Background. CD59 encodes a 77-amino acid glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein synthesized as a 128-amino acid protein that includes a signal sequence and the sequence for a GPI anchor replacement. The CD59 protein inhibits the final and most important step of membrane attack complex (MAC) formation. A novel primary homozygous Cys89Tyr CD59 deficiency was recently reported by us in 5 children. The mutation resulted in amino acid substitution of p.Cys89Tyr and function failure to of CD59 protein on the cell surface. In this study, we characterized an additional 10 children, and summarized outcomes from a clinical study of eculizumab in these patients (NCT01579838).

Methods. Participants were recruited from our new patient registry for homozygosity of the p.Cys89Tyr mutation on CD59. 15 homozygous and 42 heterozygous patients were identified and characterized using clinical history, lab results, medical treatment, hospitalizations, biopsies, and in one case post mortem analysis. 4 patients were recruited for a clinical study where participants received repeated treatment with intravenous eculizumab. In this 24-month open-label phase IIa study we aimed to determine whether eculizumab reduces chronic hemolysis and cumulative doses of steroids and IV IgG, and ameliorates neurological deficits compared to those observed before treatment. Treatment response was evaluated every 2-4 weeks over 34 weeks, including examination with gross motor scoring, ASIA score, INCAT disability score, laboratory examination, and SF-12 fulfillment. Neurological relapses and the cumulative dose of IVIG and/or corticosteroids before and after treatment initiation were documented. RBCs and neutrophils were stained to evaluate C5b-9 deposition.

Results. All 15 homozygous patients suffered from chronic Coombs' negative hemolysis with hemoglobin levels of 6.5-12 gr%. All patients had post infectious peripheral neuropathy resembling recurrent Gillian Barre syndrome (GBS) and 2 patients suffered from recurrent strokes. A dramatic and significant neurological amelioration in the upper limbs and trunk, with a more modest amelioration in the lower limbs was observed in all patients. Corticosteroid and immunoglobulin treatment, which had been used extensively prior to eculizumab initiation, was completely stopped. No patient suffered a relapse during the treatment period despite infections, and there were no hospital admissions. The SF-12 health questionnaires indicated significant improvement (p<0.003). Decreased deposition of C3bi and C5b-9 on RBCs and neutrophils was documented (p<0.0001).

Conclusions. The natural history of patients with homozygous Cys89Tyr CD59 deficiency includes chronic hemolysis and recurrent peripheral neuropathy resembling GBS. Recurrent strokes were observed in 2/15 patients. Eculizumab was safely given to 4 patients. The clinical improvement suggests this is a lifesaving treatment for patients with primary CD59 deficiency. Cys89Tyr CD59 homozygous deficiency is similar to PNH with regard to chronic hemolysis and the risk for stroke, but differs from recurrent GBS episodes that are eliminated once eculizumab was used. Heterozygous patients seem to have normal life expectancy and no hemolysis or any clinical syndromes.


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