RARE DISEASE
Hemolytic anemia due to red cell pyruvate kinase deficiency
Hemolytic anemia due to red cell pyruvate kinase deficiency
Hemolytic anemia due to red cell pyruvate kinase deficiency
Synonyms: Pyruvate kinase deficiency of erythrocytes
Synonyms: Pyruvate kinase deficiency of erythrocytes
Synonyms: Pyruvate kinase deficiency of erythrocytes
Drug discovery
6
drugs
With orphan designations
Overview
Hemolytic anemia due to red cell pyruvate kinase deficiency (PKD) is an autosomal recessive disorder caused by mutations in the PKLR gene, leading to impaired glycolysis, ATP depletion, and chronic nonspherocytic hemolysis. Clinical presentation varies from life-threatening neonatal anemia to compensated hemolysis, with complications including gallstones, iron overload, and splenomegaly [1][4][5]. Diagnosis combines PK enzyme activity assays (adjusted for reticulocytosis) and genetic testing [1][4].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism
Research Papers
83 drug discovery papers about Hemolytic anemia due to red cell pyruvate kinase deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
83 drug discovery papers about Hemolytic anemia due to red cell pyruvate kinase deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-08 | Case Report: Successful hematopoietic stem cell transplantation in pediatric pyruvate kinase deficiency: a single-center Asian case series demonstrating favorable outcomes.
Pyruvate kinase deficiency (PKD) is a rare autosomal recessive inherited hemolytic anemia caused by pathogenic variants in the PKLR gene. The disease exhibits marked clinical heterogeneity, ranging from compensated anemia to severe transfusion-dependent phenotypes presenting early in childhood. Although supportive care and emerging pharmacologic agents such as pyruvate kinase activators have improved disease management, treatment options remain limited for patients with severe, transfusion-dependent disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potential curative approach. However, clinical experience in pediatric PKD remains limited, and reported outcomes are heterogeneous. In particular, data regarding standardized conditioning strategies, donor variability, and early post-transplant outcomes are still insufficient. Here, we report a single-center case series of six pediatric patients with genetically confirmed PKD who underwent allo-HSCT between 2019 and 2026. The cohort included both matched sibling and unrelated donors with varying HLA compatibility. All patients achieved successful hematopoietic engraftment, with neutrophil and platelet recovery occurring within 12-16 days post-transplantation. Complete donor chimerism (>98%) was achieved in all evaluable patients by day +21. No primary graft failure was observed, and no severe acute or chronic graft-versus-host disease occurred during early follow-up. Importantly, patients demonstrated rapid correction of transfusion dependence following transplantation. However, follow-up duration was heterogeneous, ranging from several months to over six years, and long-term outcomes remain under continued observation. This study provides a homogeneous real-world experience suggesting that allo-HSCT using a thiotepa- and ATG-containing myeloablative regimen is feasible in selected pediatric PKD patients, including those receiving unrelated donor grafts. These findings support further investigation of standardized transplant approaches and early intervention strategies in severe pediatric PKD. Larger multicenter studies with long-term follow-up are required to validate safety, durability, and late effects of transplantation in this rare disease.
2024-12-24 | Ovarian tissue cryopreservation for a girl with combined severe hemolytic anemia due to pyruvate kinase deficiency: a case report and literature review.
To present a young girl with pyruvate kinase deficiency (PKD) and concurrent severe hemolytic anemia who underwent fertility preservation and cryopreservation. Clinical symptoms, diagnosis, treatment, and new strategies for fertility protection and preservation in PKD patients who require allogeneic hematopoietic stem cell therapy are explored. Six-year-old girl with persistent unconjugated hyperbilirubinemia and severe hemolytic anemia since birth, continuous elevation of bilirubin levels and severe splenomegaly. She was diagnosed with PKD, an open laparotomy for splenectomy was performed and ovarian tissue cryopreservation (OTC) was used to preserve fertility and ovarian endocrine function. Due to the previous donor being unsuitable, it took five months to find and match a new hematopoietic stem cell donor. Five months after OTC, the patient underwent high-dose busulfan and ciclosporin chemotherapy in preparation for peripheral blood stem cell transplantation and received rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease. Her red and white blood cells, hemoglobin and platelets are now generally within the normal range, total bilirubin and direct bilirubin in liver function have also normalized and AMH is below the lower limit of normal. Until now, no signs of a negative impact of OTC have been observed. Hematopoietic stem cell transplantation is essential for effective treatment of pyruvate kinase deficiency. We assess OTC as the only possible fertility preservation method for children who cannot undergo embryo and oocyte cryopreservation.
2024-12-05 | Case report: Modified transplantation for pediatric patients with pyruvate kinase deficiency.
Pyruvate kinase deficiency (PKD) is an autosomal recessive genetic disease caused by mutations in the PKLR gene. To date, the clinical manifestations of PKD are heterogeneous, ranging from fetal anemia, neonatal jaundice, and severe chronic hemolytic anemia to fully compensated hemolytic anemia. Successful cases of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for PKD have been reported, however, the number of cases is very small, and experiences are very limited. Here, we report two successful cases involving our modified conditioning regimen. This approach is suitable for patients with severe transfusion dependence. In conclusion, for PKD patients with severe transfusion dependence, allo-HSCT is an option and is currently a safe and effective way to completely eliminate the need for transfusions of drugs, such as Mitapivat, or genetic therapies and allow the patient to return to normal life.
2023-01-17 | Prenatal management of fetal anemia due to pyruvate kinase deficiency: A case report.
Pyruvate Kinase (PK) deficiency is the most common enzyme defect of glycolysis, leading to congenital hemolytic anemia, which can occur during the neonatal period. We report the prenatal management of fetal anemia related to PK deficiency in a family with a severe proband. The couple had a first child born with hydrops, whose PK deficiency was diagnosed at 18 months of life. He was treated with allogeneic bone marrow transplantation. The second child was free from disease. For the third pregnancy, the amniocentesis revealed a PK deficiency. Weekly ultrasound monitoring of the middle cerebral artery velocity allowed the detection of severe fetal anemia. Two intrauterine red blood cell transfusions (IUTs) were performed, raising the fetal hemoglobin from 6.6 to 14.5 g/dl at 28 weeks' gestation and from 8.9 to 15.3 g/dl at 31 weeks. A hematopoietic stem cell allograft was discussed prenatally but not chosen, as it would not have significantly changed the perinatal prognosis. The patient delivered a 2730 g girl at 37 weeks, with hemoglobin of 13.6 g/dl. The child presented with neonatal jaundice treated with phototherapy and received postnatal transfusions. When a proband is identified in a family, fetal investigation is warranted, to set up third-trimester ultrasound surveillance and perinatal management. In case of fetal severe anemia of unknown etiology, the workup on fetal blood sampling before IUT should comprise the search for erythrocytes enzymopathies, such as PK deficiency. IUTs allow safer full-term delivery in cases with PK deficiency.
2022-02-02 | A pyruvate kinase deficiency child with novel PK-LR gene mutations was successfully cured by matched unrelated donor peripheral blood stem cell transplantation.
Pyruvate kinase deficiency (PKD) is an autosomal recessive disorder caused by a PK-LR gene mutation. Allogeneic hematopoietic cell transplantation (HCT) is an effective cure for PKD. However, the experience of applying HCT in PKD is limited. We present a child with novel PK-LR gene mutations who was successfully cured by matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT). A 4-year-old, male patient suffered severe hemolytic anemia and jaundice 5 h after birth. Gene sequencing showed that the pyruvate kinase-liver and RBC (PK-LR) gene had a nonsense mutation in exon 5: c.602G>A (p.W201X), and large deletions in exons 3-9. Both of them were novel pathogenic mutations of the PK-LR gene. After transplantation, the hemoglobin level became normal and the nonsense mutation was undetectable. Grade Ⅳ acute graft-versus-host disease (aGVHD) and extensive chronic graft-versus-host disease (cGVHD) occurred in the patient. However, the GVHD was controlled effectively. The patient is alive and has good quality of life 22 months post-transplant, but has mild oral lichen planus-like lesion. Gene sequencing contributes to the diagnosis of PKD. HCT is an effective method for curing PKD, but we should explore how to reduce severe GVHD.
gene therapies
2025-10-16 | Harnessing DNA barcoding to enhance and sustain polyclonality in gene-edited hematopoietic stem cells
A challenge in gene editing for hematopoietic stem and progenitor cells (HSPCs) is achieving efficient editing while preserving long-term engraftment and clonal diversity. Tracking edited clones with high resolution is essential to understand the impact of editing on hematopoiesis. We developed a barcoded AAV6 donor template (BC-AAV) to precisely monitor the fate of edited HSPCs following transplantation. Our findings reveal that, despite initial barcode diversity in vitro, human hematopoiesis generated by edited HSPCs transplanted in immunodeficient mice is driven by a limited number of dominant clones. The engraftment of gene-edited cells follows an oligo/polyclonal pattern, indicating that editing does not alter clonal dynamics in this model. Using BC-AAV, we optimized a gene editing protocol for correcting the PKLR gene, responsible for pyruvate kinase deficiency, a rare disorder that causes severe anemia due to red blood energy imbalance. We implemented key improvements. GMP-grade StemSpan AOF medium and StemRegenin-1 increased clonal diversity while maintaining hematopoietic potential. NHEJ inhibitor AZD-7648, significantly boosted editing efficiency in vitro, and a shorter transduction period enhanced engraftment and clonal balance without compromising editing outcomes. This refined strategy for gene editing in human HSPCs optimizes both efficiency and long-term polyclonal dynamics and has important implications for clinical applications.
2025-07-04 | CRISPR-Cas Systems in Hemolytic Diseases
Hereditary hematological disorders such as β-thalassemia, pyruvate kinase deficiency, and sickle cell disease may be treated by gene therapy. Hematopoietic stem cells (HSCs) are transduced with a corrected version of the altered gene using lentiviral vectors. To make up for the lack of healthy cells brought on by genetic flaws, lentivirus-corrected HSCs produce more of them. The endogenous regulation of the therapeutic gene and the transgene’s integration into the genome, however, are two significant shortcomings in this strategy. Gene editing allows the altered gene to be repaired with greater precision and more directly using less costly, better understood methods such as CRISPR-Cas9 while leaving the rest of the genome untouched. They have been applied to thalassemia, sickle cell disease, pyruvate kinase deficiency and other hereditary erythroid diseases. Experiments have shown CRISPR-Cas9 can fix hemoglobin deficiencies and turn back on fetal globin chains in bone-marrow cells from adults. The application of gene editing showed faster therapeutic responses with cutting edge treatment strategies for red cell disorders that can provide a basis to cure hemolytic abnormalities, as well as other genetic diseases.
2024-04-08 | Mitapivat-Associated Rib Fracture in a Hemolytic Anemia Patient.
Hereditary hemolytic anemia associated with pyruvate kinase deficiency is a rare hematological disorder that affects the glycolic pathway within red blood cells. The standard of care includes splenectomy, transfusions, and hematopoietic stem cell transplantation. However, these treatments can lead to common iatrogenic side effects such as infections, surgical complications, and iron overload. The novel drug therapy Mitapivat has shown promising results in terms of both efficacy and safety, but it can cause rare side effects such as fractures. In this report, we present the case of a 75-year-old female with hereditary hemolytic anemia caused by pyruvate kinase deficiency who suffered rib and vertebral body fractures after the initiation of Mitapivat. Screening for key risk factors of bone mineral disease can help identify patients who are at higher risk of developing fractures before starting therapy. In the future, gene therapy may provide an alternative treatment option for patients with hereditary hemolytic anemia with metabolic bone disorders.
2023-12-14 | Mortality among US veterans with a physician-documented diagnosis of pyruvate kinase deficiency.
Real-world studies of pyruvate kinase (PK) deficiency and estimates of mortality are lacking. This retrospective observational study aimed to identify patients with PK deficiency and compare their overall survival (OS) to that of a matched cohort without PK deficiency. Patients with ≥1 diagnosis code related to PK deficiency were selected from the US Veterans Health Administration (VHA) database (01/1995-07/2019); patients with a physician-documented diagnosis were included (PK deficiency cohort; index: date of first diagnosis code related to PK deficiency). Patients in the PK deficiency cohort were matched 1:5 to patients from the general VHA population (non-PK deficiency cohort; index: random visit date during match's index year). OS from index was compared between the two cohorts. Eighteen patients in the PK deficiency cohort were matched to 90 individuals in the non-PK deficiency cohort (both cohorts: mean age 57 years, 94% males; median follow-up 6.0 and 8.0 years, respectively). At follow-up, patients in the non-PK deficiency cohort had significantly longer OS than the PK deficiency cohort (median OS: 17.1 vs. 10.9 years; hazard ratio: 2.3; p = 0.0306). During their first-year post-index, 75% and 40% of the PK deficiency cohort had laboratory-confirmed anemia and iron overload, respectively. Among patients who died, cause of death was highly heterogeneous. These results highlight the increased risk of mortality and substantial clinical burden among patients with PK deficiency. While the intrinsic characteristics of the VHA database may limit the generalizability of the results, this is the first real-world study to characterize mortality in patients with PK deficiency.
2020-03-16 | Gene editing of PKLR gene in human hematopoietic progenitors through 5' and 3' UTR modified TALEN mRNA.
Pyruvate Kinase Deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene, which encodes the erythroid specific Pyruvate Kinase enzyme. Erythrocytes from PKD patients show an energetic imbalance and are susceptible to hemolysis. Gene editing of hematopoietic stem cells (HSCs) would provide a therapeutic benefit and improve safety of gene therapy approaches to treat PKD patients. In previous studies, we established a gene editing protocol that corrected the PKD phenotype of PKD-iPSC lines through a TALEN mediated homologous recombination strategy. With the goal of moving toward more clinically relevant stem cells, we aim at editing the PKLR gene in primary human hematopoietic progenitors and hematopoietic stem cells (HPSCs). After nucleofection of the gene editing tools and selection with puromycin, up to 96% colony forming units showed precise integration. However, a low yield of gene edited HPSCs was associated to the procedure. To reduce toxicity while increasing efficacy, we worked on i) optimizing gene editing tools and ii) defining optimal expansion and selection times. Different versions of specific nucleases (TALEN and CRISPR-Cas9) were compared. TALEN mRNAs with 5' and 3' added motifs to increase RNA stability were the most efficient nucleases to obtain high gene editing frequency and low toxicity. Shortening ex vivo manipulation did not reduce the efficiency of homologous recombination and preserved the hematopoietic progenitor potential of the nucleofected HPSCs. Lastly, a very low level of gene edited HPSCs were detected after engraftment in immunodeficient (NSG) mice. Overall, we showed that gene editing of the PKLR gene in HPSCs is feasible, although further improvements must to be done before the clinical use of the gene editing to correct PKD.
small molecules
2026-01-31 | Features of anesthesia in a child with pyruvate kinase deficiency in an outpatient dental clinic: case report
INTRODUCTION: Pyruvate kinase deficiency is the most common enzymatic disorder of the glycolytic pathway and a leading cause of hereditary nonspherocytic hemolytic anemia. Anesthetic management in patients with pyruvate kinase deficiency carries a risk of specific complications related to impaired energy metabolism and increased susceptibility of erythrocytes and muscle cells to oxidative stress. OBJECTIVE: To present a clinical case demonstrating the successful use of combined inhalational anesthesia in outpatient pediatric dental practice in a child with pyruvate kinase deficiency. MATERIALS AND METHODS: We describe the anesthetic management and specific considerations in the administration of combined inhalational anesthesia during comprehensive dental treatment in a pediatric patient with confirmed pyruvate kinase deficiency. RESULTS: This approach provided adequate anesthesia throughout the dental procedure without the need for intravenous induction with propofol or administration of muscle relaxants, thus minimizing the risk of oxidative stress and mitochondrial dysfunction. CONCLUSIONS: Anesthetic management in patients with pyruvate kinase deficiency should be individualized, with emphasis on minimizing oxidative injury, maintaining adequate oxygen-carrying capacity, and preventing systemic metabolic complications. Inhalational techniques may offer a safe and effective alternative in selected cases.
2022-06-27 | Diagnosis, monitoring, and management of pyruvate kinase deficiency in children.
Pyruvate kinase (PK) deficiency is a rare, congenital red blood cell disorder caused by a single gene defect. The spectrum of genotypes, variants, and phenotypes are broad, commonly requiring a multimodal approach including enzyme and genetic testing for accurate and reliable diagnosis. Similarly, management of primary and secondary sequelae of PK deficiency varies, mainly including supportive care with transfusions and surgical interventions to improve symptoms and quality of life. Given the risk of acute and long-term complications of PK deficiency and its treatment, regular monitoring and management of iron burden and organ dysfunction is critical. Therefore, all children and adolescents with PK deficiency should receive regular hematology care with visits at least every 6 months regardless of transfusion status. We continue to learn more about the spectrum of symptoms and complications of PK deficiency and best practice for monitoring and management through registry efforts (NCT03481738). The treatment of PK deficiency has made strides over the last few years with newer disease-modifying therapies being developed and studied, with the potential to change the course of disease in childhood and beyond.
2021-03-24 | Management of pyruvate kinase deficiency in children and adults.
Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
proteins
2024-01-30 | Treatment with Erythropoietin Improves Ineffective Erythropoiesis in a Child with Pyruvate Kinase Deficiency
Background: Pyruvate Kinase Deficiency (PKD) drastically reduces the lifespan of erythrocytes resulting in, inter alia, jaundice, hypersplenism and dependency on regular blood transfusions due to hemolysis. Splenectomy and blood transfusions do not guarantee an improvement of clinical symptoms and cause severe side effects such as iron overload and risk of infection. Procedure: Treatment with EPO was introduced two months after birth and commenced with a dosage of < 200.0 U/kg subcutaneously twice per week. Results: Hemoglobin concentration (Hb) remained stable at 8.0 g/dl at the age of 12 months and reached a peak of 11.0 g/dl at 20 moths. No further transfusions were necessary since the effect of EPO set in. Mean corpuscular volume (MCV) showed a slower increase than the number of reticulocytes proving that treatment with EPO improved the maturation of reticulocytes to adult erythrocytes thereby overcoming ineffective erythropoiesis. Iron overload due to prior transfusions was reduced, hypersplenism and compromised liver function were not present at any time. The child’s health and neurological development were in line with its age always. Conclusions: Treatment with EPO overcomes ineffective erythropoiesis in patients with a measurable residual activity of PK preventing the risks and side effects of current standard treatment strategies
2023-12-14 | Real-World Impact of Pyruvate Kinase Deficiency in Children
Pyruvate kinase (PK) deficiency is a hereditary haemolytic anaemia caused by mutations in the PKLR gene encoding PK, which is critical for maintaining red blood cell (RBC) energy levels. Defects in PK cause chronic haemolysis. There are currently no disease-modifying therapies approved for use in children with PK deficiency, and treatment can involve regular blood transfusions, iron chelation, splenectomy, and management of disease complications. In this interview, Rachael F. Grace, a paediatric haematologist at the Dana–Farber/Boston Children's Cancer and Blood Disorders Center, Massachusetts, USA; and Julián Sevilla, a haematologist at the Hospital Infantil Universitario Niño Jesús in Madrid, Spain, shared their experience of diagnosing and treating paediatric patients with PK deficiency. They discussed the substantial variability in symptoms between patients irrespective of their haemoglobin level, the risk of iron overload even in children not receiving regular transfusions, and the effects of jaundice on children’s self-esteem. Grace and Sevilla also examined the challenges in diagnosis and management of PK deficiency in paediatrics, and the importance of regular monitoring in all patients, both to identify potential complications, and to ensure optimal medical management of their disease. Finally, they discussed new therapies that are currently being developed, which have the potential to have a major impact on future treatments for paediatric patients with PK deficiency.
2023-11-13 | Differential Gene Expression of Malaria Parasite in Response to Red Blood Cell-Specific Glycolytic Intermediate 2,3-Diphosphoglycerate (2,3-DPG)
Innovative strategies to control malaria are urgently needed. Exploring the interplay between the Plasmodium sp. parasites and host red blood cells (RBC) offers opportunities for novel antimalarial interventions. Pyruvate kinase deficiency (PKD), characterized by heightened 2,3-diphosphoglycerate (2,3-DPG) concentration, has been associated with protection against malaria. Elevated 2,3-DPG levels, a specific mammalian metabolite, may hinder glycolysis, prompting us to hypothesize its potential contribution to PKD-mediated protection. We investigated the impact of the extracellular supplementation of 2,3-DPG on the Plasmodium falciparum intraerythrocytic developmental cycle in vitro. Results showed an inhibition of parasite growth, resulting from significantly less progeny from 2,3-DPG-treated parasites. We analyzed differential gene expression and the transcriptomic profile of P. falciparum trophozoites, from in vitro cultures submitted or not submitted to the action of 2,3-DPG, using Nanopore Sequencing Technology. The presence of 2,3-DPG in the culture medium was associated to a significant differential expression of 71 genes, mostly associated to GO terms nucleic acid binding, transcription, or monoatomic anion channel. Further, several genes related to the cell cycle control were downregulated in treated parasites. These findings suggest that the presence of this RBC-specific glycolytic metabolite impact the expression of genes transcribed during the parasite trophozoite stage and the number of merozoites released from individual schizonts, which supports the potential role of 2,3-DPG in the mechanism of protection against malaria by PKD.
cell therapies
2026-09-08 | Case Report: Successful hematopoietic stem cell transplantation in pediatric pyruvate kinase deficiency: a single-center Asian case series demonstrating favorable outcomes.
Pyruvate kinase deficiency (PKD) is a rare autosomal recessive inherited hemolytic anemia caused by pathogenic variants in the PKLR gene. The disease exhibits marked clinical heterogeneity, ranging from compensated anemia to severe transfusion-dependent phenotypes presenting early in childhood. Although supportive care and emerging pharmacologic agents such as pyruvate kinase activators have improved disease management, treatment options remain limited for patients with severe, transfusion-dependent disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potential curative approach. However, clinical experience in pediatric PKD remains limited, and reported outcomes are heterogeneous. In particular, data regarding standardized conditioning strategies, donor variability, and early post-transplant outcomes are still insufficient. Here, we report a single-center case series of six pediatric patients with genetically confirmed PKD who underwent allo-HSCT between 2019 and 2026. The cohort included both matched sibling and unrelated donors with varying HLA compatibility. All patients achieved successful hematopoietic engraftment, with neutrophil and platelet recovery occurring within 12-16 days post-transplantation. Complete donor chimerism (>98%) was achieved in all evaluable patients by day +21. No primary graft failure was observed, and no severe acute or chronic graft-versus-host disease occurred during early follow-up. Importantly, patients demonstrated rapid correction of transfusion dependence following transplantation. However, follow-up duration was heterogeneous, ranging from several months to over six years, and long-term outcomes remain under continued observation. This study provides a homogeneous real-world experience suggesting that allo-HSCT using a thiotepa- and ATG-containing myeloablative regimen is feasible in selected pediatric PKD patients, including those receiving unrelated donor grafts. These findings support further investigation of standardized transplant approaches and early intervention strategies in severe pediatric PKD. Larger multicenter studies with long-term follow-up are required to validate safety, durability, and late effects of transplantation in this rare disease.
2024-12-24 | Ovarian tissue cryopreservation for a girl with combined severe hemolytic anemia due to pyruvate kinase deficiency: a case report and literature review.
To present a young girl with pyruvate kinase deficiency (PKD) and concurrent severe hemolytic anemia who underwent fertility preservation and cryopreservation. Clinical symptoms, diagnosis, treatment, and new strategies for fertility protection and preservation in PKD patients who require allogeneic hematopoietic stem cell therapy are explored. Six-year-old girl with persistent unconjugated hyperbilirubinemia and severe hemolytic anemia since birth, continuous elevation of bilirubin levels and severe splenomegaly. She was diagnosed with PKD, an open laparotomy for splenectomy was performed and ovarian tissue cryopreservation (OTC) was used to preserve fertility and ovarian endocrine function. Due to the previous donor being unsuitable, it took five months to find and match a new hematopoietic stem cell donor. Five months after OTC, the patient underwent high-dose busulfan and ciclosporin chemotherapy in preparation for peripheral blood stem cell transplantation and received rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease. Her red and white blood cells, hemoglobin and platelets are now generally within the normal range, total bilirubin and direct bilirubin in liver function have also normalized and AMH is below the lower limit of normal. Until now, no signs of a negative impact of OTC have been observed. Hematopoietic stem cell transplantation is essential for effective treatment of pyruvate kinase deficiency. We assess OTC as the only possible fertility preservation method for children who cannot undergo embryo and oocyte cryopreservation.
2024-12-05 | Case report: Modified transplantation for pediatric patients with pyruvate kinase deficiency.
Pyruvate kinase deficiency (PKD) is an autosomal recessive genetic disease caused by mutations in the PKLR gene. To date, the clinical manifestations of PKD are heterogeneous, ranging from fetal anemia, neonatal jaundice, and severe chronic hemolytic anemia to fully compensated hemolytic anemia. Successful cases of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for PKD have been reported, however, the number of cases is very small, and experiences are very limited. Here, we report two successful cases involving our modified conditioning regimen. This approach is suitable for patients with severe transfusion dependence. In conclusion, for PKD patients with severe transfusion dependence, allo-HSCT is an option and is currently a safe and effective way to completely eliminate the need for transfusions of drugs, such as Mitapivat, or genetic therapies and allow the patient to return to normal life.
2023-01-17 | Prenatal management of fetal anemia due to pyruvate kinase deficiency: A case report.
Pyruvate Kinase (PK) deficiency is the most common enzyme defect of glycolysis, leading to congenital hemolytic anemia, which can occur during the neonatal period. We report the prenatal management of fetal anemia related to PK deficiency in a family with a severe proband. The couple had a first child born with hydrops, whose PK deficiency was diagnosed at 18 months of life. He was treated with allogeneic bone marrow transplantation. The second child was free from disease. For the third pregnancy, the amniocentesis revealed a PK deficiency. Weekly ultrasound monitoring of the middle cerebral artery velocity allowed the detection of severe fetal anemia. Two intrauterine red blood cell transfusions (IUTs) were performed, raising the fetal hemoglobin from 6.6 to 14.5 g/dl at 28 weeks' gestation and from 8.9 to 15.3 g/dl at 31 weeks. A hematopoietic stem cell allograft was discussed prenatally but not chosen, as it would not have significantly changed the perinatal prognosis. The patient delivered a 2730 g girl at 37 weeks, with hemoglobin of 13.6 g/dl. The child presented with neonatal jaundice treated with phototherapy and received postnatal transfusions. When a proband is identified in a family, fetal investigation is warranted, to set up third-trimester ultrasound surveillance and perinatal management. In case of fetal severe anemia of unknown etiology, the workup on fetal blood sampling before IUT should comprise the search for erythrocytes enzymopathies, such as PK deficiency. IUTs allow safer full-term delivery in cases with PK deficiency.
2022-02-02 | A pyruvate kinase deficiency child with novel PK-LR gene mutations was successfully cured by matched unrelated donor peripheral blood stem cell transplantation.
Pyruvate kinase deficiency (PKD) is an autosomal recessive disorder caused by a PK-LR gene mutation. Allogeneic hematopoietic cell transplantation (HCT) is an effective cure for PKD. However, the experience of applying HCT in PKD is limited. We present a child with novel PK-LR gene mutations who was successfully cured by matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT). A 4-year-old, male patient suffered severe hemolytic anemia and jaundice 5 h after birth. Gene sequencing showed that the pyruvate kinase-liver and RBC (PK-LR) gene had a nonsense mutation in exon 5: c.602G>A (p.W201X), and large deletions in exons 3-9. Both of them were novel pathogenic mutations of the PK-LR gene. After transplantation, the hemoglobin level became normal and the nonsense mutation was undetectable. Grade Ⅳ acute graft-versus-host disease (aGVHD) and extensive chronic graft-versus-host disease (cGVHD) occurred in the patient. However, the GVHD was controlled effectively. The patient is alive and has good quality of life 22 months post-transplant, but has mild oral lichen planus-like lesion. Gene sequencing contributes to the diagnosis of PKD. HCT is an effective method for curing PKD, but we should explore how to reduce severe GVHD.
gene therapies
2025-10-16 | Harnessing DNA barcoding to enhance and sustain polyclonality in gene-edited hematopoietic stem cells
A challenge in gene editing for hematopoietic stem and progenitor cells (HSPCs) is achieving efficient editing while preserving long-term engraftment and clonal diversity. Tracking edited clones with high resolution is essential to understand the impact of editing on hematopoiesis. We developed a barcoded AAV6 donor template (BC-AAV) to precisely monitor the fate of edited HSPCs following transplantation. Our findings reveal that, despite initial barcode diversity in vitro, human hematopoiesis generated by edited HSPCs transplanted in immunodeficient mice is driven by a limited number of dominant clones. The engraftment of gene-edited cells follows an oligo/polyclonal pattern, indicating that editing does not alter clonal dynamics in this model. Using BC-AAV, we optimized a gene editing protocol for correcting the PKLR gene, responsible for pyruvate kinase deficiency, a rare disorder that causes severe anemia due to red blood energy imbalance. We implemented key improvements. GMP-grade StemSpan AOF medium and StemRegenin-1 increased clonal diversity while maintaining hematopoietic potential. NHEJ inhibitor AZD-7648, significantly boosted editing efficiency in vitro, and a shorter transduction period enhanced engraftment and clonal balance without compromising editing outcomes. This refined strategy for gene editing in human HSPCs optimizes both efficiency and long-term polyclonal dynamics and has important implications for clinical applications.
2025-07-04 | CRISPR-Cas Systems in Hemolytic Diseases
Hereditary hematological disorders such as β-thalassemia, pyruvate kinase deficiency, and sickle cell disease may be treated by gene therapy. Hematopoietic stem cells (HSCs) are transduced with a corrected version of the altered gene using lentiviral vectors. To make up for the lack of healthy cells brought on by genetic flaws, lentivirus-corrected HSCs produce more of them. The endogenous regulation of the therapeutic gene and the transgene’s integration into the genome, however, are two significant shortcomings in this strategy. Gene editing allows the altered gene to be repaired with greater precision and more directly using less costly, better understood methods such as CRISPR-Cas9 while leaving the rest of the genome untouched. They have been applied to thalassemia, sickle cell disease, pyruvate kinase deficiency and other hereditary erythroid diseases. Experiments have shown CRISPR-Cas9 can fix hemoglobin deficiencies and turn back on fetal globin chains in bone-marrow cells from adults. The application of gene editing showed faster therapeutic responses with cutting edge treatment strategies for red cell disorders that can provide a basis to cure hemolytic abnormalities, as well as other genetic diseases.
2024-04-08 | Mitapivat-Associated Rib Fracture in a Hemolytic Anemia Patient.
Hereditary hemolytic anemia associated with pyruvate kinase deficiency is a rare hematological disorder that affects the glycolic pathway within red blood cells. The standard of care includes splenectomy, transfusions, and hematopoietic stem cell transplantation. However, these treatments can lead to common iatrogenic side effects such as infections, surgical complications, and iron overload. The novel drug therapy Mitapivat has shown promising results in terms of both efficacy and safety, but it can cause rare side effects such as fractures. In this report, we present the case of a 75-year-old female with hereditary hemolytic anemia caused by pyruvate kinase deficiency who suffered rib and vertebral body fractures after the initiation of Mitapivat. Screening for key risk factors of bone mineral disease can help identify patients who are at higher risk of developing fractures before starting therapy. In the future, gene therapy may provide an alternative treatment option for patients with hereditary hemolytic anemia with metabolic bone disorders.
2023-12-14 | Mortality among US veterans with a physician-documented diagnosis of pyruvate kinase deficiency.
Real-world studies of pyruvate kinase (PK) deficiency and estimates of mortality are lacking. This retrospective observational study aimed to identify patients with PK deficiency and compare their overall survival (OS) to that of a matched cohort without PK deficiency. Patients with ≥1 diagnosis code related to PK deficiency were selected from the US Veterans Health Administration (VHA) database (01/1995-07/2019); patients with a physician-documented diagnosis were included (PK deficiency cohort; index: date of first diagnosis code related to PK deficiency). Patients in the PK deficiency cohort were matched 1:5 to patients from the general VHA population (non-PK deficiency cohort; index: random visit date during match's index year). OS from index was compared between the two cohorts. Eighteen patients in the PK deficiency cohort were matched to 90 individuals in the non-PK deficiency cohort (both cohorts: mean age 57 years, 94% males; median follow-up 6.0 and 8.0 years, respectively). At follow-up, patients in the non-PK deficiency cohort had significantly longer OS than the PK deficiency cohort (median OS: 17.1 vs. 10.9 years; hazard ratio: 2.3; p = 0.0306). During their first-year post-index, 75% and 40% of the PK deficiency cohort had laboratory-confirmed anemia and iron overload, respectively. Among patients who died, cause of death was highly heterogeneous. These results highlight the increased risk of mortality and substantial clinical burden among patients with PK deficiency. While the intrinsic characteristics of the VHA database may limit the generalizability of the results, this is the first real-world study to characterize mortality in patients with PK deficiency.
2020-03-16 | Gene editing of PKLR gene in human hematopoietic progenitors through 5' and 3' UTR modified TALEN mRNA.
Pyruvate Kinase Deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene, which encodes the erythroid specific Pyruvate Kinase enzyme. Erythrocytes from PKD patients show an energetic imbalance and are susceptible to hemolysis. Gene editing of hematopoietic stem cells (HSCs) would provide a therapeutic benefit and improve safety of gene therapy approaches to treat PKD patients. In previous studies, we established a gene editing protocol that corrected the PKD phenotype of PKD-iPSC lines through a TALEN mediated homologous recombination strategy. With the goal of moving toward more clinically relevant stem cells, we aim at editing the PKLR gene in primary human hematopoietic progenitors and hematopoietic stem cells (HPSCs). After nucleofection of the gene editing tools and selection with puromycin, up to 96% colony forming units showed precise integration. However, a low yield of gene edited HPSCs was associated to the procedure. To reduce toxicity while increasing efficacy, we worked on i) optimizing gene editing tools and ii) defining optimal expansion and selection times. Different versions of specific nucleases (TALEN and CRISPR-Cas9) were compared. TALEN mRNAs with 5' and 3' added motifs to increase RNA stability were the most efficient nucleases to obtain high gene editing frequency and low toxicity. Shortening ex vivo manipulation did not reduce the efficiency of homologous recombination and preserved the hematopoietic progenitor potential of the nucleofected HPSCs. Lastly, a very low level of gene edited HPSCs were detected after engraftment in immunodeficient (NSG) mice. Overall, we showed that gene editing of the PKLR gene in HPSCs is feasible, although further improvements must to be done before the clinical use of the gene editing to correct PKD.
small molecules
2026-01-31 | Features of anesthesia in a child with pyruvate kinase deficiency in an outpatient dental clinic: case report
INTRODUCTION: Pyruvate kinase deficiency is the most common enzymatic disorder of the glycolytic pathway and a leading cause of hereditary nonspherocytic hemolytic anemia. Anesthetic management in patients with pyruvate kinase deficiency carries a risk of specific complications related to impaired energy metabolism and increased susceptibility of erythrocytes and muscle cells to oxidative stress. OBJECTIVE: To present a clinical case demonstrating the successful use of combined inhalational anesthesia in outpatient pediatric dental practice in a child with pyruvate kinase deficiency. MATERIALS AND METHODS: We describe the anesthetic management and specific considerations in the administration of combined inhalational anesthesia during comprehensive dental treatment in a pediatric patient with confirmed pyruvate kinase deficiency. RESULTS: This approach provided adequate anesthesia throughout the dental procedure without the need for intravenous induction with propofol or administration of muscle relaxants, thus minimizing the risk of oxidative stress and mitochondrial dysfunction. CONCLUSIONS: Anesthetic management in patients with pyruvate kinase deficiency should be individualized, with emphasis on minimizing oxidative injury, maintaining adequate oxygen-carrying capacity, and preventing systemic metabolic complications. Inhalational techniques may offer a safe and effective alternative in selected cases.
2022-06-27 | Diagnosis, monitoring, and management of pyruvate kinase deficiency in children.
Pyruvate kinase (PK) deficiency is a rare, congenital red blood cell disorder caused by a single gene defect. The spectrum of genotypes, variants, and phenotypes are broad, commonly requiring a multimodal approach including enzyme and genetic testing for accurate and reliable diagnosis. Similarly, management of primary and secondary sequelae of PK deficiency varies, mainly including supportive care with transfusions and surgical interventions to improve symptoms and quality of life. Given the risk of acute and long-term complications of PK deficiency and its treatment, regular monitoring and management of iron burden and organ dysfunction is critical. Therefore, all children and adolescents with PK deficiency should receive regular hematology care with visits at least every 6 months regardless of transfusion status. We continue to learn more about the spectrum of symptoms and complications of PK deficiency and best practice for monitoring and management through registry efforts (NCT03481738). The treatment of PK deficiency has made strides over the last few years with newer disease-modifying therapies being developed and studied, with the potential to change the course of disease in childhood and beyond.
2021-03-24 | Management of pyruvate kinase deficiency in children and adults.
Pyruvate kinase deficiency (PKD) is an autosomal-recessive enzyme defect of the glycolytic pathway that causes congenital nonspherocytic hemolytic anemia. The diagnosis and management of patients with PKD can be challenging due to difficulties in the diagnostic evaluation and the heterogeneity of clinical manifestations, ranging from fetal hydrops and symptomatic anemia requiring lifelong transfusions to fully compensated hemolysis. Current treatment approaches are supportive and include transfusions, splenectomy, and chelation. Complications, including iron overload, bilirubin gallstones, extramedullary hematopoiesis, pulmonary hypertension, and thrombosis, are related to the chronic hemolytic anemia and its current management and can occur at any age. Disease-modifying therapies in clinical development may decrease symptoms and findings associated with chronic hemolysis and avoid the complications associated with current treatment approaches. As these disease-directed therapies are approved for clinical use, clinicians will need to define the types of symptoms and findings that determine the optimal patients and timing for initiating these therapies. In this article, we highlight disease manifestations, monitoring approaches, strategies for managing complications, and novel therapies in development.
proteins
2024-01-30 | Treatment with Erythropoietin Improves Ineffective Erythropoiesis in a Child with Pyruvate Kinase Deficiency
Background: Pyruvate Kinase Deficiency (PKD) drastically reduces the lifespan of erythrocytes resulting in, inter alia, jaundice, hypersplenism and dependency on regular blood transfusions due to hemolysis. Splenectomy and blood transfusions do not guarantee an improvement of clinical symptoms and cause severe side effects such as iron overload and risk of infection. Procedure: Treatment with EPO was introduced two months after birth and commenced with a dosage of < 200.0 U/kg subcutaneously twice per week. Results: Hemoglobin concentration (Hb) remained stable at 8.0 g/dl at the age of 12 months and reached a peak of 11.0 g/dl at 20 moths. No further transfusions were necessary since the effect of EPO set in. Mean corpuscular volume (MCV) showed a slower increase than the number of reticulocytes proving that treatment with EPO improved the maturation of reticulocytes to adult erythrocytes thereby overcoming ineffective erythropoiesis. Iron overload due to prior transfusions was reduced, hypersplenism and compromised liver function were not present at any time. The child’s health and neurological development were in line with its age always. Conclusions: Treatment with EPO overcomes ineffective erythropoiesis in patients with a measurable residual activity of PK preventing the risks and side effects of current standard treatment strategies
2023-12-14 | Real-World Impact of Pyruvate Kinase Deficiency in Children
Pyruvate kinase (PK) deficiency is a hereditary haemolytic anaemia caused by mutations in the PKLR gene encoding PK, which is critical for maintaining red blood cell (RBC) energy levels. Defects in PK cause chronic haemolysis. There are currently no disease-modifying therapies approved for use in children with PK deficiency, and treatment can involve regular blood transfusions, iron chelation, splenectomy, and management of disease complications. In this interview, Rachael F. Grace, a paediatric haematologist at the Dana–Farber/Boston Children's Cancer and Blood Disorders Center, Massachusetts, USA; and Julián Sevilla, a haematologist at the Hospital Infantil Universitario Niño Jesús in Madrid, Spain, shared their experience of diagnosing and treating paediatric patients with PK deficiency. They discussed the substantial variability in symptoms between patients irrespective of their haemoglobin level, the risk of iron overload even in children not receiving regular transfusions, and the effects of jaundice on children’s self-esteem. Grace and Sevilla also examined the challenges in diagnosis and management of PK deficiency in paediatrics, and the importance of regular monitoring in all patients, both to identify potential complications, and to ensure optimal medical management of their disease. Finally, they discussed new therapies that are currently being developed, which have the potential to have a major impact on future treatments for paediatric patients with PK deficiency.
2023-11-13 | Differential Gene Expression of Malaria Parasite in Response to Red Blood Cell-Specific Glycolytic Intermediate 2,3-Diphosphoglycerate (2,3-DPG)
Innovative strategies to control malaria are urgently needed. Exploring the interplay between the Plasmodium sp. parasites and host red blood cells (RBC) offers opportunities for novel antimalarial interventions. Pyruvate kinase deficiency (PKD), characterized by heightened 2,3-diphosphoglycerate (2,3-DPG) concentration, has been associated with protection against malaria. Elevated 2,3-DPG levels, a specific mammalian metabolite, may hinder glycolysis, prompting us to hypothesize its potential contribution to PKD-mediated protection. We investigated the impact of the extracellular supplementation of 2,3-DPG on the Plasmodium falciparum intraerythrocytic developmental cycle in vitro. Results showed an inhibition of parasite growth, resulting from significantly less progeny from 2,3-DPG-treated parasites. We analyzed differential gene expression and the transcriptomic profile of P. falciparum trophozoites, from in vitro cultures submitted or not submitted to the action of 2,3-DPG, using Nanopore Sequencing Technology. The presence of 2,3-DPG in the culture medium was associated to a significant differential expression of 71 genes, mostly associated to GO terms nucleic acid binding, transcription, or monoatomic anion channel. Further, several genes related to the cell cycle control were downregulated in treated parasites. These findings suggest that the presence of this RBC-specific glycolytic metabolite impact the expression of genes transcribed during the parasite trophozoite stage and the number of merozoites released from individual schizonts, which supports the potential role of 2,3-DPG in the mechanism of protection against malaria by PKD.
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Drug Discovery Landscape
6 orphan drug designations for Hemolytic anemia due to red cell pyruvate kinase deficiency, including 2 approved therapies.
6 orphan drug designations for Hemolytic anemia due to red cell pyruvate kinase deficiency, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Autologous CD34+ cells edited with CRISPR/Cas9 and transduced with an adeno-associated virus vector serotype 6 containing the codon-optimized version of PKLR gene | gene therapies | FDA | — | Consorcio Centro de Investigación Biomédica en Red (CIBER) |
Autologous CD34+ cells edited with CRISPR/Cas9 and transduced with an adeno-associated virus vector serotype 6 containing the codon-optimized version of PKLR gene | gene therapies | EMA | — | Consorcio Centro de Investigación Biomédica en Red |
Mitapivat sulfate [Pyrukynd] | small molecules | EMA | Approved | Agios Netherlands B.V. |
lentiviral vector containing the human liver and erythroid pyruvate kinase gene | gene therapies | FDA | Rocket Pharmaceuticals, Inc. | |
mitapivat [Pyrukynd] | small molecules | FDA | Approved | Agios Pharmaceuticals, Inc. |
Lentiviral vector containing the human liver and erythroid pyruvate kinase (PKLR) gene | gene therapies | EMA | Rocket Pharmaceuticals B.V. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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