Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in thePKLRgene (p.Arg518fs), and low hepcidin to ferritin ratios

Abstract

Summary Pyruvate kinase (PK) deficiency is an iron‐loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease‐causing PKLR mutations. Two of these mutations ‐ the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) ‐ have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease‐causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK‐deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor‐15, were increased in PK‐deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as‐yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.

DMT1-Mutant Erythrocytes have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

“…The activity of enzymes involved in anaerobic glycolysis, oxidative-defense and nucleotide metabolism was determined according to the methods recommended by the International Committee for Standardization in Haematology [23], with the use of leukocytes- and platelets-free erythrocyte lysates as we previously described [24,25]. The measurements were adopted for mouse samples.…”

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

“…Imbalances in iron metabolism (including hepcidin levels) and their interconnection with defective erythropoiesis have been widely studied in β-thalassemia (intermedia and major) (ref. 10 ), congenital dyserythropoietic anemia 11 , pyruvate kinase deficiency 12 and DiamondBlackfan anemia 13 . In this study, we investigated the relationship between iron metabolism and erythropoietic activity in pediatric patients with erythrocyte membrane defects and thalassemia traits.…”

“…The serum hepcidin levels were measured by reversephase liquid chromatography using the UltiMate 3000 Nano LC System (Thermo Fisher Scientific, Sunnyvale, CA, USA) coupled to the QTRAP 5500 mass spectrometer (AB SCIEX, Framingham, MA, USA) as we previously described 12 . Hepcidin was determined for 47 healthy controls, 12 thalassemia carriers and 20 patients with erythrocyte membrane defect.…”

Addressing the diagnostic gaps in pyruvate kinase deficiency: Consensus recommendations on the diagnosis of pyruvate kinase deficiency

“…47,48 Coinheritance of hereditary hemochromatosis mutations has also been described in iron-overloaded, PK-deficient patients. In transfusion-independent PK deficient patients, the cause of iron overload is unclear but may involve a degree of ineffective erythropoiesis.…”

“…In transfusion-independent PK deficient patients, the cause of iron overload is unclear but may involve a degree of ineffective erythropoiesis. 47,48 Coinheritance of hereditary hemochromatosis mutations has also been described in iron-overloaded, PK-deficient patients. [49][50][51][52][53] Inappropriately low levels of hepcidin were detected in PK-deficient patients with increased ferritin and no mutations in genes associated with hereditary hemochromatosis, thereby confirming the predominant effect of accelerated erythropoiesis on hepcidin production.…”