TY - JOUR
T1 - A Novel ALAS2 Missense Mutation in Two Brothers With Iron Overload and Associated Alterations in Serum Hepcidin/Erythroferrone Levels
AU - Lira Zidanes, Acaynne
AU - Marchi, Giacomo
AU - Busti, Fabiana
AU - Marchetto, Alessandro
AU - Fermo, Elisa
AU - Giorgetti, Alejandro
AU - Vianello, Alice
AU - Castagna, Annalisa
AU - Olivieri, Oliviero
AU - Bianchi, Paola
AU - Girelli, Domenico
N1 - Funding Information:
This study was performed (in part) in the LURM (Laboratorio Universitario di Ricerca Medica) Research Center, University of Verona. Funding. This work was financially supported by the Fondazione IRCCS Ca? Granda Policlinico Milano, Project number RC2020 175/05.
Publisher Copyright:
© Copyright © 2020 Lira Zidanes, Marchi, Busti, Marchetto, Fermo, Giorgetti, Vianello, Castagna, Olivieri, Bianchi and Girelli.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/12
Y1 - 2020/11/12
N2 - Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. The prototype is non-transfusion dependent ß-thalassemia (NTDT), with other entities including congenital sideroblastic anemias, congenital dyserythropoietic anemias, some hemolytic anemias, and myelodysplastic syndromes. Differential diagnosis of iron loading anemias may be challenging due to heterogeneous genotype and phenotype. Notwithstanding the recent advances in linking ineffective erythropoiesis to iron overload, many pathophysiologic aspects are still unclear. Moreover, measurement of hepcidin and erythroferrone (ERFE), two key molecules in iron homeostasis and erythropoiesis, is scarcely used in clinical practice and of uncertain utility. Here, we describe a comprehensive diagnostic approach, including next-generation sequencing (NGS), in silico modeling, and measurement of hepcidin and erythroferrone (ERFE), in two brothers eventually diagnosed as X-linked sideroblastic anemia (XLSA). A novel pathogenic ALAS2 missense mutation (c.1382T>A, p.Leu461His) is described. Hyperferritinemia with high hepcidin-25 levels (but decreased hepcidin:ferritin ratio) and mild-to-moderate iron overload were detected in both patients. ERFE levels were markedly elevated in both patients, especially in the proband, who had a more expressed phenotype. Our study illustrates how new technologies, such as NGS, in silico modeling, and measurement of serum hepcidin-25 and ERFE, may help in diagnosing and studying iron loading anemias. Further studies on the hepcidin-25/ERFE axis in additional patients with XLSA and other iron loading anemias may help in establishing its usefulness in differential diagnosis, and it may also aid our understanding of the pathophysiology of these genetically and phenotypically heterogeneous entities.
AB - Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. The prototype is non-transfusion dependent ß-thalassemia (NTDT), with other entities including congenital sideroblastic anemias, congenital dyserythropoietic anemias, some hemolytic anemias, and myelodysplastic syndromes. Differential diagnosis of iron loading anemias may be challenging due to heterogeneous genotype and phenotype. Notwithstanding the recent advances in linking ineffective erythropoiesis to iron overload, many pathophysiologic aspects are still unclear. Moreover, measurement of hepcidin and erythroferrone (ERFE), two key molecules in iron homeostasis and erythropoiesis, is scarcely used in clinical practice and of uncertain utility. Here, we describe a comprehensive diagnostic approach, including next-generation sequencing (NGS), in silico modeling, and measurement of hepcidin and erythroferrone (ERFE), in two brothers eventually diagnosed as X-linked sideroblastic anemia (XLSA). A novel pathogenic ALAS2 missense mutation (c.1382T>A, p.Leu461His) is described. Hyperferritinemia with high hepcidin-25 levels (but decreased hepcidin:ferritin ratio) and mild-to-moderate iron overload were detected in both patients. ERFE levels were markedly elevated in both patients, especially in the proband, who had a more expressed phenotype. Our study illustrates how new technologies, such as NGS, in silico modeling, and measurement of serum hepcidin-25 and ERFE, may help in diagnosing and studying iron loading anemias. Further studies on the hepcidin-25/ERFE axis in additional patients with XLSA and other iron loading anemias may help in establishing its usefulness in differential diagnosis, and it may also aid our understanding of the pathophysiology of these genetically and phenotypically heterogeneous entities.
KW - ALAS2 gene
KW - ERFE
KW - hepcidin
KW - in silico modeling
KW - iron-loading anemias
KW - next-generation sequencing
KW - XLSA
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UR - http://www.scopus.com/inward/citedby.url?scp=85096772194&partnerID=8YFLogxK
U2 - 10.3389/fphys.2020.581386
DO - 10.3389/fphys.2020.581386
M3 - Article
AN - SCOPUS:85096772194
VL - 11
JO - Frontiers in Physiology
JF - Frontiers in Physiology
SN - 1664-042X
M1 - 581386
ER -