase deficiency due to homozygous A → G substitution at codon 164 of human AK1 gene associated with chronic haemolytic anaemia

“…Five families with AK deficiency associated with non-spherocytic chronic haemolytic anaemia have been reported to date and in the cases reported by Miwa et al (1983), Boivin et al (1971) and Beutler et al (1983) no other concomitant RBC disorders were reported. In the case described by Beutler et al (1983), however, one of the proband's brothers had also a complete AK deficiency but did not suffer from chronic haemolytic anaemia. This finding suggested that a clear cause-and-effect relationship between AK deficiency and congenital haemolytic anaemia had not been established.…”