The AE1 gene encodes band 3 Cl Ϫ /HCO 3 Ϫ exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of the kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO 3 Ϫ across the basolateral membrane. Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA). However, the modest degree of in vitro hypofunction exhibited by these dRTA-associated mutations fails to explain the disease phenotype in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytosis. We report here novel AE1 mutations linked to a recessive syndrome of dRTA and hemolytic anemia in which red cell anion transport is normal. Both affected individuals were triply homozygous for two benign mutations M31T and K56E and for the loss-of-function mutation, G701D. AE1 G701D loss-of-function was accompanied by impaired trafficking to the Xenopus oocyte surface. Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A, rescued both AE1-mediated Cl Ϫ transport and AE1 surface expression in oocytes. The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with apparently normal erythroid anion transport. ( J. Clin. Invest. 1998. 102:2173-2179.)

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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 ...