bims-conane 2026-05-17 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2026–05–17
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

SNH-119014, a novel pyruvate kinase activator, enhances ATP production and reduces oxidative stress in erythroid cells from patients with β-thalassemia major.
Expanding the genetic spectrum of hereditary spherocytosis: novel mutations and phenotypic heterogeneity from a 55-patient cohort.
Expanding the PKLR mutation spectrum: discovery of two novel variants in two pediatric cases of pyruvate kinase deficiency.
Oxidative stress and antioxidant capacity in hereditary elliptocytosis and hereditary pyropoikilocytosis.
Management of Iron Overload in Infants and Toddlers With Diamond-Blackfan Anemia Syndrome: A French-Italian Study.
Diagnostic performance of flow cytometric osmotic fragility testing in hereditary spherocytosis.
Molecular and therapeutic frontiers in anemia therapy.
Novel ABCG5 and ABCG8 Variants in Sitosterolemia: Insights Into Haemolysis, Calcium Dysregulation and Therapeutic Challenges.
Fanconi Anemia in Mexican Patients: Molecular Spectrum and Clinical Manifestations in a Case Series.
Diamond-Blackfan anemia gene product RPS19 counteracts SET to maintain p53 transcriptional activity and tumor suppressor function.
Mapping Three Decades of Research on Southeast Asian Ovalocytosis: A Bibliometric Analysis.

Front Pharmacol. 2026 ;17 1719328

SNH-119014, a novel pyruvate kinase activator, enhances ATP production and reduces oxidative stress in erythroid cells from patients with β-thalassemia major.

Qiulin Huang, Yumei Huang, Lingyuan Pan, Rongrong Liu, Yongrong Lai.

   Background: Thalassemia is a common disease worldwide. Oxidative stress contributes to ineffective erythropoiesis and hemolysis in β-thalassemia major (β-TM). Increasing cellular adenosine triphosphate (ATP) production by activating the activity of the pyruvate kinase (PK) may counteract oxidative stress. SNH-119014 is a novel allosteric PK activator targeting the same protein as mitapivat (AG-348), a first-in-class agent known to ameliorate anemia in thalassemia. This study aim to evluate the effects of SNH-119014 in erythroid cells from β-TM patients.
Methods: PK activity was measured in recombinant human PKLR isoforms incubated with a range of concentrations of SNH-119014. Peripheral blood samples were obtained from 30 β-TM patients and 30 healthy controls (HCs), and the isolated red blood cells (RBCs) were assessed for ATP content and analyzed by metabolomics. Bone marrow samples were collected from 14 β-TM patients and four healthy volunteers, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated. HSPCs were differentiated into erythroid precursors. Erythroid precursors were treated with 5 μM SNH-119014, 5 µM AG-348, or vehicle, followed by assessment of ATP content, reactive oxygen species (ROS) levels, the reduced/oxidized glutathione ratio, and metabolomic profiling.
Results: SNH-119014 activated PK with an AC50 of 28.90 nM and was characterized by a higher maximal efficacy (Emax = 949.9%) compared to AG-348 (AC50 = 13.71 nM; Emax = 749.4%). Consistently, in RBCs from β-TM patients, SNH-119014 increased ATP by a mean of 129% compared to 131% for AG-348 (p = 0.0928). Based on metabolomics, KEGG pathway analysis revealed that glycolysis/gluconeogenesis and the pentose phosphate pathway were among the top ten most significantly enriched pathways for both SNH-119014 and AG-348. Considering ineffective erythropoiesis is a important factor contributor to thalassemia pathology, we further investigated the effects of SNH-119014 in erythroid precursors. SNH-119014 increased ATP levels, reduced ROS, and improved the GSH/GSSG ratio in erythroid precursors.
Conclusion: In conclusion, SNH-119014 activates PK, thereby increasing ATP production and alleviating oxidative stress in erythroid cells from β-TM patients. SNH-119014 exhibits a promising pharmacological profile, supporting its further development as a potential therapy for thalassemia.

Keywords:  adenosine triphosphate; anemia; glycolysis; metabonomics; pyruvate kinase; thalassemia

DOI:  https://doi.org/10.3389/fphar.2026.1719328
Ann Hematol. 2026 May 13.

Expanding the genetic spectrum of hereditary spherocytosis: novel mutations and phenotypic heterogeneity from a 55-patient cohort.

Huiying Shu, Liqing Yang, Yu Gao, Xuexue Yun, Min Zhou, Yuping Gong.

  To characterize the clinical and genetic profiles of patients with hereditary spherocytosis (HS) and report novel mutations. This retrospective study included 55 patients (25 males, 30 females; median age 9 years) with HS admitted between 2016 and 2023. Clinical and laboratory data were analyzed. Targeted next-generation sequencing was performed to detect pathogenic mutations. Comparisons were made using Student's t-test or Mann-Whitney U test. Anemia was present in 53 patients, including 31 with moderate-to-severe anemia; 40 exhibited splenomegaly or gallstones. A total of 60 variants were identified, of which 46 (76.7%) were novel. The most frequently involved genes were ANK1 (28, 50.9%), SPTB (17, 30.9%), SLC4A1 (10, 18.2%), and SPTA1 (2, 3.6%). Patients aged ≤ 3 years (n = 23) showed significantly lower red blood cell counts, hemoglobin levels, and absolute reticulocyte counts than those aged > 3 years (n = 32) (all P < 0.05), whereas no significant phenotypic differences were observed across mutation types. Younger patients with HS exhibited more severe anemia. ANK1 and SPTB were the predominant pathogenic genes, with no notable phenotypic differences between these two genotypes. The identification of 46 novel mutations expands the mutational spectrum of HS.

Keywords:  Clinical manifestation; Gene mutation; Hereditary spherocytosis; NGS

DOI:  https://doi.org/10.1007/s00277-026-07066-1
Ann Hematol. 2026 May 12.

Expanding the PKLR mutation spectrum: discovery of two novel variants in two pediatric cases of pyruvate kinase deficiency.

Oliver Sakalian, Yoann Huguenin, Serge Pissard, Vanessa Augis, Laurent Weinmann, Valérie Fuster, Marie Lagarde, Elise Badour, Nathalie Aladjidi, Julian Boutin, Stéphanie Dulucq.

  Diagnosing neonatal pyruvate kinase (PK) deficiency is challenging, especially when early transfusions render conventional testing inconclusive. Genetic testing, however, is not influenced by transfusions and can provide, in most cases, a definitive diagnosis. We report two unrelated infants with symptomatic PK deficiency, both compound heterozygous for PKLR mutations, including two undescribed missense variants (c.865C>T; p.(Arg289Trp) and c.1016A>G; p.(Asp339Gly)). These cases underscore the critical role of molecular testing -particularly hereditary hemolytic anemia next-generation sequencing (NGS) panels-in confirming the diagnosis when enzymatic assays are unfeasible, further shortening time to diagnosis in congenital hemolytic anemias.

Keywords:  Genetics; Neonatal Hemolysis; PK deficiency; Sequencing

DOI:  https://doi.org/10.1007/s00277-026-07018-9
Br J Haematol. 2026 May 14.

Oxidative stress and antioxidant capacity in hereditary elliptocytosis and hereditary pyropoikilocytosis.

Supawadee Maneekesorn, Chane Choed-Amphai, Supapitch Chanthong, Adisak Tantiworawit, Arunee Phusua, Narisara Paradee, Pimpisid Koonyosying, Somdet Srichairatanakool, Pimlak Charoenkwan.

  Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are red blood cell (RBC) membrane disorders caused by defects in spectrin interactions, leading to variable degrees of haemolysis. This study aimed to compare RBC fragility, oxidative stress and antioxidant capacity among individuals with HE, HPP and healthy controls. Blood samples from 15 subjects (n = 5 per group) were analysed. Chemical-induced haemolysis assays revealed significantly increased haemolysis in HPP RBCs, whereas haemolysis did not differ between HE and healthy controls. Intracellular reactive oxygen species (ROS) were highest in HPP RBCs under basal and 0.5 mM H2O2-induced conditions. Lipid peroxidation was increased in HPP RBC ghosts under basal conditions and was significantly elevated in plasma compared with both normal and HE groups. Antioxidant enzyme activities (superoxide dismutase [SOD] and glutathione peroxidase [GPx]) were largely comparable among groups, except for increased RBC SOD activity in HPP compared with normal controls. These findings indicate that HPP is characterized by marked membrane instability, elevated oxidative stress and increased lipid peroxidation, while antioxidant capacity remains relatively preserved. Collectively, these abnormalities are likely to contribute to the severe haemolytic phenotype observed in HPP compared with HE and healthy individuals.

Keywords:  antioxidant capacity; beta‐spectrin mutation; hereditary elliptocytosis; hereditary pyropoikilocytosis; oxidative stress

DOI:  https://doi.org/10.1111/bjh.70549
Am J Hematol. 2026 May 11.

Management of Iron Overload in Infants and Toddlers With Diamond-Blackfan Anemia Syndrome: A French-Italian Study.

Francesca Torchio, Baptiste Lecalvez, Emanuela Garelli, Coralie Mallebranche, Adriana Carando, Marie-Pierre Castex, Nathalie Garnier, Marco Zecca, Nathalie Aladjidi, Elisa Bertoni, Arthur Sterin, Maria Licciardello, Anne Sirvent, Antonella Sau, Isabelle Marie, Benedicte Bruno, Lydie M Da Costa, Franca Fagioli, Paola Quarello, Thierry Leblanc.

  Diamond-Blackfan Anemia Syndrome (DBAS) is a rare congenital anemia often requiring chronic red blood cell transfusions from infancy. Without appropriate chelation, iron overload develops early and may be severe; however, no data are available on chelation in patients under 3 years of age. To address this, we conducted a retrospective, multicenter study collecting data from the French and Italian DBAS national registries. A total of 167 transfused DBAS patients were screened. Of these, 64 (38%) initiated chelation before the age of three (median: 18 months). Indications for chelation were a serum ferritin ≥ 500 ng/mL (median: 1340 ng/mL) and more than 10 transfusions. Deferasirox was the most frequently used chelator (63%), followed by deferoxamine (35%). Chelation was associated with a significant reduction in serum ferritin levels (-11% per year; p < 0.001). At 5-6 years of age, ferritin level was available for 28 patients: 43% had levels < 500 ng/mL, and none exceeded 2000 ng/mL. Liver iron concentration was assessed in 31/64 patients (48%) at a median age of 3.2 years; 45% showed severe overload at first evaluation. Among 22 patients who underwent cardiac magnetic resonance, no myocardial iron overload was detected. These real-world data support the feasibility, tolerability, and effectiveness of chelation in transfusion-dependent DBAS patients under 3 years, allowing prevention of cardiac iron overload. Although derived from DBAS, these findings may inform the management of iron overload in infants and toddlers with other transfusion-dependent anemias and support development of age-specific chelation strategies.

Keywords:  Diamond–Blackfan Anemia Syndrome; early iron chelation; iron overload

DOI:  https://doi.org/10.1002/ajh.70354
Cytometry B Clin Cytom. 2026 May 12.

Diagnostic performance of flow cytometric osmotic fragility testing in hereditary spherocytosis.

Silvia Escribano Serrat, Patricia Molina, Pilar Gómez, Mireia Garre, Meritxell Nomdedeu, Blanca De Moner, Estefanía García, Ana Belén Moreno-Castaño, Álex Ramos, Julia Martinez-Sanchez, Marc Pino, Ginés Escolar, Maribel Díaz-Ricart.

  Hereditary spherocytosis (HS) is the most common congenital red blood cell membrane disorder, characterized by structural protein defects that lead to hemolytic anemia. Although several diagnostic tests exist, including osmotic fragility tests (OFTs), acidified glycerol lysis test (AGLT), and the EMA-binding test (EMA), each presents specific limitations regarding sensitivity, specificity, or technical requirements. Flow cytometric osmotic fragility testing (OFT-FCM) emerges as a promising complementary assay, offering a standardized workflow and rapid turnaround time. We conducted a retrospective study including 106 subjects (20 HS patients and 86 healthy controls) recruited at Hospital Clínic de Barcelona between September 2024 and September 2025. Clinical and laboratory data were collected, and all participants underwent OFT, AGLT, EMA, and OFT-FCM using two acquisition protocols (300 and 214 s). Logistic regression and receiver operating characteristic curve analysis were performed to evaluate diagnostic performance and determine optimal cut-off values. HS patients exhibited significantly altered hematologic parameters compared with controls, including higher reticulocyte counts, red cell distribution width, and mean corpuscular hemoglobin. The EMA-binding test demonstrated high specificity (100%) but lower sensitivity (57.9%). OFT achieved high sensitivity (>97%) but low specificity (<47%). AGLT showed balanced accuracy (sensitivity 68.4%, specificity 96.1%). OFT-FCM yielded areas under the curve of 0.85 for both protocols, with optimal thresholds providing specificities of 95-100% and sensitivities of 57-59%. No significant differences were observed between OFT-FCM and EMA performance. OFT-FCM effectively discriminates HS patients from healthy controls and showed diagnostic performance comparable to EMA and favorable relative to classical OFT and AGLT in this cohort, while offering practical advantages in terms of workflow simplicity and turnaround time, and supporting its use as a complementary flow-cytometric assay within the diagnostic work-up of HS.

Keywords:  diagnosis, osmotic fragility test; flow cytometry; hereditary spherocytosis

DOI:  https://doi.org/10.1002/cyto.b.70040
J Clin Invest. 2026 May 15. pii: e203401. [Epub ahead of print]136(10):

Molecular and therapeutic frontiers in anemia therapy.

Nilesh Rai, Omar Abdel-Wahab, Lingbo Zhang.

Anemia affects one-third of the population globally and is marked by impaired erythropoiesis that results in substantial mortality and morbidity. Over the past few decades, our understanding of the molecular mechanisms underlying anemia has progressed but translating that knowledge into effective targeted therapeutics remains challenging. Preclinical and clinical studies substantiate the efficacy of modulating erythropoietin-driven signaling pathways to stimulate erythropoiesis. Additional approaches include strategies to maintain iron homeostasis and control iron metabolism, using small molecules and oral supplements. New frontiers in molecular regulation of anemia include perturbation of regulatory genes and spliceosome proteins in erythroid cells, as well as mutation-specific therapeutic approaches. Finally, new evidence supporting the importance of neuronal signaling and mitochondrial dynamics in shaping erythropoiesis is pointing toward novel interventions. Here, we discuss the molecular and genetic factors underlying defective erythropoiesis and highlight current and emerging therapies, including molecular targets to overcome drug resistance.

DOI: https://doi.org/10.1172/JCI203401
Hum Mutat. 2026 ;2026 9208468

Novel ABCG5 and ABCG8 Variants in Sitosterolemia: Insights Into Haemolysis, Calcium Dysregulation and Therapeutic Challenges.

Prashant Warang, Rashmi Dongerdiye, Pradnya Dehadrai, Prachi Kamble, Neha Samanpalliwar, Manisha Madkaikar, Chandrakala Shanmukhaiah, Prabhakar S Kedar.

  Sitosterolemia is a rare autosomal recessive lipid metabolic disorder caused by mutations in ABCG5 or ABCG8, leading to pathological accumulation of dietary plant sterols. The condition is clinically heterogeneous, presenting with xanthomas, premature atherosclerosis and haematological abnormalities such as stomatocytosis, haemolytic anaemia and thrombocytopenia, making diagnosis particularly challenging. We investigated four patients with unexplained inherited haemolytic anaemia and a history of recurrent transfusions to identify molecular and functional mechanisms and explore therapeutic options. Haematological work-up, including CBC, peripheral smear, reticulocyte count, EMA binding assay, red cell enzyme activity and HPLC for haemoglobinopathies, was performed, along with biochemical assays for liver, renal and lipid function. Plasma sterol levels were quantified using GC-MS, whereas functional assays included intracellular calcium flux under osmotic stress, red cell density profiling and ROS measurement. Whole-exome sequencing identified homozygous nonsense variants: a novel ABCG8 (p.Trp584∗) in two siblings, ABCG5 (p.Arg243∗) in one patient and ABCG8 (p.Ser129∗) in another. Two patients showed markedly elevated plasma phytosterols, predominantly stigmasterol and β-sitosterol. Ezetimibe therapy (10 mg/day for 6 months) effectively reduced sterol levels but failed to normalise haemoglobin or significantly reduce overhydrated red cell populations. Functional studies demonstrated elevated intracellular Ca2+, enhanced influx under stress, increased ROS and a persistent population of stomatocytes. In silico prediction tools confirmed the pathogenicity of the identified variants. Persistent haemolysis despite sterol-lowering therapy suggests irreversible red cell membrane damage due to sterol incorporation, altered fluidity, oxidative stress and calcium dysregulation. Our findings indicate that combining ezetimibe with Ca2+-modulating therapy may represent a novel strategy to reduce haemolysis in sitosterolemia.

Keywords:  ABCG5; ABCG8; calcium dysregulation; ezetimibe therapy; lipid metabolic disorder; plasma phytosterols; sitosterolemia

DOI:  https://doi.org/10.1155/humu/9208468
Int J Mol Sci. 2026 Apr 30. pii: 4015. [Epub ahead of print]27(9):

Fanconi Anemia in Mexican Patients: Molecular Spectrum and Clinical Manifestations in a Case Series.

Fernando Alexis Flores-Leura, Sinhue Alejandro Brukman-Jiménez, Alfredo Corona-Rivera, Idalid Cuero-Quezada, José de Jesús Pérez-Becerra, Juan Antonio Ramírez-Corona, Víctor Ulises Rodríguez-Machuca, María Magdalena Ortiz-Sandoval, Fátima Jazmín Hinojosa-Piña, Olga Lidia Navarro-Barba, Jorge Román Corona-Rivera, Lucina Bobadilla-Morales.

  Fanconi anemia (FA) is a rare inherited disorder characterized by genomic instability, congenital anomalies, and progressive bone marrow failure; such manifestations may vary across populations, partly due to differences in genetic background. This study aims to describe the clinical and molecular spectrum of FA in Mexican patients. A total of 14 patients with clinical suspicion of FA were evaluated; cytogenetic and molecular analyses were successfully performed using MLPA and NGS. Clinically, short stature was present in 100% (n = 14) of the patients, followed by upper limb abnormalities, which were present in 78.6% (n = 11) of the patients, and microphthalmia, which was present in 71.4% (n = 10) of the patients. Molecular analysis identified pathogenic variants in FANCA (78.6%, n = 11), FANCC (14.3%, n = 2), and FANCE (7.1%, n = 1), with a relatively balanced distribution of homozygous (57.1%, n = 8) and compound heterozygous variants (42.9%, n = 6). Notably, the FANCA:c.3931_3932del variant was recurrent in six patients from the same geographic region (Michoacan), suggesting possible regional enrichment. Our findings expand the clinical and molecular characterization of FA in Mexican patients and underscore the importance of integrating phenotypic and genomic data to better understand population-specific patterns of this disorder.

Keywords:  FANCA; FANCC; FANCE; Fanconi anemia; Mexico; case series

DOI:  https://doi.org/10.3390/ijms27094015
Cell Rep. 2026 May 13. pii: S2211-1247(26)00411-0. [Epub ahead of print] 117333

Diamond-Blackfan anemia gene product RPS19 counteracts SET to maintain p53 transcriptional activity and tumor suppressor function.

Hiroki Fujiyama, Takuya Takafuji, Ryoma Kokubo, Natsumi Yanagi, Yukino Mori, Natsuka Tsutsui, Yuka Okuyama, Yusaku Nakahara, Tohru Kiyono, Yoko Katsuki, Kazumasa Yoshida, Hidetaka Kosako, Nozomi Sugimoto, Masatoshi Fujita.

  Diamond-Blackfan anemia (DBA), a congenital ribosomopathy, is associated with a predisposition to cancer. The most commonly mutated gene in DBA is RPS19; however, it remains unclear whether RPS19 actually functions as a tumor suppressor and, if so, by what mechanism. Here, we show that RPS19 prevents human cell transformation by counteracting SET oncoprotein-mediated attenuation of p53 transcriptional activity. Thus, silencing RPS19, in combination with expression of HPV16 E7 and activated KRAS G12V, transforms normal human cells; conversely, its overexpression inhibits cancer cell growth in a p53-dependent manner. RPS19 binds to SET and counteracts SET-mediated inhibition of p53 transcriptional activity. Importantly, we find that point mutations in RPS19, which are recurrently found in cancer cells, specifically abrogate its binding to SET and tumor suppressor function. Mechanistically, RPS19 binds to the p53-responsive promoters, where it counteracts SET-mediated histone hypoacetylation. Together, these findings reveal a crucial tumor suppressor function of RPS19.

Keywords:  CP: cancer; CP: molecular biology; Diamond-Blackfan anemia; RPS19; SET; cancer-prone ribosomopathy; p53

DOI:  https://doi.org/10.1016/j.celrep.2026.117333
Mediterr J Hematol Infect Dis. 2026 ;18(1): e2026036

Mapping Three Decades of Research on Southeast Asian Ovalocytosis: A Bibliometric Analysis.

Muhd Alwi Muhd Helmi, Nor Zamzila Abdullah, Ahmad Marzuki Omar, Nour El Huda Abd Rahim, Norlelawati A Talib.



Keywords:  Bibliometric; Malaria resistance; Red blood cell; SLC4A1 (Band 3) mutation; Southeast Asian Ovalocytosis

DOI:  https://doi.org/10.4084/MJHID.2026.036