bims-conane 2025-03-02 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–03–02
seven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Combined heterozygosity for hemoglobin Paksé, α-thalassemia and for hemoglobin E, β- thalassemia ̵ first appearance in Europe.
Are Mitochondria a Potential Target for Treating β-Thalassemia?
Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of the ALAS2 gene leading to X-linked sideroblastic anemia-a family study.
Clinical characteristics of hereditary spherocytosis with red blood cell membrane protein gene variants.
Unveiling the role of RPS17 and SLC4A1 in diamond-Blackfan Anemia: A zebrafish-based study.
An overview of hereditary spherocytosis and the curative effects of splenectomy.
Correlation of Genetic Mutation With Outcomes in Children With Hereditary Spherocytosis Undergoing Partial Splenectomy: A Multicentre Study.

Ann Hematol. 2025 Feb 28.

Combined heterozygosity for hemoglobin Paksé, α-thalassemia and for hemoglobin E, β- thalassemia ̵ first appearance in Europe.

Wolfgang J Schnedl, Georg Leixner, Astrid Voill-Glaninger, Simon Michaelis, Dietmar Enko, Harald Mangge.

  Hemoglobinopathies are among the most common inherited diseases and they are believed to be one of the major etiologic factors contributing to anemia. Thalassemia is characterized by an altered hemoglobin (Hb) chain synthesis and may appear as alpha-(α-)thalassemia and/or beta-(β-)thalassemia. The clinical manifestations of thalassemia may range from asymptomatic to severe, with the potential to ultimately result in death. The search for an underlying cause was prompted by the discovery of an asymptomatic patient of Thai origin with microcytic anemia and no iron deficiency during a routine hematological examination. Genetic sequencing results revealed Hb Paksé, α2 CD 142 [A > T] (HBA2:c.429 A > T) and HbE β2 CD 26 [G > A] (HBB: c.79 G > A). It is essential that the identification and knowledge of Hb mutations facilitate the clinical recognition, genetic testing, and counseling of patients with thalassemia. The combination of two thalassemia Hb variants, one in the α-globin gene as Hb Paksé and one in β-globin gene as Hb E, in a single individual is occasionally described in East Asia. The first appearance of combined heterozygosity for Hb Paksé, and Hb E in Europe provides evidence that this is the result of a migration-caused occurrence.

Keywords:  Alpha-thalassemia; Beta-thalassemia; Hemoglobin E; Hemoglobin Paksé; Hemoglobin varian

DOI:  https://doi.org/10.1007/s00277-025-06286-1
J Clin Med. 2025 Feb 08. pii: 1095. [Epub ahead of print]14(4):

Are Mitochondria a Potential Target for Treating β-Thalassemia?

Elena Di Pierro, Valeria Di Stefano, Margherita Migone De Amicis, Giovanna Graziadei.

  The inherited genetic disorder β-thalassemia affects the hematopoietic system and is caused by the low production or absence of adult hemoglobin (HbA). Ineffective erythropoiesis is the hallmark of β-thalassemia pathophysiology and is characterized by an erythropoietin-driven substantial increase in erythroblast proliferation, coupled with an increase in late-stage precursor apoptosis, which results in low levels of circulating mature red blood cells (RBCs) and chronic anemia. Mitochondrial dysfunction commonly occurs in these cells because of the increased demand for energy production and the need to manage abnormal hemoglobin chain synthesis. Moreover, several studies have highlighted the importance of gradual mitochondrial clearance for mature erythroid cell production. This review offers an overview of the mitochondrial role in essential cellular processes, particularly those crucial for maintaining RBC health and function. Additionally, recent evidence regarding the contribution of mitochondrial dysfunction to the pathophysiology and severity of β-thalassemia is discussed, along with updated insights into indirect mitochondria-targeting treatments, which present potential pharmacological targets.

Keywords:  ineffective erythropoiesis; mitochondria; β-thalassemia

DOI:  https://doi.org/10.3390/jcm14041095
Front Med (Lausanne). 2024 ;11 1452873

Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of the ALAS2 gene leading to X-linked sideroblastic anemia-a family study.

Salam Al Kindi, Altaf Al-Mamari, Shoaib Al-Zadjali, Mohamed Al-Rawahi, Ali Al Madhani, Anil V Pathare.

  X-linked sideroblastic anemia (XLSA) (MIM 300752) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. It is due to mutations of the erythroid-specific enzyme ALAS2, the first enzyme of the heme biosynthetic pathway. Herein, we report a novel 11-bp deletion in exon 11 leading to a frameshift in the C-terminal region of the ALAS2 gene with a non-functional longer polypeptide of 614 amino acids leading to a loss-of-function mutation manifested as an X-linked sideroblastic anemia phenotype. The proband was a 29-year-old man with moderately severe microcytic hypochromic anemia with splenomegaly and increased ring sideroblasts in the bone marrow with considerable iron overload. Sanger sequencing documented a missense mutation leading to a frameshift with an elongated polypeptide of 614 AA instead of the normal 587 AA protein c.1743_1753 del (p.Gln581Hisfs*35). This mutation affected the interaction with cofactor pyridoxal 5'-phosphate since the patient's hemoglobin improved with oral administration of pyridoxine tablets. His iron overload also responded to sustained oral iron chelation therapy with deferasirox. The screening of the entire family's kindred revealed that two other male siblings were also hemizygous for the same mutation with hypochromic microcytic anemia and tissue iron overload, whereas, three female siblings and their mother were heterozygous for the mutant allele. They did not have anemia or iron overload.

Keywords:  ALAS2; X-linked; XLSA; congenital; sideroblastic anemia

DOI:  https://doi.org/10.3389/fmed.2024.1452873
Front Pediatr. 2025 ;13 1523288

Clinical characteristics of hereditary spherocytosis with red blood cell membrane protein gene variants.

Jingying Cheng, Liqiang Zhang, Jiafeng Yao, Shasha Zhao, Jin Jiang.

  The clinical manifestations of hereditary spherocytosis (HS) are often heterogeneous, spanning from asymptomatic to severe symptoms that may pose life-threatening risks. Genotype-phenotype correlations remain controversial in clinical research. This retrospective study evaluated the correlation between genetic variants and clinical characteristics in a cohort of 64 Chinese pediatric patients with HS. The predominant variants were found in the ANK1 (27 cases, 42%) and SPTB (26 cases, 41%) genes, while variants in the SPTA1 (6 cases, 9%) and SLAC4A1 genes (5 cases, 8%) were less common. No EPB42 variants were detected. A total of 71 variants were identified. Variation types included nonsense (21%), missense (27%), frameshift mutations (39%), splicing (8%), and large fragment deletions (4%). No statistical differences in hemoglobin levels, MCV, MCH, MCHC, or reticulocytes were observed across the various genetic variant groups. Bilirubin levels were remarkably elevated in patients with HS variants, and those with SPTB-HS had significantly higher bilirubin levels, including total bilirubin (p = 0.033) and indirect bilirubin (p = 0.018) compared to those with SPTA1-HS. Moreover, those with the ANK1 variants displayed reduced resistance to lysis at varying NaCl concentrations in comparison to those with the SPTA1 variants (p = 0.047). In short, patients with the ANK1 and SPTB variants had the most severe disease, while those with the SPTA1 variants had the mildest. Genetic testing is advised in patients without a family history or who are difficult to diagnose with routine laboratory tests, as this may also provide references for clinical treatment and genetic counseling.

Keywords:  genetic testing; hereditary spherocytosis; pathogenic variants; red blood cell membrane protein; splenectomy

DOI:  https://doi.org/10.3389/fped.2025.1523288
Blood Cells Mol Dis. 2025 Feb 25. pii: S1079-9796(25)00004-X. [Epub ahead of print]112 102912

Unveiling the role of RPS17 and SLC4A1 in diamond-Blackfan Anemia: A zebrafish-based study.

Kyeongmin Kim, Hyerin Lee, Soyul Ahn, Yun Hak Kim, Chang-Kyu Oh.

  Diamond-Blackfan Anemia (DBA) is a rare congenital disorder characterized by macrocytic anemia, physical abnormalities, and growth delays. Although RPS19 mutations have been more extensively studied in DBA compared to other ribosomal protein genes, the pathological mechanisms of genes such as RPS17 remain largely unexplored. This study aimed to investigate the role of RPS17 haploinsufficiency in DBA, focusing on its downstream effects on erythropoiesis and the involvement of SLC4A1, a critical erythrocyte membrane protein essential for red blood cell stability. Transcriptomic analysis of publicly available RNA sequencing data from DBA patients revealed significant downregulation of SLC4A1 in RPS17-mutated cases. To validate these findings, we generated a zebrafish model of DBA by knocking down rps17 using morpholino injections. Zebrafish embryos with rps17 knockdown exhibited reduced erythropoiesis, impaired hemoglobin synthesis, consistent with DBA. Further analysis confirmed decreased slc4a1a expression in rps17-morphants. Independent knockdown of slc4a1a in zebrafish resulted in similar erythropoietic defects, highlighting its critical role in red blood cell membrane integrity and function. This study identifies slc4a1 as a key downstream target of RPS17 haploinsufficiency and provides novel insights into the molecular mechanisms of DBA. By establishing zebrafish as an effective in vivo model, this research offers potential therapeutic targets for treating DBA and related erythropoietic disorders.

Keywords:  Diamond-Blackfan Anemia; RNA sequencing; RPS17; SLC4A1; Zebrafish

DOI:  https://doi.org/10.1016/j.bcmd.2025.102912
Front Physiol. 2025 ;16 1497588

An overview of hereditary spherocytosis and the curative effects of splenectomy.

Kyril Turpaev, Elizaveta Bovt, Soslan Shakhidzhanov, Elena Sinauridze, Nataliya Smetanina, Larisa Koleva, Nikita Kushnir, Anna Suvorova, Fazoil Ataullakhanov.

  Hereditary spherocytosis is a common hemolytic anemia with different severity. The causes of hereditary spherocytosis are mutations in genes that encode red blood cell (RBC) membrane and cytoskeletal proteins, including ankyrin-1, Band 3 (or AE1), α spectrin, β spectrin, and protein 4.2. Molecular defects in these proteins decrease membrane integrity, leading to vesiculation, decreased membrane surface area, and reduced deformability of the cells. Eventually, this leads to the trapping the abnormal RBCs (spherocytes) in the spleen. In most severe cases, splenectomy may be necessary to prevent general RBC collapse during the passage of RBCs through the narrow slits of venous sinuses in the spleen. The clinical benefit of splenectomy results from elimination the primary site of RBC damage and destruction. Splenectomy is a curative approach but can cause complications and should be undertaken after examination by various laboratory approaches. Splenectomy does not correct most genetically determined membrane abnormalities in erythrocytes in patients with hereditary spherocytosis. The transformation of biconcave erythrocytes into spherocytes continues, although to a lesser degree than before surgery. Nevertheless, splenectomy increases the lifespan of red cells, significantly reducing the severity of anemia and improving many physiological signs of HS.

Keywords:  erythrocyte cytoskeleton; erythrocyte deformability; gene mutations; hereditary spherocytosis; interendothelial slits; microcirculation; spherocytes; splenectomy

DOI:  https://doi.org/10.3389/fphys.2025.1497588
J Pediatr Surg. 2025 Jan 30. pii: S0022-3468(25)00074-0. [Epub ahead of print]60(4): 162229

Correlation of Genetic Mutation With Outcomes in Children With Hereditary Spherocytosis Undergoing Partial Splenectomy: A Multicentre Study.

Joshua K Ramjist, Tamara Dubljevic, Eveline Lapidus-Krol, Rachael F Grace, Matthew M Heeney, Morohuntodun O Oni, Alison Towerman, Andrew Davidoff, Clifford Takemoto, Rebeccah L Brown, Joseph Brungardt, Makenzie Beaman, Henry E Rice, Shari Nichols, Payam Saadai, Manuel Carcao, Jacob C Langer.

   PURPOSE: Hereditary Spherocytosis (HS) is a common genetic hematological disorder causing a life-long hemolytic anemia, with sequela of hemolysis. Children with severe HS commonly undergo partial or total splenectomy (PS, TS); PS confers the theoretical advantage of maintaining splenic immune function, but may be associated with regrowth, ongoing hemolysis, and need for completion splenectomy. HS can be caused by 5 different pathogenic gene variants. A rare and severe form is caused by homozygous/compound heterozygous mutations in the SPTA1 gene, coding for alpha spectrin. We hypothesized this form of HS is associated with worse outcomes following PS.
METHODS: Following REB approval, a retrospective chart review of children with HS undergoing PS between 2000 and 2023 was conducted across 7 sites in the USA and Canada. Pre- and post-operative hematological values and need for completion splenectomy were analyzed. P < 0.05 was significant.
RESULTS: Of 51 eligible patients, 10 had SPTA and 41 had non-SPTA1 HS. The SPTA1 group underwent PS at a younger age to non-SPTA1 (5.1 vs 9.6 yr, p = 0.003), and had lower pre-operative hemoglobin (86.2 vs 98.8 g/L, p = 0.04). There were no differences between groups regarding peri-operative surgical or hematological outcomes. The SPTA1 group required completion splenectomy at a higher rate than the non-SPTA1 group (70.0 % vs 24.4 %, p = 0.01).
CONCLUSION: Children with SPTA1 HS are more likely to require completion splenectomy following PS than children with other HS-causing mutations. These results support the role of genetic testing to permit an evidence-based individualized approach to patient selection for partial vs. total splenectomy.
LEVEL OF EVIDENCE: III.

Keywords:  ANK1; Completion splenectomy; Genetic mutation; Hereditary spherocytosis; Partial splenectomy; SPTA1

DOI:  https://doi.org/10.1016/j.jpedsurg.2025.162229