Mutation analysis of the acid β-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase

The beneficial effects of macrophage-targeted glucocerebrosidase (alglucerase, Ceredas (TM)) in patients with Gaucher disease are well established. A minority of recipients develop transient non-neutralizing antibodies to the exogenous enzyme. A 7-year-old patient with type 3 Gaucher disease, whose clinical course began to deteriorate while receiving alglucerase developed a progressively increasing titer of IgG antibody, that blocked the catalytic activity of alglucerase. We investigated the acid p-glucosidase genotype in this patient. Direct sequencing of both cDNA and genomic PCR products was used to characterize the mutations underlying acid p-glucosidase deficiency. The patient was shown to be a compound heterozygote for a previously reported missense mutation (G377S), and a novel single nucleotide deletion (g5255deIT). The transcript originating from the latter allele was undetectable in RT-PCR experiments. We report the first characterization of a GBA genotype associated with the development of neutralizing antibody to alglucerase, in a patient affected with type 3 Gaucher disease. Our results may help to shed light on the mechanisms underlying this phenomenon which, in the rare instances where it occurs, hampers the efficacy of enzyme replacement therapy. (C) 2001 Elsevier Science B.V. All rights reserved.