Enzyme Therapy in Gaucher Disease Type 1: Effect of Neutralizing Antibodies to Acid β-Glucosidase

Abstract Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid β-glucosidase locus. Periodic infusions of macrophage-targeted acid β-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid β-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid β-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid β-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid β-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.

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Enzyme Therapy in Gaucher Disease Type 1: Effect of Neutralizing Antibodies to Acid β-Glucosidase

Blood ◽

10.1182/blood.v90.1.43.43_43_48 ◽

1997 ◽

Vol 90 (1) ◽

pp. 43-48 ◽

Cited By ~ 1

Author(s):

Elvira Ponce ◽

Jay Moskovitz ◽

Gregory Grabowski

Keyword(s):

Disease Progression ◽

Gaucher Disease ◽

Neutralizing Antibodies ◽

Disease Type ◽

High Dose ◽

Enzyme Therapy ◽

Lysosomal Storage ◽

Gaucher Disease Type 1

Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid β-glucosidase locus. Periodic infusions of macrophage-targeted acid β-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid β-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high-dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid β-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression and need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild-type, but not the N370S, acid β-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid β-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.

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Individualized long-term enzyme therapy for Gaucher disease type 1 in Slovenia

Pediatrics International ◽

10.1111/j.1442-200x.2011.03451.x ◽

2011 ◽

Vol 53 (6) ◽

pp. 1018-1022 ◽

Cited By ~ 1

Author(s):

Majda Benedik-Dolničar ◽

Lidija Kitanovski

Keyword(s):

Gaucher Disease ◽

Disease Type ◽

Enzyme Therapy ◽

Gaucher Disease Type 1

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Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months

Blood ◽

10.1182/blood.v82.2.408.408 ◽

1993 ◽

Vol 82 (2) ◽

pp. 408-416 ◽

Cited By ~ 133

Author(s):

GM Pastores ◽

AR Sibille ◽

GA Grabowski

Keyword(s):

Gaucher Disease ◽

Enzyme Therapy ◽

Lysosomal Storage ◽

Ashkenazi Jews ◽

Gaucher Disease Type 1 ◽

Beta Glucosidase ◽

Age Range ◽

Different Doses ◽

Dose Reductions

Abstract Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among the Ashkenazi Jews (q approximately 0.047). The disease results from inherited defects of acid beta-glucosidase and the accumulation of the substrate, glucosylceramide, in cells of monocyte/macrophage origin. The therapeutic response to macrophage-targeted (alpha-mannosyl-terminated) alglucerase (Ceredase, at 60 to 15 IU/kg every 2 weeks) was analyzed in 33 patients (age range, 2 to 63 years; 15 splenectomized) with extensive Gaucher disease over periods of 6 to 24 months. The efficacy of several different doses and dosage reductions was evaluated. In patients with anemia (n = 30) and/or thrombocytopenia (n = 19), hemoglobin levels and platelet counts increased by 0% to 178% and 15% to 155%, respectively, within 3 to 12 months. In patients with splenomegaly (n = 17) and/or hepatomegaly (n = 28), liver and spleen volumes decreased in 6 months from 7% to 64% and 8% to 84% by 12 months, respectively. Hematologic and visceral improvements were noted at any doses between 60 and 15 IU/kg every 2 weeks. Furthermore, these positive initial therapeutic responses were persistent throughout therapy, with doses reduced by 50%. Pulmonary Gaucher disease did not improve clinically in 3 patients. Unrelated cirrhotic (n = 2), cholestatic (n = 1), or renal disease (n = 1) did not influence the rate of patient improvement. Two of five patients who developed serum antibodies against alglucerase during the first 6 to 12 months of therapy had mild antibody reactions. This study shows similar regression of clinical Gaucher disease manifestations with enzyme therapy, using doses between 30 and 60 IU/kg every 2 weeks. Therapeutic efficacy was not diminished after 50% to 75% dose reductions or in the presence of anti-enzyme antibodies.

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Coxarthritis as the Presenting Symptom of Gaucher Disease Type 1

Arthritis ◽

10.1155/2011/361279 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Giacomo Brisca ◽

Maja Di Rocco ◽

Paolo Picco ◽

Maria Beatrice Damasio ◽

Alberto Martini

Keyword(s):

Gaucher Disease ◽

Lysosomal Storage Disorder ◽

Signs And Symptoms ◽

Mononuclear Phagocyte ◽

Disease Type ◽

Lysosomal Storage ◽

Skeletal Disease ◽

Abnormal Accumulation ◽

Gaucher Disease Type 1

Gaucher disease (GD) type 1 is the most common lysosomal storage disorder due to beta glucocerebrosidase deficiency leading to an abnormal accumulation of its substrate, glucocerebroside, in the mononuclear phagocyte system. The disease presentation is usually characterized by signs and symptoms related to hypersplenism, such as splenomegaly, anaemia, thrombocytopenia and leucopenia. Skeletal disease may occur later for the infiltration of bone marrow by macrophages infiltration and bone resorption: bone involvement may be heterogeneously manifested by symptoms ranging from bone crisis to avascular necrosis, osteoporosis and defect in remodeling of long bones. Herein, we report a patient in whom the osteoarticular involvement has been the only symptom of the disease stressing that this unusual presentation of GD has prompted a wide differential diagnosis with more common forms of coxitis.

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Gaucher disease: masquerading as chronic malaria

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20182588 ◽

2018 ◽

Vol 5 (4) ◽

pp. 1688

Author(s):

Seema Rai ◽

Gurmeet Kaur Sethi ◽

Rama Kumari ◽

Varun Kaul

Keyword(s):

Gaucher Disease ◽

Bone Marrow Involvement ◽

Disease Type ◽

Neurological Involvement ◽

Type Ii ◽

Lysosomal Storage ◽

Lysosomal Disorder ◽

History Of ◽

Gaucher Disease Type 1

Gaucher disorder s rare lysosomal disorder characterized by glycolipid laden lysosomes leading to hepatosplenomegaly, bone marrow involvement. Three types of Gaucher disease have been described based on the clinical features, ethnicity and the natural history of the disease. Gaucher disease Type 1 (GD1) occurs mainly in infancy to adulthood and is the commonest lysosomal storage disorder. Gaucher Disease Type II (GD2) and Gaucher disease type III (GD3) patients have onset at less than 1 year, and 2-20 years, respectively.1 GD1 patients do not have neurological involvement. GD2 is the acute neuronopathic and GD3 is the chronic neuronopathic type.

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Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months

Blood ◽

10.1182/blood.v82.2.408.bloodjournal822408 ◽

1993 ◽

Vol 82 (2) ◽

pp. 408-416 ◽

Cited By ~ 1

Author(s):

GM Pastores ◽

AR Sibille ◽

GA Grabowski

Keyword(s):

Gaucher Disease ◽

Enzyme Therapy ◽

Lysosomal Storage ◽

Ashkenazi Jews ◽

Gaucher Disease Type 1 ◽

Beta Glucosidase ◽

Age Range ◽

Different Doses ◽

Dose Reductions

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among the Ashkenazi Jews (q approximately 0.047). The disease results from inherited defects of acid beta-glucosidase and the accumulation of the substrate, glucosylceramide, in cells of monocyte/macrophage origin. The therapeutic response to macrophage-targeted (alpha-mannosyl-terminated) alglucerase (Ceredase, at 60 to 15 IU/kg every 2 weeks) was analyzed in 33 patients (age range, 2 to 63 years; 15 splenectomized) with extensive Gaucher disease over periods of 6 to 24 months. The efficacy of several different doses and dosage reductions was evaluated. In patients with anemia (n = 30) and/or thrombocytopenia (n = 19), hemoglobin levels and platelet counts increased by 0% to 178% and 15% to 155%, respectively, within 3 to 12 months. In patients with splenomegaly (n = 17) and/or hepatomegaly (n = 28), liver and spleen volumes decreased in 6 months from 7% to 64% and 8% to 84% by 12 months, respectively. Hematologic and visceral improvements were noted at any doses between 60 and 15 IU/kg every 2 weeks. Furthermore, these positive initial therapeutic responses were persistent throughout therapy, with doses reduced by 50%. Pulmonary Gaucher disease did not improve clinically in 3 patients. Unrelated cirrhotic (n = 2), cholestatic (n = 1), or renal disease (n = 1) did not influence the rate of patient improvement. Two of five patients who developed serum antibodies against alglucerase during the first 6 to 12 months of therapy had mild antibody reactions. This study shows similar regression of clinical Gaucher disease manifestations with enzyme therapy, using doses between 30 and 60 IU/kg every 2 weeks. Therapeutic efficacy was not diminished after 50% to 75% dose reductions or in the presence of anti-enzyme antibodies.

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Transition to eliglustat in an individual with Gaucher disease type 1 on antipsychotic medication

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2020.12.189 ◽

2021 ◽

Vol 132 (2) ◽

pp. S80

Author(s):

Damara Ortiz ◽

Joshua Barch ◽

Kayla Segady ◽

Nadene Henderson

Keyword(s):

Antipsychotic Medication ◽

Gaucher Disease ◽

Disease Type ◽

Gaucher Disease Type 1

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Cardiac Manifestations in a Group of Romanian Patients with Gaucher Disease Type 1 (a Monocentric Study)

Diagnostics ◽

10.3390/diagnostics11060989 ◽

2021 ◽

Vol 11 (6) ◽

pp. 989

Author(s):

Cecilia Lazea ◽

Simona Bucerzan ◽

Camelia Al-Khzouz ◽

Anca Zimmermann ◽

Ștefan Cristian Vesa ◽

...

Keyword(s):

Gaucher Disease ◽

Cardiac Involvement ◽

Disease Type ◽

Clinical Onset ◽

Lysosomal Disorders ◽

Electrocardiographic Changes ◽

Gaucher Disease Type 1 ◽

And Function ◽

Cardiac Manifestations

Gaucher disease (GD), one of the most common lysosomal disorders, is characterised by clinical heterogeneity. Cardiac involvement is rare and refers to pulmonary hypertension (PH), valvular abnormalities and myocardial infiltrative damage. The aim of this study was to evaluate cardiac involvement in a group of Romanian GD patients. Phenotypic and genotypic characterisation was carried out in 69 patients with GD type 1. Annual echocardiography and electrocardiography were performed to assess pulmonary pressure, morphology and function of the valves and electrocardiographic changes. Nine patients (13%) exhibited baseline echocardiographic signs suggesting PH. Mitral regurgitation was present in 33 patients (48%) and aortic regurgitation in 11 patients (16%). One patient presented aortic stenosis. Significant valvular dysfunction was diagnosed in 10% of patients. PH was associated with greater age (p < 0.001), longer time since splenectomy (p = 0.045) and longer time between clinical onset and the start of enzyme replacing therapy (p < 0.001). Electrocardiographic changes were present in five patients (7%).

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