Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-

Nieves Perdigones,Philip Mason,Monica Bessler,Mariela Morales

doi:10.12688/f1000research.4980.1

Abstract

We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene. PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking Bactrim, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode.

Highlights

In paroxysmal nocturnal hemoglobinuria (PNH) one or more clones of blood cells develops from stem cells that have an acquired mutation in the X-linked PIGA gene1
The family history and the case history suggested that the patient may have both Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency and PNH, since the G6PD deficiency might explain the hemolysis precipitated by Bactrim, a drug that is reported to cause hemolysis in G6PD patients
The sequencing trace showed that the vast majority of expressed G6PD cDNA contained the wild type (G6PD B) sequence at both nucleotides where it differs from G6PD A(Figure 2), leaving us to conclude that the PIGA mutations had taken place on the X-chromosome containing the G6PD B allele

Summary

Introduction

In paroxysmal nocturnal hemoglobinuria (PNH) one or more clones of blood cells develops from stem cells that have an acquired mutation in the X-linked PIGA gene. The PIGA gene encodes phosphatidylinositol glycan complementation class A, an enzyme that catalyses an early and essential step in glycosylphosphatidylinositol (GPI) anchor synthesis. Cells are deficient in all GPI anchored proteins, including CD55 and CD59 which regulate complement activation. PNH usually develops in patients with aplastic anemia (AA) and it is thought that PNH cells have a growth or survival advantage over the AA cells the mechanism is not known. PNH cells can be completely deficient in GPI anchored proteins (Type III) or partially deficient due to residual activity of the PIGA protein (Type II), while PNH Type I cells express GPI-linked proteins normally. Blood samples for fluorescent cytometry and electrophoretic analyses were obtained from EDTA tubes and experiments were performed within 2 hours of blood withdrawal

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