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.