Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies

Abstract

Mutations of the human SLC4A1 gene encoding erythroid and kidney isoforms of anion exchanger 1 (AE1, band 3) result in erythrocyte abnormalities or distal renal tubular acidosis (dRTA) and such mutations are observed in Southeast Asia, where hemoglobinopathies are prevalent. Genetic and hematological studies in 18 Thai patients with dRTA have shown that 12 of them (67%) carried SLC4A1 mutations (7 G701D/G701D, 3 SAO/G701D, and 2 G701D/A858D). Of these 12 patients, three had homozygous G701D/G701D and heterozygous Hb E; one compound heterozygous SAO/G701D and heterozygous a þ -thalassemia; and one compound heterozygous G701D/A858D and heterozygous Hb E. Of 6 patients without SLC4A1 mutation, two each carried heterozygous or homozygous Hb E and one of the latter also had Hb H disease (--SEA /-a 4.2 ). The blood smears of patients with homozygous G701D/G701D showed 25% ovalocytes. Strikingly, the patients with coexistence of homozygous G701D/G701D and heterozygous Hb E had 58% ovalocytes. Similarly, the patients who had compound heterozygous SAO/G701D showed 49% ovalocytes, but the patient with coexistence of compound heterozygous SAO/G701D and heterozygous a þ -thalassemia had 70% ovalocytes. Our previous study has shown that under metabolic acidosis, the patients with homozygous G701D/ G701D or compound heterozygous SAO/G701D had reticulocytosis, indicating compensated hemolysis. A patient with compound heterozygous SAO/G701D and heterozygous a þ -thalassemia presented with hemolytic anemia and hepatosplenomegaly which was alleviated by alkaline therapy. Taken together, the coexistence of both homozygous or compound heterozygous SLC4A1 mutations and hemoglobinopathy has a combined effect on red cell morphology and degree of hemolytic anemia, which is aggravated by acidosis. Am. J. Hematol. 83:465-471, 2008. V

Distal Renal Tubular Acidosis in Filipino Children, Caused by Mutations of the Anion-Exchanger SLC4A1 (AE1, Band 3) Gene

“…1) and the 3 homozygous G701D patients in this study, 3, 5a and 5b, were initially misdiagnosed as SAO from their blood smears. This ovalocytic morphology in homozygous G701D red cells has been reported from Thailand [4,14] and our data confirm that it is typical of the homozygous G701D phenotype. Although we found up to 50% of ovalocytes in the blood film red cells of our 3 homozygous G701D patients, close study of these films suggested that stomatocytes and macrocytes were less common in this syndrome than in SAO; these changes are scanty in fig.…”

“…G701D homozygotes and G701D/SAO compound heterozygotes were both moderately anaemic initially (table 1), suggesting excess haemolysis, as has been reported previously in G701D/SAO and G701D/G701D [3,14], but unexpectedly the red cells from both groups of patients appeared to have SAO morphology (fig. 1) and the 3 homozygous G701D patients in this study, 3, 5a and 5b, were initially misdiagnosed as SAO from their blood smears.…”

“…1a and 1b from patients with the SAO mutation. Recently, Khositseth et al [14 ]have also suggested that the ovalocytic red cells of homozygous G701D patients may show less abundant stomatocytes and large red cells than are present in SAO.…”

“…Hb E disease is common in some parts of Southeast Asia, and can cause changes in the peripheral blood film with similarities to those of homozygous G701D [2,4,14]. Although Hb E is rare in the Philippines [11], Hb electrophoresis was carried out on the blood of patient 5a, and confirmed the absence of Hb E.…”

“…Most patients were moderately anaemic at the time of diagnosis, with haemoglobin (Hb) values of 88–120 g/l (table 1), but other features of excess haemolysis, such as jaundice, reticulocytosis and splenomegaly were not noted. However, most children were receiving alkali treatment sufficient to correct acidosis at the time of follow-up visits to the clinic, so they did not show the increased tendency to haemolysis that has been observed in dRTA patients with AE1 mutations when they become seriously acidotic [7,14]. Patient 3, with G701D homozygosity, was unexpectedly found to be severely anaemic (Hb 58 g/l) when she attended the clinic aged 8 years, allegedly receiving her normal alkali medication but with a plasma bicarbonate of only 11 mmol/l.…”