Combined glucose-6-phosphate dehydrogenase and glucosephosphate isomerase deficiency can alter clinical outcome.
Glucosephosphate isomerase (GPI) deficiency in humans is an autosomal recessive disorder, which results in nonspherocytic hemolytic anemia of variable clinical expression. A 4-year-old female with severe congenital hemolytic anemia had low red cell GPI activity of 15.5 IU/g Hb (50% of normal mean) indicating GPI deficiency. Subsequent DNA sequence analysis revealed a novel homozygous 921C to G mutation in the GPI gene sequence, predicting a Phe307 to Leu replacement. Strikingly, the red cell GPI activity in this patient was higher than that found in a second patient expressing the same GPI variant, with a more severe clinical phenotype. We propose that the hemolysis in the first patient may be modified by an accompanying deficiency of glucose-6-phosphate dehydrogenase (G6PD). The proband's red cell G6PD activity was reduced at 4.5 IU/g Hb (50% of normal mean) and molecular studies revealed heterozygosity for the G6PD Viangchan mutation and a skewed pattern of X-chromosome inactivation, producing almost exclusive expression of the mutated allele. The G6PD Viangchan variant is characterised by severe enzyme deficiency, but not chronic hemolysis. This study suggests that the metabolic consequences of a combined deficiency of GPI and G6PD might be responsible for a different clinical outcome than predicted for either defect in isolation.
Department of Haematology, Faculty of Medicine, Imperial College of Science Technology and Medicine, Hammersmith Hospital, London, UK.
Julia L
JL
Clarke
Tom J
TJ
Vulliamy
David
D
Roper
Seyed A
SA
Mesbah-Namin
Barbara J
BJ
Wild
James I
JI
Walker
Andrew M
AM
Will
Paula H
PH
Bolton-Maggs
Philip J
PJ
Mason
D Mark
DM
Layton
D000743:Anemia, Hemolytic / Q000235:genetics; D000746:Anemia, Hemolytic, Congenital Nonspherocytic; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004303:Dosage Compensation, Genetic; D005192:Family Health; D005260:Female; D005956:Glucose-6-Phosphate Isomerase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation
D005956:Glucose-6-Phosphate Isomerase