Could Enzyme Replacement Therapy for Long Time Normalize Chitotriosidase Activity in Type 1 Gaucher Disease?.
Authors: Giraldo Pilar , Alfonso Pilar , Perez-Calvo Juan , Giralt Manuel 
Published: October 2019

Background: Extreme elevations of plasma chitotriosidase (CT) are observed in Gaucher’s disease (GD) patients. This enzyme has been considered as a response marker to enzyme replacement therapy (ERT). It has been previously described the normalization of enzymatic activity only in patients who have been treated by bone marrow transplantation (Young E et al, 1997). It is widely accepted that GD subjects receiving ERT show improvements in clinical symptoms and regression of signs of disease, such as disappearance or reduction of visceral enlargement, normalized haematological parameters and skeletal improvement and also reduce the CT activity values, but these do not actually reach a normal range. Surprisingly, in the follow-up of patients included in the Spanish Gaucher Registry, some cases showed normalization of their CT activity after several years under therapy. The purpose of this study is to analyze the clinical, analytical and genotype characteristics of type 1 GD patients that have normalized their CT activity and to compare with the rest of patients under ERT for same period of follow-up. Patients and Methods: We have studied a cohort of 64 type 1 GD patients receiving ERT. We observed 20 GD patients who reach a normal CT activity range (CT activity < 200 nmol/mL.h) under therapy 2–7 years (group A) and 44 GD patients whose CT activity maintained increased under therapy 2–10 years (group B). Clinical and analytical data have been obtained from Spanish GD registry. Assessment of response included serial measurement of haemoglobin (Hb), platelet count, liver and spleen sizes and CT activity. Plasma CT activity was measured with the fluorogenic substrate 4-methylumbelliferyl-β-D-N, N′, N″ triacetylchitotrioside. Determination of the 24-bp duplication in the CT gene was performed by PCR followed by electrophoresis of the amplified fragments. For statistical analysis we used the StatView database (version 4.5). Results: At baseline characteristics of both groups were as indicated in tables. Patients of group B had worse indicators of disease severity at baseline. SSI, percentages of bone disease and spleen removal were higher in group B than group A. In addition we found twice more heterozygous patients for 24 bp duplication of the CT gene in group A compared to group B Nevertheless, as the table shows, patients of group B received higher doses of ERT and for a longer time. Conclusion: The normalization of CT activity is infrequent in GD patients under ERT. It is influenced by CT genotype and probably by severity of disease.

Clinical data

Age at diagnosis Male/Female SSI Spleen removal(%) Bone disease (%) N370S Homozygous/N370S Heterozygous N: number, SSI: severity score system Analytical data Group A (n=20) 32 ± 15.0 7/13 7.6 ± 2.55 5 55 0/20 Group B (n=44) 29 ± 15.9 19/25 8.4 ± 3.15 27 66 5/39

Analytical data

Hb (g/dL) Platelets x 109/L CT activity(nmol/mL.h) Heterozygous CT genotype(%) ERT Dose (Units/2 weeks) N: number; Hb: Haemoglobin; CT: chitotriosidase; ERT: Enzyme replacement theraphy Group A (n=20) 12.3 ± 1.85 72.8 ± 31.27 7,489 ± 3,751 65 34.3 ± 10.33 Group B (n=44) 11.9 ± 1.84 107.5 ± 83.85 8,459 ± 3,563 32 41.4 ± 15.08