scholarly journals Severe iron overload in a woman with homeostatic iron regulator ( HFE ) and a novel 5ʹ‐aminolevulinate synthase 2 (ALAS2 ) mutations: interactions of multiple genetic determinants

2021 ◽  
Author(s):  
Christian Gennes ◽  
Jérôme Lamoril ◽  
Adrien Borgel ◽  
Camille Boi ◽  
Raphael Yao ◽  
...  
Keyword(s):  
Iron Overload ◽  
Genetic Determinants ◽  
Aminolevulinate Synthase

Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia: Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1757-1769 ◽  
Author(s):  
Philip D. Cotter ◽  
Alison May ◽  
Liping Li ◽  
A.I. Al-Sabah ◽  
Edward J. Fitzsimons ◽  
...  
Keyword(s):  
Iron Overload ◽  
De Novo ◽  
Normal Population ◽  
Hereditary Hemochromatosis ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
C282y Homozygote ◽  
New Mutations

X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

Three Kinships with ALAS2 P520L Mutations, Two in Association with Severe Iron Overload, and One with Sideroblastic Anemia and Severe Iron Overload.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3723-3723
Author(s):  
Pauline L. Lee ◽  
James C. Barton ◽  
Sreenivas V. Rao ◽  
Ronald T. Acton ◽  
Brian K. Adler ◽  
...  
Keyword(s):  
Iron Overload ◽  
Novel Mutation ◽  
White Male ◽  
Missense Mutations ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
C282y Homozygote ◽  
Sequencing Studies ◽  
Unknown Gene ◽  
Distinctive Phenotype

Abstract Aminolevulinate synthase 2 (ALAS2) is an erythroid-expressed gene located on chromosome Xp11.21. Mutations in ALAS2 have been shown to be associated with sideroblastic anemia. We have identified a novel mutation in ALAS2, P520L, in three kinships. The P520L mutation was not found in 316 white male control subjects. The proline in this position is highly conserved across species from humans to zebrafish. In the C kinship, the P520L mutation was first identified in a white man who presented with severe iron overload at an early age and was a HFE C282Y homozygote. Genetic analyses of members of the C kinship suggest that the presence of P520L alone in hemizygous males, or simple heterozygosity in females, is not associated with anemia or iron overload. Females heterozygous for both HFE C282Y and ALAS2 P520L also had normal ferritin levels. Only subjects homozygous for HFE C282Y and hemizygous or heterozygous for ALAS2 P520L had severe iron overload. Sequencing studies revealed that the propositus did not have missense mutations in HAMP, HJV, FPN1, ABC7, IL6, or RAG1. In the H kinship, the propositus was a white woman with severe iron overload who was heterozygous for ALAS2 P520L; she had a wildtype HFE genotype. The pedigree of the H kinship identified 5 additional females who were heterozygous for the P520L ALAS2 mutation. Only the propositus had iron overload and none of the subjects with P520L had sideroblastic anemia. The propositus did not have missense mutations in FPN1, HAMP, HJV, TFR2, B2M, IRP2, ABC7, or SFT. We speculate that the propositus in the H kinship has a mutation in a currently unknown gene that contributes to her severe iron overload. In the S kinship, the P520L mutation was identified in a white man with sideroblastic anemia and severe iron overload. The patient had a second mutation in ALAS2, R560H, a mutation previously described in two brothers with sideroblastic anemia of variable penetrance (Blood100:4236–4238, 2002). It is not possible to determine the effect of the P520L mutation on the penetrance of the R560H-associated sideroblastic anemia and iron overload. We conclude that the ALAS2 P520L occurs at a very low allele frequency in the white population. The present observations also suggest that there is no distinctive phenotype associated with the P520L mutation alone, but that P520L may act as a modifier of iron overload in the presence of HFE homozygosity, other missense mutations of ALAS2, or mutations of uncharacterized iron regulatory genes.

Four New Mutations in the Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene Causing X-Linked Sideroblastic Anemia: Increased Pyridoxine Responsiveness After Removal of Iron Overload by Phlebotomy and Coinheritance of Hereditary Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1757-1769 ◽  
Author(s):  
Philip D. Cotter ◽  
Alison May ◽  
Liping Li ◽  
A.I. Al-Sabah ◽  
Edward J. Fitzsimons ◽  
...  
Keyword(s):  
Iron Overload ◽  
De Novo ◽  
Normal Population ◽  
Hereditary Hemochromatosis ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
C282y Homozygote ◽  
New Mutations

Abstract X-linked sideroblastic anemia (XLSA) in four unrelated male probands was caused by missense mutations in the erythroid-specific 5-aminolevulinate synthase gene (ALAS2). All were new mutations: T647C, C1283T, G1395A, and C1406T predicting amino acid substitutions Y199H, R411C, R448Q, and R452C. All probands were clinically pyridoxine-responsive. The mutation Y199H was shown to be the first de novo XLSA mutation and occurred in a gamete of the proband’s maternal grandfather. There was a significantly higher frequency of coinheritance of the hereditary hemochromatosis (HH)HFE mutant allele C282Y in 18 unrelated XLSA hemizygotes than found in the normal population, indicating a role for coinheritance ofHFE alleles in the expression of this disorder. One proband (Y199H) with severe and early iron loading coinherited HH as a C282Y homozygote. The clinical and hematologic histories of two XLSA probands suggest that iron overload suppresses pyridoxine responsiveness. Notably, reversal of the iron overload in the Y199H proband by phlebotomy resulted in higher hemoglobin concentrations during pyridoxine supplementation. The proband with the R452C mutation was symptom-free on occasional phlebotomy and daily pyridoxine. These studies indicate the value of combined phlebotomy and pyridoxine supplementation in the management of XLSA probands in order to prevent a downward spiral of iron toxicity and refractory anemia.

scholarly journals The porphyrias: advances in diagnosis and treatment

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4496-4504 ◽  
Author(s):  
Manisha Balwani ◽  
Robert J. Desnick
Keyword(s):  
Stem Cell ◽  
Iron Overload ◽  
Porphyria Cutanea Tarda ◽  
Molecular Genetic ◽  
Diagnosis And Treatment ◽  
Decarboxylase Activity ◽  
Erythropoietic Protoporphyria ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Aminolevulinate Synthase

Abstract The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as “acute hepatic,” “hepatic cutaneous,” and “erythropoietic cutaneous” diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.

scholarly journals Iron overload in thalassemia: different organs at different rates

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 265-271 ◽  
Author(s):  
Ali T. Taher ◽  
Antoine N. Saliba
Keyword(s):  
Iron Overload ◽  
Imaging Techniques ◽  
Globin Gene ◽  
Iron Chelation ◽  
Response To Therapy ◽  
Clinical Severity ◽  
Iron Loading ◽  
Genetic Determinants ◽  
Transfusion Therapy ◽  
Treatment And Prevention

Abstract Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.

scholarly journals The porphyrias: advances in diagnosis and treatment

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 19-27 ◽  
Author(s):  
Manisha Balwani ◽  
Robert J. Desnick
Keyword(s):  
Stem Cell ◽  
Iron Overload ◽  
Porphyria Cutanea Tarda ◽  
Molecular Genetic ◽  
Diagnosis And Treatment ◽  
Decarboxylase Activity ◽  
Erythropoietic Protoporphyria ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Aminolevulinate Synthase

Abstract The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as “acute hepatic,” “hepatic cutaneous,” and “erythropoietic cutaneous” diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.

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