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Hereditary non‐spherocytic haemolytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain: clinical and molecular studies

In four unrelated patients with chronic haemolysis and markedly reduced red blood cell (RBC) glutathione (49·5%, 12·6%, 11·5% and 15% of the normal concentration respectively), a severe glutathione synthetase (GSH‐S, EC 6.3.2.3) deficiency was found. One case exhibited a neonatal haemolytic anaemia associated with oxoprolinuria, but without neurological manifestations. The family study revealed GSH‐S activity in both parents to be around half the normal level, a finding consistent with the presumed autosomal recessive mode of inheritance of this enzymopathy. Two cases exhibited a well‐compensated haemolytic syndrome without anaemia or splenomegaly at steady state. One of these cases was diagnosed after an episode of acute haemolytic anaemia after fava bean ingestion. The remaining patient suffered from moderate to severe chronic non‐spherocytic haemolytic anaemia and splenomegaly, and required occasional blood transfusion for a haemolytic crisis associated with drug ingestion. In this patient, the anaemia was corrected by splenectomy. In addition to GSH‐S, a panel of 16 other RBC enzyme activities was also studied in all the patients. Hexokinase, aldolase, glucose‐6‐phosphate dehydrogenase and pyruvate kinase activities all increased; these increases were to be expected, given the rise in the number of circulating reticulocytes. In two patients, the incubation of RBCs with hydrogen peroxide revealed an enhanced production of malonyldialdehyde. DNA analysis showed a homozygous state for 656 A→G mutation in patients 2 and 3. The GSH‐S gene of patient 1, studied elsewhere, revealed an 808 T→C. The GSH‐S gene of patient 4 was not available for study. The present study demonstrates that GSH‐S deficiency is also present in Spain and further supports the molecular and clinical heterogeneity of this enzymopathy