Original Articles
The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher’s disease,☆☆

https://doi.org/10.1067/mpd.2001.112171Get rights and content

Abstract

Objective: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Study design: Patients with type 3 Gaucher’s disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. Results: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. Conclusions: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher’s disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease. (J Pediatr 2001;138:539-47)

Section snippets

Patients

Twenty-one patients (12 males and 9 females), ranging in age from 8 months to 35 years, with neuronopathic Gaucher’s disease were evaluated (Table I).At the time of enrollment, 3 patients were adults (age range, 18-30 years) and 18 were children (age range, 8 months-15 years). Seven patients underwent partial or complete splenectomy before enrollment, and one patient had a partial splenectomy during the follow-up period. Four patients were receiving ERT when they entered the study. The length

Enzyme Doses

The enzyme doses ranged between 120 IU/kg and 480 IU/kg of body weight/4 wk; 18 patients received biweekly doses of 60 IU/kg. Patient 3 responded only to 120 IU/kg/2 wk; patient 9 received 60 IU to 120 IU/kg/wk in an attempt to induce tolerance to the enzyme after development of neutralizing antibodies.32 Initially, patient 11 did not respond to an enzyme dose of 120 IU/kg/wk but did respond after a partial splenectomy (see below). Currently, all but 3 patients receive 60 IU/kg every 2 weeks.

Discussion

ERT is safe and effective in reversing most of the systemic manifestations of chronic neuronopathic (type 3) Gaucher’s disease in a large cohort of patients. The treatment rapidly reduced organomegaly and corrected hematologic abnormalities. ERT improved femoral cortical bone thickness and normalized the bone marrow signal on T1-weighted MRI images. Although cortical bone thickness was determined only in the femur and does not necessarily reflect other skeletal regions, this finding documented

Acknowledgements

We thank the patients and their families for their participation, Dr Thierry Billette de Villemeur for referral of patients, and Devera G. Schoenberg, MS, for editorial assistance.

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    *Collaborators: Tappas K. Bannarjee, MD, K. Crutchfield, MD, Karen Frei, MD, Mary-Ann McKee, MD, David F. Moore, MD, PhD, DIC, and Ann Tournay, MD

    ☆☆

    Reprint requests: Raphael Schiffmann, MD, National Institutes of Health, Building 10, Room 3D03, 9000 Rockville Pike, Bethesda, MD 20892-1260.

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