scholarly journals Identification of a Reliable Biomarker Profile for the Diagnosis of Gaucher Disease Type 1 Patients Using a Mass Spectrometry-Based Metabolomic Approach

2020 ◽  
Vol 21 (21) ◽  
pp. 7869
Author(s):  
Iskren Menkovic ◽  
Michel Boutin ◽  
Abdulfatah Alayoubi ◽  
François E. Mercier ◽  
Georges-Étienne Rivard ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gaucher Disease ◽  
Ultra Performance Liquid Chromatography ◽  
Lysosomal Storage ◽  
Accurate Mass Measurements ◽  
Gaucher Disease Type 1 ◽  
And Gender ◽  
Phenotypic And Genotypic Variability ◽  
Metabolomic Study

Gaucher disease (GD) is a rare autosomal recessive multisystemic lysosomal storage disorder presenting a marked phenotypic and genotypic variability. GD is caused by a deficiency in the glucocerebrosidase enzyme. The diagnosis of GD remains challenging because of the large clinical spectrum associated with the disease. Moreover, GD biomarkers are often not sensitive enough and can be subject to polymorphic variations. The main objective of this study was to perform a metabolomic study using an ultra-performance liquid chromatography system coupled to a time-of-flight mass spectrometer to identify novel GD biomarkers. Following the analysis of plasma samples from patients with GD, and age- and gender-matched control samples, supervised statistical analyses were used to find the best molecules to differentiate the two groups. Targeted biomarkers were structurally elucidated using accurate mass measurements and tandem mass spectrometry. This metabolomic study was successful in highlighting seven biomarkers associated with GD. Fragmentation tests revealed that these latter biomarkers were lyso-Gb1 (glucosylsphingosine) and four related analogs (with the following modifications on the sphingosine moiety: -C2H4, -H2, -H2+O, and +H2O), sphingosylphosphorylcholine, and N-palmitoyl-O-phosphocholineserine. Based on the plasma biomarker distribution, we suggest the evaluation of this GD biomarker profile, which might facilitate early diagnosis, monitoring, and follow-up of patients.

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

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 43-48 ◽  
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

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.

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

Blood ◽  
1997 ◽  
Vol 90 (1) ◽  
pp. 43-48 ◽  
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.

scholarly journals Gaucher Disease: Case Report

2021 ◽  
Keyword(s):  
Gaucher Disease ◽  
Autosomal Recessive ◽  
Genetic Disorder ◽  
Autosomal Recessive Inheritance ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Disease Case ◽  
Gaucher Disease Type 1 ◽  
The Common

Gaucher disease is the most common lysosomal storage disease. It is marked by deficient glucocerebrosidase enzyme activity, leading to elective accumulation of its substrate in the lysosomes of macrophages. Macrophages are most often deposited in the liver, spleen and bone marrow, creating typical symptomatology in these organs. It is a genetic disorder with autosomal recessive inheritance pattern. The extent of the damage and severity of the symptoms increase in proportion to the genetic damage in the culprit gene, GBA1. As a result, the symptoms and course of the disease may range from mild to quite acute, with potential death of the patient at a young age. Case: Patient, 29, was diagnosed with Gaucher disease type 1 and underwent enzyme replacement therapy, with satisfactory response. Along with the common symptoms of the disease, he had also developed the rare Erlenmeyer flask deformity.

scholarly journals Mass Spectrometry Evaluation of Biomarkers in the Vitreous Fluid in Gaucher Disease Type 3 with Disease Progression Despite Long-Term Treatment

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 69
Author(s):  
Aizeddin Mhanni ◽  
Michel Boutin ◽  
Frank Stockl ◽  
Janine Johnston ◽  
Jeff Barnes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Visual Acuity ◽  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
High Concentration ◽  
Enzyme Replacement ◽  
Long Term Treatment ◽  
Type 3

Intraocular lesions have been infrequently reported in patients with Gaucher disease type 3 (GD3). We previously reported siblings with GD3 who responded well to the combination of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Here we report progressive bilateral vitreous and preretinal deposits with declining visual acuity requiring bilateral vitrectomies in one of these siblings. These ocular manifestations had progressed despite combined ERT and SRT with improvement in visual acuity after vitrectomies. Vitrectomy fluid analysis performed for the first time by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) identified a high concentration of glucosylceramide (GluCer) in the patient (262.842 nM) compared to a sample (0.428 nM from a patient without a lysosomal storage or known hereditary metabolic disorder). The GluCer detected in our patient was resolved into 12 different isoforms including two methylated ones. No evidence of galactosylceramide (GalCer) was detected. The development of these intraocular manifestations and their characterization by UPLC-MS/MS indicate a need for ongoing ophthalmologic evaluation of all GD patients and for new therapies that can cross the blood–retinal and blood–brain barriers for patients with GD and other neuropathic lysosomal storage disorders.

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

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 408-416 ◽  
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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