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1.
Blood ; 136(11): 1241-1249, 2020 09 10.
Article in English | MEDLINE | ID: mdl-32702739

ABSTRACT

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.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/therapy , Adolescent , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Anemia, Hemolytic, Congenital Nonspherocytic/epidemiology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Blood Transfusion , Chelation Therapy , Child , Child, Preschool , Cholelithiasis/etiology , Cholelithiasis/surgery , Clinical Trials as Topic , Disease Management , Female , Fetal Diseases/genetics , Genetic Therapy , Genotype , Hematopoietic Stem Cell Transplantation , Humans , Infant , Infant, Newborn , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Iron Overload/etiology , Jaundice, Neonatal/etiology , Jaundice, Neonatal/therapy , Male , Mutation , Pregnancy , Prevalence , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/diagnosis , Pyruvate Metabolism, Inborn Errors/epidemiology , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy , Splenomegaly/etiology , Splenomegaly/surgery
2.
Pediatrics ; 141(Suppl 5): S385-S389, 2018 04.
Article in English | MEDLINE | ID: mdl-29610156

ABSTRACT

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic hemolytic anemia, and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and splenomegaly. Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal cholestasis and a young adult with a severe form of PKD and having been transfusion dependent during childhood. After transplant, both patients have normal liver function test results and have considerably decreased their need for blood transfusion despite ongoing, mild hemolysis. We suggest that PKD can lead to severe liver dysfunction and that LT and splenectomy can be life-saving procedures in such cases.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/complications , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Liver Failure/etiology , Liver Failure/surgery , Liver Transplantation , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/complications , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy , Anemia, Neonatal/etiology , Blood Transfusion , Cholestasis/etiology , Humans , Infant , Male , Young Adult
3.
J Pediatr Hematol Oncol ; 40(7): e458-e460, 2018 10.
Article in English | MEDLINE | ID: mdl-29309376

ABSTRACT

Pyruvate kinase (PK) deficiency is the most common defect of the glycolytic pathway leading to congenital hemolytic anemia. We present the case of an 18-year-old boy with chronic nonspherocytic hemolytic anemia, who had remarkable sensitivity to heat. Moreover, the patient showed clinical impairment in the last year. For this reason, we excluded the immunologic or infectious nature (malaria, babesia), which may play a role in the worsening of anemia. Red blood cell enzyme assay showed the presence of a significant increase in other enzyme activities, except for PK, suggesting a PK deficiency in the patient. The molecular analysis of the PK-LR gene revealed the presence of a novel homozygote missense mutation (c.581G>C, p.Arg194Pro). The mutant enzyme displayed heat instability. In addition, we analyzed bilirubin uridine diphosphate (UDP)-glucuronosyltransferase 1A1 gene that revealed a heterozygous state ([TA]6/[TA]7). After a clear diagnosis of PK deficiency, the patient underwent splenectomy.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Hot Temperature , Mutation, Missense , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/genetics , Adolescent , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Glucuronosyltransferase/genetics , Heterozygote , Humans , Male , Pyruvate Kinase/genetics , Pyruvate Metabolism, Inborn Errors/diagnosis , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy
7.
Pediatr Int ; 58(7): 634-6, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27460399

ABSTRACT

Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion-dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase-liver and RBC (PK-LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Erythrocytes/cytology , Fetal Blood/cytology , Hematopoietic Stem Cell Transplantation/methods , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/surgery , Anemia, Hemolytic, Congenital Nonspherocytic/blood , Anemia, Hemolytic, Congenital Nonspherocytic/diagnosis , Female , Humans , Infant , Pyruvate Kinase/blood , Pyruvate Metabolism, Inborn Errors/blood , Pyruvate Metabolism, Inborn Errors/diagnosis
8.
Am J Hematol ; 90(9): 825-30, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26087744

ABSTRACT

Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell pyruvate kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.


Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/therapy , Erythrocyte Transfusion , Exchange Transfusion, Whole Blood , Pyruvate Kinase/deficiency , Pyruvate Metabolism, Inborn Errors/therapy , Adult , Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Anemia, Hemolytic, Congenital Nonspherocytic/pathology , Anemia, Hemolytic, Congenital Nonspherocytic/surgery , Child , Disease Management , Humans , Infant, Newborn , Phototherapy , Pyruvate Metabolism, Inborn Errors/enzymology , Pyruvate Metabolism, Inborn Errors/pathology , Pyruvate Metabolism, Inborn Errors/surgery , Splenectomy
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