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.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

2008 ◽  
Vol 31 (6) ◽  
pp. 745-752 ◽  
Author(s):  
J. Cox-Brinkman ◽  
M. J. van Breemen ◽  
B. T. van Maldegem ◽  
L. Bour ◽  
W. E. Donker ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Type Iii ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Potential Efficacy

scholarly journals Gaucher Disease Type I: A Case Report

2020 ◽  
Vol 47 (3) ◽  
pp. 22-25
Author(s):  
D. Nikolova ◽  
A. Yordanov ◽  
V. Damyanova ◽  
A. Yavorova ◽  
A. Radinov
Keyword(s):  
Gaucher Disease ◽  
Clinical Symptoms ◽  
Systemic Disease ◽  
Disease Type ◽  
Type I ◽  
Lysosomal Storage ◽  
Laboratory Findings ◽  
Enzyme Replacement ◽  
Targeted Analysis ◽  
Laboratory Test Results

AbstractGaucher disease (GD) is a multi-systemic disease with a low population frequency. It is a lysosomal storage disorder (LSD) that causes accumulation of glucocerebroside in the so called Gaucher cells predominantly in areas like the spleen, liver and bone marrow. Type I GD (GDI) is the most common form and usually does not involve the brain and the spinal cord. The symptoms can range from mild to severe and may appear anytime from childhood to adulthood. Diagnostics can often be challenging and imposes looking at person’s medical history, symptoms, physical exam, and laboratory test results. We present a difficult to diagnose case of a 34-year-old woman admitted to the Clinic of Hematology, “Sv. I. Rilski” hospital with splenomegaly, normal laboratory findings and non-enlarged liver. She didn’t show focal neurological symptoms. A series of tests were assigned including genetic targeted analysis. The case is an example of a rare genetic disease with mild clinical symptoms. Diagnosis of Gaucher disease, type I was confirmed by measurement of a GBA enzyme activity and identification of mutations in the GBA gene inherited in an autosomal recessive manner. Thanks to the efforts of the clinical team, the assignment of adequate clinical and laboratory tests and their correct interpretation, the patient was subjected to enzyme replacement therapy (ERT). Although the diagnosis was settled relatively late (at 34 years of age), the correct therapy slowed down the invalidation and improved the quality of life of the patient.

scholarly journals Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3

2020 ◽  
Vol 11 (20) ◽  
pp. 3464-3473
Author(s):  
Michael W. Wilson ◽  
Liming Shu ◽  
Vania Hinkovska-Galcheva ◽  
Yafei Jin ◽  
Walajapet Rajeswaran ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Glucosylceramide Synthase ◽  
Substrate Reduction ◽  
Type 3

Clinical Evaluation of CCL18/PARC and Chitotriosidase Biomarkers in Gaucher Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3885-3885
Author(s):  
Pilar Alfonso ◽  
Paz Latre ◽  
Ignacio de Blas ◽  
Pilar Giraldo ◽  
Manuel Giralt ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Combined Therapy ◽  
Clinical Manifestations ◽  
Therapeutic Interventions ◽  
Substrate Reduction Therapy ◽  
Enzyme Analysis ◽  
Poor Correlation ◽  
Surrogate Markers ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Abstract Gaucher’s disease (GD) is an autosomal recessive lysosomal storage disorder, characterized by accumulation of glycosphingolipid in so-called Gaucher cells. The clinical manifestations of Gaucher disease are highly variable, and although certain genotypes are often associated with mild or severe symtomps, a defined correlation between genotype and phenotype does not exist. Identification of serum biochemical markers characteristic of disease may be useful in the diagnosis and monitoring of GD, nevertheless about 6% of the population does not express the chitotriosidase (CT) gene. In this study, we analyzed using currently available enzyme analysis the relationship among two known surrogate markers: CT, which utility in initiation and optimization of costly therapeutic interventions has been highly demonstrated, and a newly-described chemokine, pulmonary and activation-regulated chemokine (CCL18/PARC) as associated to Gaucher disease. Patients and methods: We have analysed 21 control samples, 149 samples of GD patients on enzyme replacement therapy (ERT), and 52 samples of GD patients on substrate reduction therapy (SRT), 4 samples of GD on combined therapy (ERT+SRT) and 7 samples of GD patients without therapy. The samples were stored at −80°C in the biobank of Biochemistry and Molecular and Cellular Biology Department of Zaragoza University. The CT activity and CCL18/PARC quantification were performed simultaneously in the samples obtained at baseline and yearly during 7 years under ERT. Results: our results concluded that both markers levels similarly fell with time and their variations correlated strongly each other, mainly in patients under ERT. The poor correlation of both variables in the case of SRT might be due to small number of samples. These findings demonstrated that CCL18 is a good biomarker of monitoring GD, comparable to CT and very useful in patients without expression of CT gene. Conclusion: The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of treatment, especially in cases of deficiencies of some marker.

scholarly journals Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease

2003 ◽  
Vol 358 (1433) ◽  
pp. 955-960 ◽  
Author(s):  
Chris Moyses
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Residual Activity ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Clinical Consequences ◽  
Type 1 Gaucher Disease

Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9–16.4, p < 0.001) and 19% (14.3–23.7, p < 0.001), respectively. Mean haemoglobin increased by 0.26 g dl −1 (−0.5−0.57, not statistically significant) and platelet count by 8.3 × 10 9 l −1 (1.9–14.7, p = 0.014).

scholarly journals Gaucher Disease and Cancer: Concept and Controversy

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Francis Y. M. Choy ◽  
Tessa N. Campbell
Keyword(s):  
Gaucher Disease ◽  
Wide Spectrum ◽  
Treatment Options ◽  
Substrate Reduction Therapy ◽  
Neurological Involvement ◽  
Enzyme Replacement ◽  
Skeletal Disease ◽  
Increased Risk ◽  
Risk Of Malignancy ◽  
Type 3

Gaucher disease is an inherited disorder caused by a deficiency in the lysosomal hydrolase glucocerebrosidase. There is a wide spectrum of clinical presentations, with the most common features being hepatosplenomegaly, skeletal disease, and cytopenia. Gaucher disease has been classified into three broad phenotypes based upon the presence or absence of neurological involvement: Type 1 (nonneuronopathic), Type 2 (acute neuronopathic), and Type 3 (subacute neuronopathic). The two main treatment options include enzyme replacement therapy and substrate reduction therapy. Recently, discussion has escalated around the association of Gaucher disease and cancer, with conflicting reports as to whether Gaucher patients have an increased risk of malignancy. In this review, we present both the concept and controversy surrounding the association of Gaucher disease with cancer.

scholarly journals From Symptoms and Signs to Diagnosis in a Rare Disease, Type I Gaucher Disease

2018 ◽  
Vol 15 (1) ◽  
pp. 69-76
Author(s):  
Mihaela Ghinea ◽  
Sabina Ciocodei ◽  
Gabriela Butoi ◽  
Geandan Memet ◽  
Andreea Stoica ◽  
...  
Keyword(s):  
Laboratory Testing ◽  
Gaucher Disease ◽  
Storage Disease ◽  
Disease Type ◽  
Genetic Mutations ◽  
Type I ◽  
Lysosomal Storage ◽  
Specific Enzyme ◽  
Enzyme Replacement ◽  
Symptoms And Signs

AbstractGaucher disease is the most frequent lysosomal storage disease, caused by the deficiency of an enzyme called β-glucocerebrosidase. Three types of Gaucher disease are described. Type I Gaucher disease benefits from lifelong enzyme replacement therapy with imiglucerase.Herein, we present the case of a 34-year-old female patient, a commercial worker, who was admitted to our Department of Haematology in the Emergency Clinical Hospital of Constanta in order to investigate the aetiology of a persistent splenomegaly. Clinical examination and laboratory testing evidenced the following: splenomegaly, hepatomegaly, anaemia, leukopenia and neutropenia, thrombocytopenia, and a myelogram showing Gaucher cells. In this context, the suspicion of Gaucher disease was raised and the investigations were further completed through specific enzyme testing and genetic testing. The low values of lysosomal enzymes, coupled with the detection of two specific genetic mutations confirmed the diagnosis of Gaucher disease.In January 2017, treatment with 2400U of imiglucerase in intravenous perfusion every two weeks was begun.

scholarly journals Finding and Treating Gaucher Disease Type 1 – The Role of the Haematologist

2018 ◽  
Vol 14 (1) ◽  
pp. 50
Author(s):  
Maria-Domenica Cappellini ◽  
Elena Cassinerio ◽  
Irene Motta ◽  
William Morello ◽  
Jesús Villarubia
Keyword(s):  
Gaucher Disease ◽  
Clinical Symptoms ◽  
Genetic Disorder ◽  
Diagnostic Delay ◽  
Screening Tools ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Ashkenazi Jews ◽  
Enzyme Replacement

Gaucher disease (GD) type 1 is the most common lysosomal storage disease and the most common genetic disorder among Ashkenazi Jews. The majority of patients with GD present with unexplained splenomegaly and/or thrombocytopenia, and the disorder often affects children; consequently, haematologists and paediatricians are ideally placed to diagnose this condition. Prompt management of GD type 1 using enzyme-replacement therapy or substrate reduction therapy can reduce the risk of developing long-term GD complications and reverse many of the initial signs/symptoms, thereby improving both quality and duration of life. Treatment is most effective when initiated early; consequently, a prompt diagnosis is essential. Despite this, the average time to diagnosis following the onset of clinical symptoms is 4 years. Reasons for the delay include the heterogeneous nature of the disease, together with a lack of awareness of rare haematological disorders and the benefits of early treatment. Indeed, studies show that only 20% of haematologists consider GD type 1 in their differential diagnosis for patients presenting with splenomegaly and/or thrombocytopenia. To help raise awareness of GD, reduce the diagnostic delay and prevent unnecessary tissue biopsies, simple diagnostic algorithms and screening tools have been developed and validated, both in adults and in children.

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