Mutation analysis of the acid beta-glucosidase gene in a patient with type 3 Gaucher disease and neutralizing antibody to alglucerase
Germain, D.P.; Kaneski, C.R.; Brady, R.O.
Mutation Research 483(1-2): 89-94
2001
ISSN/ISBN: 0027-5107 PMID: 11600137 Document Number: 529468
The beneficial effects of macrophage-targeted glucocerebrosidase (alglucerase, CeredaseTM) 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 beta-glucosidase genotype in this patient. Direct sequencing of both cDNA and genomic PCR products was used to characterize the mutations underlying acid beta-glucosidase deficiency. The patient was shown to be a compound heterozygote for a previously reported missense mutation (G377S), and a novel single nucleotide deletion (g5255delT). 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.