scholarly journals Improvements in bone pain and patient quality of life in adults with Gaucher disease during substrate reduction therapy: a case series

2019 ◽  
Vol 8 (3) ◽  
Author(s):  
Dominick Amato ◽  
Patterson MA
Keyword(s):  
Quality Of Life ◽  
Gaucher Disease ◽  
Bone Pain ◽  
Age At Onset ◽  
Case Series ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Mineral Density ◽  
Enzyme Replacement

Background: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by a deficiency of glucocerebrosidase, and is characterised by haematological, visceral and bone manifestations that vary widely in terms of severity and age at onset. In particular, the bone manifestations of GD1 can restrict physical activity and impact heavily on patient quality of life (QoL). Here, we describe three GD1 patients who showed remarkable improvements in bone-related outcomes during treatment with oral miglustat, two of whom had previously failed to respond to relatively high doses of enzyme replacement therapy (ERT). In the third, needle phobia led to oral miglustat being used as the initial treatment. Case presentation: Case 1 is a 39 year-old female diagnosed aged 4 years (genotype N370S/L444P) and underwent ERT (alglucerase then imiglucerase) since 1994. In 2013 she discontinued ERT (treatment duration 19 years) due to ongoing and debilitating bone pain and fatigue, and switched to miglustat therapy. She has since experienced substantial reductions in bone pain and improved physical function. Case 2 is a 59 year-old female diagnosed aged 17 years (genotype N370S/H162P). She commenced ERT treatment in 2002, with a brief interruption in 2007, and continued on ERT (imiglucerase followed by velaglucerase) up to 2014: total ERT monotherapy duration 12 years. She subsequently received combination therapy (velaglucerase plus miglustat) for 2 years but finally switched to miglustat monotherapy in 2016 due to ongoing bone manifestations. Her bone pain has since improved a great deal, alongside improvements in QoL parameters. Case 3 is a 48 year-old male diagnosed aged 11 years (genotype R463C/L105R). Having not received any previous treatment he avoided ERT due to life-long needle phobia. He therefore started miglustat therapy in late-2017, and has received it for approximately 1 year. During this time he experienced vast improvements in QoL due to decreased bone pain. Interestingly in all three cases, there were little or no observed changes in objective bone parameters (bone marrow burden, bone mineral density). Conclusions: These three GD1 cases illustrate the potential to achieve substantial reductions in bone pain and improvements in QoL, even in patients who have failed to respond to long-term ERT with regard to bone status.

scholarly journals The usage of enzyme replacement treatments, economic burden, and quality of life of patients with four lysosomal storage diseases in Shanghai, China

2021 ◽  
Author(s):  
Jiahao Hu ◽  
Lin Zhu ◽  
Jiangjiang He ◽  
Dingguo Li ◽  
Huiwen Zhang ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Economic Burden ◽  
Gaucher Disease ◽  
Lysosomal Storage Diseases ◽  
The Other ◽  
Lysosomal Storage ◽  
Total Health Expenditure ◽  
Enzyme Replacement ◽  
Reimbursement Level

Abstract Background Lysosomal storage diseases (LSDs) are a group of rare diseases that caused progressive physical dysfunction and organ failure, which significantly affected patients’ quality of life. Enzyme replacement treatments (ERTs) are now acknowledged as the advanced therapies for LSDs while cost millions per patient per year. Previous studies seldom reported the usage of ERTs and disease burden of patients with LSDs in China. The objective of this study was to explore the characteristics and usage of ERTs of patients with the four different LSDs (Gaucher, Fabry, Pompe disease and Mucopolysaccharidosis) in Shanghai and then evaluate the economic burden and quality of life of these patients. Methods The study used data extracted from a large survey of living conditions of patients with rare diseases in Shanghai, which was conducted from April to August 2020. A total of 31patients, involving 5, 14, 4 and 8 patients with Gaucher, Fabry, Pompe disease and Mucopolysaccharidosis, respectively, was included in analysis. Descriptive statistics was used to describe the socio-demographic information (age, gender, education and etc.), economic burden caused by LSDs (direct medical and non-medical costs, and indirect cost in 2019), the treatment (usage of drugs) and the patients’ quality of life. Results Five Gaucher disease patients in Shanghai used Imiglucerase in 2019, while the other 26 patients with the other three LSDs didn’t receive ERTs. The total health expenditure of Gaucher disease patients was 2,273,000CNY on average mainly resulted by the high cost of Imiglucerase. The total health expenditure of the other 26 patients was 37,765CNY on average. The average total disease burdens of Gaucher disease patients and the patients with the other three LSDs were 164,301CNY and 58,352CNY, respectively. The mean EQ-VAS score of GD patients was 76.4 ± 15.5, which was higher than that of the other three LSDs. All the patients with LSDs in this study reported poor quality of life, which was significantly worse than the Chinese general population. Conclusion Few patients with LSDs in Shanghai could have access to available ERTs without a high reimbursement level. Though the cost-sharing mechanism of basic medical insurance, charity fund and patients had been explored for Gaucher disease in Shanghai, the Out-of-pocket part still laid a heavy economic burden on the patients and their families. The scope of drug reimbursement list and the reimbursement level should be further expanded and raised to help improve the quality of life of patients with LSDs.

Home-based service for enzyme replacement therapy in lysosomal storage disorders: patient reported outcomes

2018 ◽  
Vol 6 (4) ◽  
pp. 669
Author(s):  
Paolo Tirelli ◽  
Fiorina Giona ◽  
Maja Di Rocco ◽  
Elena Cassinerio ◽  
Antonio Pisani ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Nursing Service ◽  
Enzyme Replacement ◽  
Home Based ◽  
Patient Reported

Background:  Lysosomal storage diseases (LSDs) are a heterogeneous group of rare chronic genetic conditions. The standard-of-care treatment for LSDs is hospital-based infusion of enzyme replacement therapy (ERT), however, over time this can be stressful and inconvenient. The Italian TuTor program, established in 2011 by Sanofi Genzyme, is a professional nursing service providing home-based ERT to patients with LSDs.Objectives:  The current questionnaire-based study was conducted to investigate the level of patient satisfaction with theTuTor program and to shed light on disease perception.Methods:  Patients were enrolled in the TuTor program from 2011 onwards. The first 100 patients enrolled were interviewed at baseline with follow-up interviews conducted at 6, 12 and 18 months.Results: Overall, 52 patients were female; 46 had Gaucher’s disease, 46 had Fabry disease and 8 had mucopolysaccharidosis type 1. Patients took on average >2 hours to receive hospital-based ERT, plus time associated with the infusion; 2 out of 3 patients needed a caregiver to travel to the hospital. After receiving home-based ERT for 6 months, 37% of patients considered their quality of life ‘greatly improved’ (60% at 18 months). Overall, 99% to 100% of patients rated the home-based nursing service as ‘positive’ or ‘very positive’ and reported that they would recommend the service to other patients with their condition.Conclusions: For patients with LSDs eligible for ERT, a disease-specific home-based nursing service increased their perception of quality of life over a hospital-based service and was advantageous in terms of their time and expenditure.

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 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.

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.

Ophthalmic manifestations of Gaucher disease: the most common lysosomal storage disorder

2019 ◽  
Vol 103 (3) ◽  
pp. 315-326 ◽  
Author(s):  
Aaron W Winter ◽  
Ali Salimi ◽  
Luis H Ospina ◽  
Jonathan C P Roos
Keyword(s):  
Gaucher Disease ◽  
Substrate Reduction Therapy ◽  
Type I ◽  
Lysosomal Storage ◽  
Ocular Abnormalities ◽  
Enzyme Replacement ◽  
Ocular Manifestations ◽  
Ophthalmic Manifestations ◽  
Increased Risk ◽  
Risk Of Malignancy

Gaucher disease (GD) results from a deficiency of glucocerebrosidase activity and the subsequent accumulation of the enzyme’s metabolites, principally glucosylsphingosine and glucosylceramide. There are three principal forms: Type I, which is the most common, is usually considered non-neuronopathic. Type II, III and IIIc manifest earlier and have neurological sequelae due to markedly reduced enzyme activity. Gaucher’s can be associated with ophthalmological sequelae but these have not been systematically reviewed. We therefore performed a comprehensive literature review of all such ophthalmic abnormalities associated with the different types of Gaucher disease. We systematically searched the literature (1950 – present) for functional and structural ocular abnormalities arising in patients with Gaucher disease and found that all subtypes can be associated with ophthalmic abnormalities; these range from recently described intraocular lesions to disease involving the adnexae, peripheral nerves and brain. In summary, Gaucher can affect most parts of the eye. Rarely is it sight-threatening; some but not all manifestations are amenable to treatment, including with enzyme replacement and substrate reduction therapy. Retinal involvement is rare but patients with ocular manifestations should be monitored and treated early to reduce the risk of progression and further complications. As Gaucher disease is also associated with Parkinsons disease and may also confer an increased risk of malignancy (particularly haematological forms and melanoma), any ocular abnormalities should be fully investigated to exclude these potential underlying conditions.

scholarly journals Pulmonary Involvement Responsive to Enzyme Replacement Therapy in an Elderly Patient with Gaucher Disease

2021 ◽  
Author(s):  
Dylan Vellas ◽  
Baptiste Gramont ◽  
Rémi Grange ◽  
Pascal Cathébras
Keyword(s):  
Elderly Patient ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Gaucher Disease ◽  
Pulmonary Involvement ◽  
Reticuloendothelial System ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Type 1 Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder caused by deficient activity of beta-glucocerebrosidase, leading to accumulation of its substrate (glucosylceramide) in macrophages of the reticuloendothelial system, which are then referred to as Gaucher cells. The most frequent symptoms are asthenia, spleen and liver enlargement, bone abnormalities and cytopenia due to bone marrow infiltration. Lung involvement in GD is a rare finding, and it is unclear whether it may regress under enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Here we report a case of type 1 GD recently diagnosed in an elderly patient complicated by infiltrative lung disease, which responded to ERT.

scholarly journals Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease

2021 ◽  
Author(s):  
Margarita Ivanova ◽  
Julia Dao ◽  
Neil Kasaci ◽  
Benjamin Adewale ◽  
Shaista Nazari ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Lines ◽  
Gaucher Disease ◽  
Molecular Mechanisms ◽  
Substrate Reduction Therapy ◽  
Mineral Density ◽  
Equal Distribution ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Mitochondrial Functions

AbstractGaucher disease (GD) is caused by the deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase), and the subsequent accumulation of its substrate, glucosylceramide substrate (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) lead to GCase misfolding and inhibiting the lysosome’s proper trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway.GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes the GC biosynthesis, reducing a GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density.The effects of EGT and ABX on GCase activity and autophagy-lysosomal pathway (ALP) were assessed in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. While both compounds enhanced GCase activity in control cells, an individualized response was observed in cells from patients with GD2-3 that varied with GBA mutations. EGT and AMB enhanced the formation of lysosomal/ late endosomal compartments and autophagy, and this effect was independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of the mitochondrial function by activating the mitochondrial membrane potential.These results suggest that EGT and ABX may have different molecular mechanisms of action, but both enhance GCase activity, improve autophagy-lysosome dynamics and mitochondrial functions.

scholarly journals Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0247211
Author(s):  
Margarita M. Ivanova ◽  
Julia Dao ◽  
Neil Kasaci ◽  
Benjamin Adewale ◽  
Shaista Nazari ◽  
...  
Keyword(s):  
Nervous System ◽  
Cell Lines ◽  
Gaucher Disease ◽  
Molecular Mechanisms ◽  
Substrate Reduction Therapy ◽  
Mineral Density ◽  
Equal Distribution ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Mitochondrial Functions

Gaucher disease (GD) is caused by deficiency of the lysosomal membrane enzyme glucocerebrosidase (GCase) and the subsequent accumulation of its substrate, glucosylceramide (GC). Mostly missense mutations of the glucocerebrosidase gene (GBA) cause GCase misfolding and inhibition of proper lysosomal trafficking. The accumulated GC leads to lysosomal dysfunction and impairs the autophagy pathway. GD types 2 and 3 (GD2-3), or the neuronopathic forms, affect not only the Central Nervous System (CNS) but also have severe systemic involvement and progressive bone disease. Enzyme replacement therapy (ERT) successfully treats the hematologic manifestations; however, due to the lack of equal distribution of the recombinant enzyme in different organs, it has no direct impact on the nervous system and has minimal effect on bone involvement. Small molecules have the potential for better tissue distribution. Ambroxol (AMB) is a pharmacologic chaperone that partially recovers the mutated GCase activity and crosses the blood-brain barrier. Eliglustat (EGT) works by inhibiting UDP-glucosylceramide synthase, an enzyme that catalyzes GC biosynthesis, reducing GC influx load into the lysosome. Substrate reduction therapy (SRT) using EGT is associated with improvement in GD bone marrow burden score and bone mineral density parallel with the improvement in hematological parameters. We assessed the effects of EGT and AMB on GCase activity and autophagy-lysosomal pathway (ALP) in primary cell lines derived from patients with GD2-3 and compared to cell lines from healthy controls. We found that EGT, same as AMB, enhanced GCase activity in control cells and that an individualized response, that varied with GBA mutations, was observed in cells from patients with GD2-3. EGT and AMB enhanced the formation of lysosomal/late endosomal compartments and improved autophagy, independent of GBA mutations. Both AMB and EGT increased mitochondrial mass and density in GD2-3 fibroblasts, suggesting enhancement of mitochondrial function by activating the mitochondrial membrane potential. These results demonstrate that EGT and AMB, with different molecular mechanisms of action, enhance GCase activity and improve autophagy-lysosome dynamics and mitochondrial functions.

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