Genotype-phenotype relationship in pyruvate kinase deficiency: baseline transfusion dependence and splenectomy response

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Introduction: Pyruvate kinase deficiency is a congenital anemia treated mainly with transfusion support and splenectomy. Classically, the genotype-transfusion requirement relationship has been studied by considering whether mutations do or do not determine amino acid changes, thus ignoring other relevant molecular mechanisms. Objective: To reclassify mutations based on severity and study the association among genotypes with transfusion dependence (TD) at baseline and after splenectomy.Method: We analyzed a cohort of 58 patients with pyruvate kinase deficiency.Their mutations were categorized as severe (S), intermediate (I), or mild (M) based on former studies and the results of bioinformatic analyses.Results: Regarding baseline TD, significant differences have been reported among patients without mild mutations (genotypes I/I, S/I, and S/S; 94% TD) compared to the group with, at least, 1 mild mutation (genotypes M/M, M/I, and M/S; 36% TD) (p = 0.000).In splenectomized patients, TD is not resolved after the procedure in 67% of patients with genotypes S/S and S/I, which has only been reported in 17.6% of other patients (p = 0.025).Conclusions: Our categorization allows for significant genotype-phenotype associations to be established.These findings may be useful to assess other treatments in patients with baseline transfusion dependence.

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