P.6.9 Childhood relapsing immune-mediated polyneuropathy and hemolysis is associated with CD59 deficiency

Abstract

The objective of the present study was to elucidate the molecular basis of a new clinical entity of childhood familial immune mediated relapsing polyneuropathy associated with chronic Coombs-negative hemolysis. Since infancy these children had recurrent episodes of weakness and hemolysis with partial improvement following immune modulating therapy. One child died at the age of 3.5years while the others demonstrated severe lower limb paralysis. A founder mutation was searched for using homozygosity mapping followed by exome sequencing in 5 infants of North-African Jewish origin from 4 unrelated families. The expression of CD59, CD55, and CD14 was examined in blood cells by flow cytometry followed by Western blot of the CD59 protein. Homozygous missense mutation, p.Cys89Tyr in CD59, was identified in all patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jewish subjects of North-African origin. The mutated protein was present in the patients' cells in reduced amounts and was undetectable on the membrane surface. CD59 deficiency is a common finding in RBCs and WBCs in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria in which the acquired mutation in the PIGA gene leads to membrane loss of glycosylphosphatidylinositol-anchored membrane proteins, including CD59. Based on the results of the present study, we suggest that the Cys89Tyr mutation in CD59 is associated with a failure of proper localization of the CD59 protein in the cell surface and decreased complement inhibition. This mutation is manifested clinically in infancy by relapsing peripheral demyelinating disease and chronic hemolysis.