Introduction GPI deficiency is one of the three most common RBC enzyme defects causing chronic hemolytic anemia (the other two are PK and P5’N1) with approximately 100 affected families described. Most patients are compound heterozygous for mutations that partially inactivate the enzyme.
Pathobiology
GPI converts glucose-6-phosphate to fructose-6-phosphate in the second step of glycolysis. The GPI enzyme is a homodimer and only the dimeric form has enzyme activity. The monomeric form of GPI has non-erythroid functions as a neuroleukin, i.e. a neuro trophic factor for spinal and sensory neurons and as an autocrine motility factor, which is also secreted by cancer cells and stimulates cancer metastasis. GPI also has a role in glycerolipid biosynthesis. The GPI gene is large (50 kb) with 18 exons and cDNA of 1.9 kb. Approximately 50 missense mutations altering the catalytic site have been reported. In some families, impaired granulocyte and neuro muscular function occurs, likely due to the non-erythroid functions of GPI.
Clinical and Laboratory Features
Most patients are compound heterozygotes, although some are homozygotes, usually as the consequence of a consanguineous union. Splenomegaly is often present. The severity of the hemolysis is variable. Many affected patients do not require therapy, other than blood transfusions during hemolytic periods, but some are transfusion dependent. In many splenectomized patients, reticulocytes increase after splenectomy, but not as strikingly as in PK deficiency; the pathophysiology of this phenomenon remains unclear.
Like any other chronic hemolytic anemia, patients are at risk for iron overload, gallstones, and for parvoviral-induced pure red-cell aplasia. Severe enzyme deficiency can be associated with hydrops fetalis, neonatal death, and neurological impairment.
In isolated GPI-deficient families, severe neuromuscular symptoms, mental retardation, and granulocyte dysfunction have been documented and dominate the disease phenotype.
Therapy
Patients may be transfused as needed. In those who are transfusion dependent, splenectomy should be considered. Anemia significantly improves in the majority, but not all, GPI-deficient patients following splenectomy. Iron status should be monitored in all patients, even in those who have never been transfused. If iron overload is detected, iron chelation should be instituted.
