A Family Affected by a Life-Threatening Erythrocyte Defect Caused by Pyruvate Kinase Deficiency With Normal Iron Status: A Case Report.

Karolina Maciak,Monika Gora,Anna Adamowicz-Salach,Beata Burzynska,Jaroslaw Poznanski,Jan Fronk

doi:10.3389/fgene.2020.560248

Abstract

BackgroundRed cell pyruvate kinase deficiency (PKD) is a defect of glycolysis causing congenital non-spherocytic hemolytic anemia. PKD is transmitted as an autosomal recessive trait. The clinical features of PKD are highly variable, from mild to life-threatening anemia which can lead to death in the neonatal period. Most patients with PKD must receive regular transfusions in early childhood and as a consequence suffer from iron overloading.PatientHere, we report a Polish family with life-threatening hemolytic anemia of unknown etiology. Whole exome sequencing identified two heterozygous mutations, c.1529 G > A (p.R510Q) and c.1495 T > C (p.S499P) in the PKLR gene. Molecular modeling showed that the both PKLR mutations are responsible for major disturbance of the protein structure and functioning. Despite frequent transfusions the patients do not show any signs of iron overload and hepcidin, a major regulator of iron uptake, is undetectable in their serum. The patients were homozygous for the rs855791 variant of the TMPRSS6 gene which has earlier been shown to down-regulate iron absorption and accumulation.ConclusionThe lack of iron overload despite a reduced level of hepcidin in two transfusion-dependent PKD patients suggests the existence of a hepcidin-independent mechanism of iron regulation preventing iron overloading.

Highlights

Pyruvate kinase deficiency (PKD) is a common cause of hereditary non-spherocytic hemolytic anemia
We report a Polish family with two sons carrying a compound defect of the PKLR gene causing a life-threatening hemolytic anemia
The Whole exome sequencing (WES) data showed 42,823 and 41,937 SNPs along with 5402 and 5,137 small insertions or deletions. They were inspected for mutations in the 71 known hereditary anemia genes (Russo et al, 2018)

Summary

Introduction

Pyruvate kinase deficiency (PKD) is a common cause of hereditary non-spherocytic hemolytic anemia. Most patients with PKD must receive regular transfusions in early childhood and as a consequence suffer from iron overloading (Zanella et al, 2007). Even in nonregularly transfused patients, iron overload has been reported (Van Beers et al, 2019). Red cell pyruvate kinase deficiency (PKD) is a defect of glycolysis causing congenital non-spherocytic hemolytic anemia. Most patients with PKD must receive regular transfusions in early childhood and as a consequence suffer from iron overloading. Despite frequent transfusions the patients do not show any signs of iron overload and hepcidin, a major regulator of iron uptake, is undetectable in their serum. The patients were homozygous for the rs855791 variant of the TMPRSS6 gene which has earlier been shown to down-regulate iron absorption and accumulation

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Conclusion