Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency

Abstract

Summary:We report the first successful use of BMT for the treatment of RBC pyruvate kinase (PK) deficiency in a boy who developed neonatal jaundice and severe transfusion-dependent hemolytic anemia a few months after birth. He received a BMT at the age of 5 from an HLAidentical sister who has normal PK activity after conditioning with busulfan and cyclophosphamide. The post-transplant course was uneventful. At present, 3 years after transplant, he is 8 years old and has a normal hemoglobin level and normal RBC PK activity without evidence of hemolysis. DNA analysis has confirmed full engraftment. Bone Marrow Transplantation (2000) 26, 689-690. Keywords: BMT; PK deficiency; pyruvate kinase; stem cell transplantation; DNA-short tandem repeat markers; enzymopathies Pyruvate kinase (PK) deficiency is the most common hereditary RBC enzymopathy of the glycolytic pathway. To date, nearly 400 patients have been reported. 1 The clinical manifestations of PK deficiency are heterogenous, ranging from fetal anemia, neonatal jaundice, severe chronic hemolytic anemia to a fully compensated hemolytic anemia. [1][2][3] Treatment of this disease is mostly symptomatic, including blood transfusion and splenectomy. 1 Bone marrow transplantation has been used to cure the disease in mice and dogs. [4][5][6] In humans, gene transfer of human PK cDNA has been attempted. 7 We briefly reported the first successful use of BMT for the treatment of PK deficiency in a boy who had severe chronic hemolytic anemia from birth. 8 This report describes this case in detail, with long-term follow-up. Case reportThe patient was the product of uneventful pregnancy delivered by caesarean section because of a previous caesarean. His birth weight was 3.2 kg and 12 h after birth, pallor and jaundice were noticed. The Hb was 9.6 g/dl, reticulocytes 9.6%, RBC morphology revealed mild hypochromia, anisocytosis, poikilocytosis, polychromasia and the presence of 445 nucleated RBC per 100 WBC. The mother was blood group 'O' and the patient blood group 'B'. His bilirubin level was 14.9 mg/dl. Blood group 'B-O' incompatibility was diagnosed and an exchange blood transfusion was given on the second day of life followed by phototherapy for a few days. He was sent home at the age of 7 days.At the age of 4 months, he was markedly anemic with a Hb level of 5.5 g/dl. RBC glucose-6-phosphate dehydrogenase (G-6-PD) was normal and Hb typing revealed E F A (21.7, 13.1, 65.2%). Several packed red cell transfusions were given to improve symptoms of anemia. At the age of 13 months mild hepatosplenomegaly was noted with a Hb level of 6 g/dl. He was diagnosed at the age of 3 years as having PK deficiency and Hb E trait. His father was heterozygous for both Hb E and PK deficiency, his mother was heterozygous for PK deficiency and his elder sister had Hb E trait but normal red blood cell PK activity. 9 Since he was markedly anemic and the spleen was getting larger, he received hypertransfusion and iron chelation at the age of 3 years. His Hb was maintained above 10 g/dl with an ...

In VitroandIn VivoExpression of Human Erythrocyte Pyruvate Kinase in Erythroid Cells: A Gene Therapy Approach

“…Splenectomy can be clinically useful in patients with severe disease, and in some cases allogeneic hematopoietic transplantation is required (Suvatte et al, 1998;Tanphaichitr et al, 2000). In these patients, hematopoietic stem cell gene therapy could be an effective, less invasive alternative.…”

Worldwide study of hematopoietic allogeneic stem cell transplantation in pyruvate kinase deficiency

“…4,5 To date, only four human cases of HSCT have been published in the literature. [6][7][8] The total number of cases transplanted worldwide is unknown.…”

Transgenic rescue of hemolytic anemia due to red blood cell pyruvate kinase deficiency

“…HSCT has been used in animal models, 13,16,17 and a case of successful bone marrow transplantation has been reported recently. 15 Non-myeloablative HSCT seems a favorable strategy for the treatment of PK deficiency, as indicated in animal model studies, since erythroid progenitors with normal R-PK show a selective growth advantage. 13,17 Enzyme-replacement therapy is another candidate for causative-targeted therapy of severe hemolytic anemia due to RBC enzyme defects.…”

“…Although hematopoietic stem cell transplantation (HSCT) has been considered as a therapeutic strategy for PK deficiency in a PK-deficient subject 15 as well as in animal models, 13,16,17 a curative therapy without any lifethreatening complications needs to be developed. In addition, the majority of the identified PK gene mutations are missense mutations, 2,3 and previous studies revealed that there were some kinetically aberrant enzymes, which showed normal intracellular stability in erythroid cells.…”