Chitotriosidase genotype and plasma activity in patients with type 1 Gaucher's disease and their relatives (carriers and non-carriers)

Background and Objectives. Chitinases are enzymes that hydolyze chitin and have been found in a wide variety of non-vertebrate species; recently a human analog of chitinases, chitotriosidase (CT) has been identified. Extreme elevations of plasma CT activity are observed in patients with Gaucher's disease (GD), Gaucher cells being the source of the CT. A 24 by duplication in the CT gene, resulting in an inactive protein, has been reported. The carrier prevalence is as high as 30 to 40% and the CT activity is half that in individuals with the wild-type gene. However no systematic evaluation of plasma CT activity has been carried out in GD patients taking into account the status of the allele defective for CT and dose in patients on enzyme replacement therapy (ERT). Design and Methods. We had previously studied 210 subjects from 99 unrelated Spanish GD families (121 non-affected carriers and 89 non-carriers) in order to establish carrier prevalence of CT genotypes. Plasma CT activity and CT genotypes evaluated by polymerase chain reaction (PCR) and gel electrophoresis were measured in 109 GD patients before treatment. We also evaluated CT activity after ERT with alglucerase in 68 patients. Results. Three patients had defective activities of CT. The carrier prevalence for the 24 by duplication was 35% and the allele frequency 0.20. No correlation between CT activity and GBA genotype was detected nor between CT activity and visceral or skeletal disease in GD patients. Untreated affected patients, non-carriers for the duplication, had higher CT activity than carriers (p < .0001). CT activity decreased dramatically during the first 12 months of ERT; even after 3 years of therapy a persistent fall of CT activity was observed. However, within 3 years of treatment, a significant difference in the mean decrease of CT activity was present among the group of patients receiving varying alglucerase doses (p < .01). After 12 months of ERT the activity of plasma CT declined by the same percentage in both groups: heterozygous carriers of the 24bp duplication and wild type allele, but thereafter CT activity declined more slowly in carriers than non-carriers. Interpretation and Conclusions. The present data can be used as a reference to interpret CT activity in GD patients with or without ERT, as well as to evaluate dose-response. It can also be used as a reference to interpret CT activity in carriers and non-carriers. (C) 2001, Ferrata Storti Foundation.