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Corazolla EM, Eskes ECB, Veldwijk J, Brands MMMG, Dekker H, van de Mheen E, Langeveld M, Hollak CEM, Sjouke B. Different diseases, different needs: Patient preferences for gene therapy in lysosomal storage disorders, a probabilistic threshold technique survey. Orphanet J Rare Dis 2024; 19:367. [PMID: 39363355 PMCID: PMC11451020 DOI: 10.1186/s13023-024-03371-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 09/18/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND Gene therapy is currently in development for several monogenetic diseases including lysosomal storage disorders. Limited evidence is available on patient preferences for gene therapy in this population. In this study, we compare gene therapy-related risk tolerance between people affected by three lysosomal storage diseases currently faced with different therapeutic options and prognoses. METHODS A survey including the probabilistic threshold technique was developed in which respondents were asked to choose between gene therapy and the current standard of care. The attributes included to establish participants' risk tolerance were previously identified in focus groups of affected people or their representatives, namely: risk of mild side effects, severe side effects, the need for additional medication, and the likelihood of long-term effectiveness. The survey was distributed among people receiving outpatient care for type 1 Gaucher disease (good prognosis with current treatment options), Fabry disease (varying prognosis with current treatment options, XY-genotype on average more severely affected than XX), and parents representing people with severe forms of mucopolysaccharidosis type III A/B (poor prognosis, no disease-specific therapy available). RESULTS A total of 85 surveys were completed (15 Gaucher disease respondents, 62 Fabry disease respondents (17 self-identifying male), eight parents of ten people with mucopolysaccharidosis type III). Disease groups with higher disease severity trended towards higher risk tolerance: Gaucher disease respondents were most cautious and predominantly preferred the current standard of care as opposed to MPS III representatives who were more risk tolerant. Respondents with Fabry disease were most heterogeneous in their risk tolerance, with male participants being more risk tolerant than female participants. Long-term effectiveness was the attribute in which respondents tolerated the least risk. CONCLUSIONS People affected by a lysosomal storage disease associated with a poorer prognosis and less effective current treatment options trended towards more risk tolerance when choosing between gene therapy and the current standard of care. This study shows the importance of involvement of patient preferences before and during the development process of new treatment modalities such as gene therapy for rare diseases, to ensure that innovative therapies align with the wishes and needs of people affected by these diseases.
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Affiliation(s)
- Eleonore M Corazolla
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands
| | - Eline C B Eskes
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands
| | - Jorien Veldwijk
- Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
- Erasmus Choice Modelling Centre, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Marion M M G Brands
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands
- Department of Pediatrics, Division of Metabolic Diseases, Emma Children's Hospital, Amsterdam UMC, Location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
| | - Hanka Dekker
- The Dutch Patient Association for Inherited Metabolic Diseases (VKS), Zwolle, The Netherlands
| | - Erica van de Mheen
- Fabry Support and Information Group the Netherlands (FSIGN), Drachten, The Netherlands
| | - Mirjam Langeveld
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands
| | - Carla E M Hollak
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands
| | - Barbara Sjouke
- Inborn Errors of Metabolism, Research Institute of Amsterdam Gastroenterology Endocrinology and Metabolism, Meibergdreef 9, Amsterdam, The Netherlands.
- Department of Internal Medicine, Radboudumc, Nijmegen, The Netherlands.
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Goker-Alpan O, Ivanova MM. Neuronopathic Gaucher disease: Rare in the West, common in the East. J Inherit Metab Dis 2024; 47:917-934. [PMID: 38768609 DOI: 10.1002/jimd.12749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/25/2024] [Accepted: 04/29/2024] [Indexed: 05/22/2024]
Abstract
Gaucher disease (GD) stands as one of the most prevalent lysosomal disorders, yet neuronopathic GD (nGD) is an uncommon subset characterized by a wide array of clinical manifestations that complicate diagnosis, particularly when neurological symptoms are understated. nGD may manifest as the acute neuronopathic type, or GD type 2 (GD2), either prenatally or within the first weeks to months of life, whereas GD type 3 (GD3) symptoms may emerge at any point during childhood or occasionally in adolescence. The clinical presentation encompasses severe systemic involvement to mild visceral disease, often coupled with a spectrum of progressive neurological signs and symptoms such as cognitive impairment, ataxia, seizures, myoclonus, varying degrees of brainstem dysfunction presenting with stridor, apneic episodes, and/or impaired swallowing. This manuscript aims to provide a comprehensive review of the incidence, distinctive presentations, and diverse clinical phenotypes of nGD across various countries and regions. It will explore the natural history of the neurodegenerative process in GD, shedding light on its various manifestations during infancy and childhood, and offer insights into the diagnostic journey, the challenges faced in the clinical management, and current and investigative therapeutic approaches for GD's neurological variants.
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Affiliation(s)
- Ozlem Goker-Alpan
- Lysosomal and Rare Disorder Research and Treatment Center, Fairfax, Virginia, USA
| | - Margarita M Ivanova
- Lysosomal and Rare Disorder Research and Treatment Center, Fairfax, Virginia, USA
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Stepien KM, Žnidar I, Kieć-Wilk B, Jones A, Castillo-García D, Abdelwahab M, Revel-Vilk S, Lineham E, Hughes D, Ramaswami U, Collin-Histed T. Transition of patients with Gaucher disease type 1 from pediatric to adult care: results from two international surveys of patients and health care professionals. Front Pediatr 2024; 12:1439236. [PMID: 39346636 PMCID: PMC11430091 DOI: 10.3389/fped.2024.1439236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/15/2024] [Indexed: 10/01/2024] Open
Abstract
Introduction Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. The most common subtype in Europe and the USA, type 1 (GD1), is characterized by fatigue, cytopenia, splenomegaly, hepatomegaly, bone disease, and rarely pulmonary disease. Increased life expectancy brought about by improved treatments has led to new challenges for adolescents and their transition to adult care. Efficient healthcare transition to adult care is essential to manage the long-term age-related complications of the disease. Methods This international study consisted of two online surveys: one survey for patients with GD1 and one survey for healthcare professionals (HCPs) involved in treatment of patients with GD1. The aims of this international, multi-center project were to evaluate the current transition process in various countries and to understand the challenges that both HCPs and patients experience. Results A total of 45 patients and 26 HCPs took part in the survey, representing 26 countries. Our data showed that a third (11/33) of patients were aware of transition clinics and most stated that the clinic involved patients with metabolic diseases or with GD. Seven patients attended a transition clinic, where most patients (5/7) received an explanation of the transition process. Approximately half of HCPs (46%; 12/26) had a transition clinic coordinator in their healthcare center, and 10 of HCPs had a transition clinic for patients with metabolic diseases in their healthcare center. HCPs reported that transition clinics were comprised of multi-disciplinary teams, with most patients over the age of 18 years old managed by hematology specialists. The main challenges of the transition process reported by HCPs included limited funding, lack of expertise and difficulty coordinating care amongst different specialties. Discussion Our study demonstrates the lack of a standardized process, the need to raise awareness of transition clinics amongst patients and the differences between the transition process in different countries. Both patients and HCPs expressed the need for a specialist individual responsible for transition, efficient coordination between pediatricians and adult specialists and for patient visits to the adult center prior to final transition of care.
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Affiliation(s)
- Karolina M. Stepien
- Adult Inherited Metabolic Diseases, Salford Royal Organization, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
| | - Irena Žnidar
- International Gaucher Alliance (IGA), London, United Kingdom
| | - Beata Kieć-Wilk
- Metabolic Diseases Office, Krakow Specialist Hospital St. John Paul II, Krakow, Poland
- Unit of Rare Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland
| | - Angel Jones
- International Gaucher Alliance (IGA), London, United Kingdom
| | - Daniela Castillo-García
- Department of Pediatrics, Hospital Infantil de México Federico Gómez Instituto Nacional de Salud, México City, México
| | - Magy Abdelwahab
- Pediatric Hematology/BMT Unit and Social and Preventive Center KasrAlainy Hospital, Faculty of Medicine, Cairo University Pediatric Hospital, Cairo, Egypt
| | - Shoshana Revel-Vilk
- Gaucher Unit, Pediatric Hematology/Oncology Unit, the Eisenberg R&D Authority, Shaare Zedek Medical Center, Jerusalem, Israel
- Faculty of Medicine, Hebrew University, Jerusalem, Israel
| | - Ella Lineham
- Rare Disease Research Partners (RDRP), MPS House, Amersham, United Kingdom
| | - Derralynn Hughes
- Lysosomal Disorders Unit, University College London and Royal Free London NHS Foundation Trust, London, United Kingdom
| | - Uma Ramaswami
- Lysosomal Disorders Unit, Department of Infection, Immunity and Rare Diseases, Royal Free London NHS Foundation Trust, London, United Kingdom
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Huang YN, Huang JY, Liao WL, Chiang SL, Liu KW, Bau DAT, Wang CH, Su PH. Incidence of Pulmonary and Respiratory Conditions in Gaucher Disease from 2000 to 2020: A Multi-institutional Cohort Study. In Vivo 2023; 37:2276-2283. [PMID: 37652520 PMCID: PMC10500493 DOI: 10.21873/invivo.13330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023]
Abstract
BACKGROUND/AIM Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management. PATIENTS AND METHODS We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020. RESULTS Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years. CONCLUSION Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.
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Affiliation(s)
- Yu-Nan Huang
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan, R.O.C
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Jing-Yang Huang
- Center for Health Data Science, Chung Shan Medical University Hospital, Taichung, Taiwan, R.O.C
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
| | - Wen-Ling Liao
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C
- Center for Personalized Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
| | - Shang-Lun Chiang
- Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Kai-Wen Liu
- Division of Genetics and Metabolism, Children's Hospital of China Medical University, Taichung, Taiwan, R.O.C
| | - DA-Tian Bau
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C
| | - Chung-Hsing Wang
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan, R.O.C.;
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
- Division of Genetics and Metabolism, Children's Hospital of China Medical University, Taichung, Taiwan, R.O.C
- School of Medicine, China Medical University, Taichung, Taiwan, R.O.C
| | - Pen-Hua Su
- Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan, R.O.C.;
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C
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Muacevic A, Adler JR. Targeted Screening for Gaucher Disease in High Suspicion Patients and Clinical Profile of Screen Positives in a Large Pediatric Multispecialty Hospital. Cureus 2022; 14:e29868. [PMID: 36348851 PMCID: PMC9630059 DOI: 10.7759/cureus.29868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/03/2022] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES The proposed screening study was aimed at determining the prevalence of Gaucher disease in a selected high-risk population of patients and describing the clinical profile of diagnosed patients. METHODOLOGY It was a prospective observational study from January 2020 to September 2022 (two years and eight months) in the genetic clinic of the pediatric department. A total of 22 patients were suspected to be having Gaucher disease based on clinical findings of hepatosplenomegaly with bicytopenia or isolated thrombocytopenia. In these patients, chronic liver disease, portal hypertension, and other hematological conditions were ruled out. Three patients with Gaucher disease applied for enzyme replacement therapy (ERT) support under India Charitable Access Program and one patient received therapy for two months. Clinical findings were compared before and after ERT. Clinical findings were noted in all patients. RESULTS Among the 22 patients, nine (40.9%) patients were confirmed to be suffering from Gaucher disease with six based on enzyme assay on dry blood spot and three based on DNA mutation analysis. One patient among the screen positives received ERT for two months and was noted to have an improvement in hemoglobin and platelet count, a reduction in liver size, and better general well-being. CONCLUSION High-suspicion targeted screening of Gaucher disease in patients with splenomegaly and thrombocytopenia based on a dry blood spot enzyme assay is high yielding, effective strategy in identifying Gaucher disease patients. Clinical features were variable in severity, though a common mutation was found in the majority of patients.
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Global Epidemiology of Gaucher Disease: an Updated Systematic Review and Meta-analysis. J Pediatr Hematol Oncol 2022; 45:181-188. [PMID: 35867706 PMCID: PMC10115488 DOI: 10.1097/mph.0000000000002506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/01/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Gaucher disease [GD], an autosomal recessive lysosomal storage disorder, is characterized by progressive lysosomal storage of glucocerebroside in macrophages predominantly in bone, bone marrow, liver, and spleen. Meta-analysis of global GD epidemiology was not available before this study. METHODS To provide a systematic review and meta-analysis of birth prevalence and prevalence of GD in multiple countries. MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of GD from inception until July 21, 2021. Meta-analysis, adopting a random-effects logistic model, was performed to estimate the birth prevalence and prevalence of GD. RESULTS Eighteen studies that were screened out of 1874 records were included for data extraction. The studies that fulfilled the criteria for inclusion involved 15 areas/countries. The global birth prevalence of GD was 1.5 cases [95% confidence interval: 1.0 to 2.0] per 100,000 live births. The global prevalence of GD was 0.9 cases [95% confidence interval: 0.7 to 1.1] per 100,000 inhabitants. CONCLUSIONS This is the first comprehensive systematic review that presented quantitative data of GD global epidemiology. Quantitative data on global epidemiology of GD could be the fundamental to evaluate the global efforts on building a better world for GD patients.
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Weinreb NJ, Goker-Alpan O, Kishnani PS, Longo N, Burrow TA, Bernat JA, Gupta P, Henderson N, Pedro H, Prada CE, Vats D, Pathak RR, Wright E, Ficicioglu C. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022; 136:4-21. [PMID: 35367141 DOI: 10.1016/j.ymgme.2022.03.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/04/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023]
Abstract
Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.
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Affiliation(s)
- Neal J Weinreb
- Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Ozlem Goker-Alpan
- Lysosomal and Rare Disorders Research and Treatment Center, Fairfax, VA, USA.
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
| | - Nicola Longo
- Division of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
| | - T Andrew Burrow
- Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
| | - John A Bernat
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
| | - Punita Gupta
- St Joseph's University Hospital, Paterson, NJ, USA.
| | - Nadene Henderson
- Division of Genetic and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
| | - Helio Pedro
- Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, NJ, USA.
| | - Carlos E Prada
- Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital and Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
| | - Divya Vats
- Kaiser Permanente Southern California, Los Angeles, CA, USA.
| | - Ravi R Pathak
- Takeda Pharmaceuticals USA, Inc., Lexington, MA, USA.
| | | | - Can Ficicioglu
- Division of Human Genetics and Metabolism, The Children's Hospital of Philadelphia, Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, PA, USA.
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Sam R, Ryan E, Daykin E, Sidransky E. Current and emerging pharmacotherapy for Gaucher disease in pediatric populations. Expert Opin Pharmacother 2021; 22:1489-1503. [PMID: 33711910 PMCID: PMC8373623 DOI: 10.1080/14656566.2021.1902989] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/10/2021] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The past decades have witnessed a remarkable improvement in the health of patients with Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, resulting from the availability of enzyme replacement and substrate reduction therapies. Especially in pediatric populations, early diagnosis and initiation of treatment is essential to achieving optimal outcomes. AREAS COVERED The authors review the literature pertaining to the effectiveness of currently available therapies and describe new pharmacotherapies under development, especially for young patients. EXPERT OPINION For pediatric patients with non-neuronopathic Gaucher disease, there may be new therapeutic options on the horizon in the form of gene therapy or small molecule glucocerebrosidase chaperones. These have the potential to result in a cure for systemic disease manifestations and/or to reduce the cost and convenience of treatment. For children with neuronopathic Gaucher disease, the challenge of targeting therapy to the central nervous system is being explored through new modalities including brain-targeted gene therapy, in-utero therapy, brain-penetrant small molecule chaperones, and other methods that convey enzyme across the blood-brain barrier. Indeed, these are exciting times for both pediatric patients with Gaucher disease and those with other lysosomal storage disorders.
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Affiliation(s)
- Richard Sam
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
| | - Emory Ryan
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
| | - Emily Daykin
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
| | - Ellen Sidransky
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, USA
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Almeida-Calpe A, López de Frutos L, Medrano-Engay B, García-García CB, Ribate MP, Giraldo P. Metabolizing profile of the cytochrome pathway CYP2D6, CYP3A4 and the ABCB 1 transporter in Spanish patients affected by Gaucher disease. Chem Biol Interact 2021; 345:109527. [PMID: 34058179 DOI: 10.1016/j.cbi.2021.109527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 04/15/2021] [Accepted: 05/16/2021] [Indexed: 10/21/2022]
Abstract
Several therapeutic options are available for type 1 Gaucher disease (GD1), including enzymatic replacement therapy (ERT) and substrate reduction therapy (SRT). Eliglustat is a selective inhibitor of glucosylceramide synthase that is extensively metabolized by CYP2D6 and, to a lesser extent by CYP3A4; it is also an inhibitor of the P-gp transporter. The aim of this study is to evaluate the metabolizer profile of these cytochrome isoforms in 61 GD1 patients, and to analyze interferences with concomitant therapies. Patients were selected from the Spanish Gaucher Disease Registry considering clinical data, GBA genotype, severity score index, comorbidities, concomitant drugs, type and response to therapy and adverse effects. The polymorphisms of CYP2D6, CYP3A4 and three ABCB1 transporter variants were analyzed by Polymerase Chain Reaction (PCR). The most frequent metabolizer profile was extensive or intermediate for CYP2D6, extensive for CYP3A4*1B and CYP3A4*22 and normal activity for ABCB1. Correlations between metabolizer profile and other variables were analyzed by multiple regression study. Twenty-eight patients received ERT, 17 eliglustat and seven miglustat. Forty-two patients (68.8%) had associated diseases and 54.5% were taking daily concomitant medication. Nine patients under eliglustat therapy received concomitant drugs that interact with the CYPs and/or ABCB1, five of these did not reach therapeutic goals and three presented mild or moderate adverse effects (headache and gastrointestinal disorders). Detailed analysis in four patients with TTT haplotype, corresponding to lack of activity of the transporter, was performed. In order to apply personalized medicine and avoid interferences and adverse effects, the individual CYP metabolizer profile and transporter must be considered when choosing the concomitant medication and/or making dose adjustments.
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Affiliation(s)
- A Almeida-Calpe
- Facultad de Ciencias de la Salud. Universidad San Jorge, Zaragoza, Spain
| | - L López de Frutos
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG), Zaragoza, Spain; Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012), Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain; Grupo Español de Enfermedades de Depósito Lisosomal, Sociedad Española de Hematología y Hemoterapia, Zaragoza, Spain
| | - B Medrano-Engay
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG), Zaragoza, Spain
| | - C B García-García
- Facultad de Ciencias de la Salud. Universidad San Jorge, Zaragoza, Spain
| | - M P Ribate
- Facultad de Ciencias de la Salud. Universidad San Jorge, Zaragoza, Spain
| | - P Giraldo
- Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher y otras lisosomales (FEETEG), Zaragoza, Spain; Grupo de Investigación en Enfermedades Metabólicas y Hematológicas Raras (GIIS-012), Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain; Grupo Español de Enfermedades de Depósito Lisosomal, Sociedad Española de Hematología y Hemoterapia, Zaragoza, Spain.
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Barney AM, Danda S, Abraham A, Fouzia NA, Gowdra A, Abraham SSC, Sony M, Das S, Korula S, Mathai S, Simon A, Kumar S. Clinicogenetic Profile, Treatment Modalities, and Mortality Predictors of Gaucher Disease: A 15-Year Retrospective Study. Public Health Genomics 2021; 24:139-148. [PMID: 33823526 DOI: 10.1159/000514507] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 01/12/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder, in which biallelic pathogenic variants in the Glucosidase beta acid (GBA) gene result in defective functioning of glucosylceramidase that causes deposition of glucocerebroside in cells. GD has 3 major types namely, non-neuronopathic (type I), acute neuronopathic (type II), and chronic neuronopathic (type III). Definite treatment options are limited and expensive. They succumb early to the disease, if untreated. There is paucity of studies from the Indian subcontinent, which elicit the factors resulting in their premature mortality. MATERIALS AND METHODS A retrospective study was carried out in a tertiary care setting of South India to assess the clinical profile, mutation spectrum, and various management strategies (only supportive therapy, enzyme replacement therapy [ERT], substrate reduction therapy [SRT] haematopoietic stem cell transplant [HSCT]), and mortality predictors of patients with GD from 2004 to 2019. A Kaplan-Meier survival curve was plotted. In silico predictions were performed for novel variants. RESULTS There were 60 patients with all types of GD seen over the study period of 15 years. Their median age at diagnosis was 2 years. The median follow-up was for 5 years (interquartile range [IQR] = 2-8). The overall mortality rate was 35%; however, it was only 10% in those receiving definite treatment. Mortality was higher (47.5%) by more than 4 folds in those only on supportive therapy. The median survival from the time of diagnosis was 6.3 years (IQR = 3.5-10.8) in the definite treatment group and 3.5 years (IQR = 1-5) in those on supportive therapy. The Kaplan-Meier survival analysis showed significant (p value 0.001) mortality difference between these groups. The multiple logistic regression analysis found the neuronopathic type (OR = 5) and only supportive therapy (OR = 6.3) to be the independent risk factors for premature mortality. CONCLUSION GD is a rare disease with a high mortality rate, if left untreated. ERT and SRT are the definitive treatments which increase the survival. In resource-limited settings like India, with higher prevalence of the neuronopathic type, HSCT may be a more suitable definitive treatment option, due to its one-time intervention and cost, assuming similar efficacy to ERT. However, the efficacy and safety of HSCT in GD needs to be established further by substantial patient numbers undergoing it.
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Affiliation(s)
- Anitha M Barney
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Sumita Danda
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Aby Abraham
- Department of Clinical Haematology, Christian Medical College, Vellore, India
| | - N A Fouzia
- Department of Clinical Haematology, Christian Medical College, Vellore, India
| | - Aruna Gowdra
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | | | - Mohan Sony
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Sweta Das
- Department of Medical Genetics, Christian Medical College, Vellore, India
| | - Sophy Korula
- Department of Child Health, Christian Medical College, Vellore, India
| | - Sarah Mathai
- Department of Child Health, Christian Medical College, Vellore, India
| | - Anna Simon
- Department of Child Health, Christian Medical College, Vellore, India
| | - Sathish Kumar
- Department of Child Health, Christian Medical College, Vellore, India
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11
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Serratrice C, Stirnemann J, Berrahal A, Belmatoug N, Camou F, Caillaud C, Billette de Villemeur T, Dalbies F, Cador B, Froissart R, Masseau A, Brassier A, Hivert B, Swiader L, Bertchansky I, de Moreuil C, Chabrol B, Durieu I, Leguy Seguin V, Astudillo L, Humbert S, Pichard S, Marcel C, Hau Rainsard I, Bengherbia M, Yousfi K, Berger MG. A Cross-Sectional Retrospective Study of Non-Splenectomized and Never-Treated Patients with Type 1 Gaucher Disease. J Clin Med 2020; 9:jcm9082343. [PMID: 32708003 PMCID: PMC7464688 DOI: 10.3390/jcm9082343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 01/16/2023] Open
Abstract
Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4–75.1), and their median follow-up was 7.8 years (0.4–32.4). Moreover, 38.7% were heterozygous for the GBA1 N370S variant, and 22.6% for the GBA1 L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up.
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Affiliation(s)
- Christine Serratrice
- Department of Internal Medicine for the Aged, Geneva University Hospitals, 1226 Thonex- Geneva, Switzerland
- Correspondence: ; Tel.: +4179-873-1474
| | - Jérôme Stirnemann
- Department of Internal Medicine, Department of Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland;
| | - Amina Berrahal
- University Hospital of Clermont Ferrand, Hematology Biology Department, 63000 Clermont-Ferrand, France; (A.B.); (M.G.B.)
| | - Nadia Belmatoug
- Department of Internal Medicine, Centre de Référence des Maladies Lysosomales, AP-HP.Nord, Site Beaujon, Paris University, 92110 Clichy, France; (N.B.); (C.M.); (M.B.); (K.Y.)
| | - Fabrice Camou
- Intensive Care Unit, Hôpital Saint-André, CHU Bordeaux, 33000 Bordeaux, France;
| | - Catherine Caillaud
- Biochemistry, Metabolomics, and Proteomics Department, Necker Enfants Malades University Hospital, AP-HP. Center-Paris University, 75015 Paris, France;
| | | | - Florence Dalbies
- Institute of Cancerology and Hematology, CHRU Morvan, 29200 Brest, France;
| | - Bérengère Cador
- Department of Internal Medicine, CHU Pontchaillou, 35000 Rennes, France;
| | - Roseline Froissart
- Biochemical and Molecular Biology Department, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France;
| | - Agathe Masseau
- Department of Internal Medicine, CHU Hôtel Dieu, 44093 Nantes, France;
| | - Anaïs Brassier
- Reference Centre for Hereditary Metabolic Diseases, Hôpital Necker-Enfants Malades, AP-HP, IHU Institut Imagine, 75015 Paris, France;
| | - Bénédicte Hivert
- Department of Clinical Hematology, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l’Institut Catholique de Lille, 59800 Lille, France;
| | - Laure Swiader
- Department of Internal Medicine, CHU Timone, 13005 Marseille, France;
| | - Ivan Bertchansky
- Department of Internal Medicine, Saint-Eloi Hospital, CHU Montpellier, 34000 Montpellier, France;
| | - Claire de Moreuil
- Department of Internal Medicine, Hôpital de la Cavale Blanche, CHRU de Brest, 29200 Brest, France;
| | - Brigitte Chabrol
- Department of Pediatric Neurology, CHU Timone, 13005 Marseille, France;
| | - Isabelle Durieu
- Department of Internal Medicine, Hospices Civils de Lyon, University Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
| | - Vanessa Leguy Seguin
- Department of Internal Medicine and Clinical Immunology, CHU F. Mitterrand, 21000 Dijon, France;
| | | | - Sébastien Humbert
- Department of Internal Medicine, Besancon University Hospital, 25000 Besancon, France;
| | - Samia Pichard
- Service of Metabolic Diseases, Hôpital Robert Debré, 75019 Paris, France;
| | - Catherine Marcel
- Department of Internal Medicine, Centre de Référence des Maladies Lysosomales, AP-HP.Nord, Site Beaujon, Paris University, 92110 Clichy, France; (N.B.); (C.M.); (M.B.); (K.Y.)
| | | | - Monia Bengherbia
- Department of Internal Medicine, Centre de Référence des Maladies Lysosomales, AP-HP.Nord, Site Beaujon, Paris University, 92110 Clichy, France; (N.B.); (C.M.); (M.B.); (K.Y.)
| | - Karima Yousfi
- Department of Internal Medicine, Centre de Référence des Maladies Lysosomales, AP-HP.Nord, Site Beaujon, Paris University, 92110 Clichy, France; (N.B.); (C.M.); (M.B.); (K.Y.)
| | - Marc G. Berger
- University Hospital of Clermont Ferrand, Hematology Biology Department, 63000 Clermont-Ferrand, France; (A.B.); (M.G.B.)
- University Clermont Auvergne, EA 7453 CHELTER, 63000 Clermont-Ferrand, France
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12
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Mistry P, Balwani M, Barbouth D, Burrow TA, Ginns EI, Goker-Alpan O, Grabowski GA, Kartha RV, Kishnani PS, Lau H, Lee CU, Lopez G, Maegawa G, Packman S, Prada C, Rosenbloom B, Lal TR, Schiffmann R, Weinreb N, Sidransky E. Gaucher disease and SARS-CoV-2 infection: Emerging management challenges. Mol Genet Metab 2020; 130:164-169. [PMID: 32471800 PMCID: PMC7211677 DOI: 10.1016/j.ymgme.2020.05.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 01/08/2023]
Affiliation(s)
- Pramod Mistry
- Department of Internal Medicine and Pediatrics,Yale School of Medicine, New Haven, CT, United States of America.
| | - Manisha Balwani
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, United States of America.
| | - Deborah Barbouth
- Department of Human Genetics, University of Miami, Miller School of Medicine, United States of America.
| | - T Andrew Burrow
- Department of Human Genetics, University of Miami, Miller School of Medicine, United States of America; Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Section of Genetics and Metabolism, Little Rock, AR, United States of America.
| | - Edward I Ginns
- Lysosomal Disorders Treatment and Research Program, Departments of Psychiatry and Neurology, University of Massachusetts Medical School, Worcester, MA, United States of America.
| | - Ozlem Goker-Alpan
- Lysosomal and Rare Disorders Research and Treatment Center, Fairfax, VA, United States of America.
| | - Gregory A Grabowski
- Departments of Pediatrics, and Molecular Genetics and Biochemistry, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
| | - Reena V Kartha
- Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, United States of America.
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.
| | - Heather Lau
- Division of Neurogenetics, Department of Neurology, New York University, New York, NY, United States of America.
| | - Chung U Lee
- Lucile Packard Children's Hospital Stanford, Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Palo Alta, CA, United States of America.
| | - Grisel Lopez
- Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, United States of America.
| | - Gustavo Maegawa
- Division of Genetics and Metabolism, Departments of Pediatrics, Neuroscience, Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United States of America.
| | - Seymour Packman
- Department of Pediatrics, Division of Medical Genetics, University of California San Francisco, San Francisco, CA, United States of America.
| | - Carlos Prada
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
| | - Barry Rosenbloom
- Cedars-Sinai Tower Hematology Oncology, Beverly Hills, CA, United States of America.
| | - Tamanna Roshan Lal
- Rare Disease Institute, Children's National Medical Center, Washington DC, United States of America.
| | - Rapheal Schiffmann
- Baylor, Scott & White Research Institute, Dallas, TX, United States of America.
| | - Neal Weinreb
- Departments of Human Genetics and Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, United States of America.
| | - Ellen Sidransky
- Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, United States of America.
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Abrams R, Kaddi CD, Tao M, Leiser RJ, Simoni G, Reali F, Tolsma J, Jasper P, van Rijn Z, Li J, Niesner B, Barrett JS, Marchetti L, Peterschmitt MJ, Azer K, Neves-Zaph S. A Quantitative Systems Pharmacology Model of Gaucher Disease Type 1 Provides Mechanistic Insight Into the Response to Substrate Reduction Therapy With Eliglustat. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2020; 9:374-383. [PMID: 32558397 PMCID: PMC7376290 DOI: 10.1002/psp4.12506] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/17/2020] [Indexed: 12/27/2022]
Abstract
Gaucher’s disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first‐line SRT approved for GD1, on treatment‐naïve or patients with ERT‐stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype‐phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population.
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Affiliation(s)
- Ruth Abrams
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Chanchala D Kaddi
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Mengdi Tao
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Randolph J Leiser
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Giulia Simoni
- Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Italy
| | - Federico Reali
- Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Italy
| | | | | | - Zachary van Rijn
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Jing Li
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Bradley Niesner
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Jeffrey S Barrett
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Luca Marchetti
- Fondazione The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto, Italy
| | | | - Karim Azer
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
| | - Susana Neves-Zaph
- Translational Disease Modelling, Digital Data Science, Sanofi, Bridgewater, New Jersey, USA
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14
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Carubbi F, Cappellini MD, Fargion S, Fracanzani AL, Nascimbeni F. Liver involvement in Gaucher disease: A practical review for the hepatologist and the gastroenterologist. Dig Liver Dis 2020; 52:368-373. [PMID: 32057684 DOI: 10.1016/j.dld.2020.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 01/02/2020] [Accepted: 01/12/2020] [Indexed: 02/06/2023]
Abstract
Gaucher disease (GD), a rare lysosomal storage disorder caused by deficient glucocerebrosidase activity and consequent accumulation of glycosphingolipids in the mononuclear phagocyte system, may progress to disabling and potentially life-threatening complications when left undiagnosed and untreated. Unfortunately, because of non-specific signs and symptoms and lack of awareness, patients with type 1 GD, the most common non-neuropathic variant, frequently experience diagnostic delays. Since splenomegaly and thrombocytopenia are the dominant clinical features in many GD patients leading to first medical contact, the hepatologist and the gastroenterologist need to be aware of this condition. Liver involvement has been reported in the majority of GD patients, and comprises hepatomegaly, with or without liver enzymes alteration, fibrosis/cirrhosis, portal hypertension, focal liver lesions, and cholelithiasis. Moreover, GD is associated with several biochemical alterations of potential interest for the hepatologist and the gastroenterologist, including hypergammaglobulinemia, hyperferritinemia and metabolic abnormalities, that may lead to misdiagnoses with chronic liver diseases of common etiology, such as primary hemochromatosis, autoimmune liver diseases or nonalcoholic fatty liver disease. This comprehensive review, based on the collaborative experience of physicians managing patients with GD, provides practical information on the clinical, histological and radiological hepatic manifestations of GD aiming at facilitating the diagnosis of GD for the hepatologist and the gastroenterologist.
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Affiliation(s)
- Francesca Carubbi
- Regional Referral Centre for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Civil Hospital, AOU of Modena, University of Modena and Reggio Emilia, Modena, Italy.
| | - Maria Domenica Cappellini
- Rare Diseases Center, Department of Medicine, "Ca' Granda" Foundation IRCCS, Policlinico Hospital, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Silvia Fargion
- "Ca' Granda" Foundation IRCCS, Policlinico Hospital, University of Milan, Milan, Italy
| | - Anna Ludovica Fracanzani
- "Ca' Granda" Foundation IRCCS, Policlinico Hospital, University of Milan, Milan, Italy; Department of Pathophysiology and Transplantation, Unit of Medicine and Metabolic Disorders, Milan, Italy
| | - Fabio Nascimbeni
- Regional Referral Centre for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Civil Hospital, AOU of Modena, University of Modena and Reggio Emilia, Modena, Italy
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15
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Nascimbeni F, Dionisi Vici C, Vespasiani Gentilucci U, Angelico F, Nobili V, Petta S, Valenti L. AISF update on the diagnosis and management of adult-onset lysosomal storage diseases with hepatic involvement. Dig Liver Dis 2020; 52:359-367. [PMID: 31902560 DOI: 10.1016/j.dld.2019.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 12/07/2019] [Accepted: 12/10/2019] [Indexed: 12/11/2022]
Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment.
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Affiliation(s)
- Fabio Nascimbeni
- Regional Referral Centre for Lysosomal Storage Diseases, Division of Internal Medicine and Metabolism, Civil Hospital, AOU of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Dionisi Vici
- Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | | | - Francesco Angelico
- Department of Public Health and Infective Diseases, Università Sapienza, Roma, Italy
| | - Valerio Nobili
- Division of Hepatology and Gastroenterology, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Salvatore Petta
- Gastroenterology and Hepatology, PROMISE, Palermo University, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, and Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
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16
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Saing S, van der Linden N, Hayward C, Goodall S. Why is There Discordance between the Reimbursement of High-Cost 'Life-Extending' Pharmaceuticals and Medical Devices? The Funding of Ventricular Assist Devices in Australia. APPLIED HEALTH ECONOMICS AND HEALTH POLICY 2019; 17:421-431. [PMID: 30906972 DOI: 10.1007/s40258-019-00470-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
New health technologies often yield health benefits, but often at a high cost. In Australia, the processes for public reimbursement of high-cost pharmaceuticals and medical devices are different, potentially resulting in inequity in support for new therapies. We explore how reimbursement is different for medical devices compared with pharmaceuticals, including whether higher cost-effectiveness thresholds are accepted for pharmaceuticals. A literature review identified the challenges of economic evaluations for medical devices compared with pharmaceuticals. We used the ventricular assist device as a case study to highlight specific features of medical device funding in Australia. We used existing guidelines to evaluate whether ventricular assist devices would fulfil the requirements for the "Life-Saving Drugs Program", which is usually reserved for expensive life-extending pharmaceutical treatments of serious and rare medical conditions. The challenges in conducting economic evaluations of medical devices include limited data to support effectiveness, device-operator interaction (surgical experience) and incremental innovations (miniaturisation). However, whilst high-cost pharmaceuticals may be funded by a single source (federal government), the funding of high-cost devices is complex and may be funded via a combination of federal, state and private health insurance. Based on the Life-Saving Drugs Program criteria, we found that ventricular assist devices could be funded by a similar mechanism to that which funds high-cost life-extending pharmaceuticals. This article highlights the complexities of medical device reimbursement. Whilst differences in available evidence affect the evaluation process, differences in funding methods contribute to inequitable reimbursement decisions between medical devices and pharmaceuticals.
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Affiliation(s)
- Sopany Saing
- Centre for Health Economics Research and Evaluation (CHERE), University of Technology Sydney, PO Box 123, Sydney, NSW, 2007, Australia.
| | - Naomi van der Linden
- Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Christopher Hayward
- Heart Failure and Transplant Unit, St Vincent's Hospital, Sydney, NSW, Australia
- Victor Chang Cardiac Research Institute, Sydney, NSW, Australia
| | - Stephen Goodall
- Centre for Health Economics Research and Evaluation (CHERE), University of Technology Sydney, PO Box 123, Sydney, NSW, 2007, Australia
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Vujosevic S, Medenica S, Vujicic V, Dapcevic M, Bakic N, Yang R, Liu J, Mistry PK. Gaucher disease in Montenegro - genotype/phenotype correlations: Five cases report. World J Clin Cases 2019; 7:1475-1482. [PMID: 31363476 PMCID: PMC6656677 DOI: 10.12998/wjcc.v7.i12.1475] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/01/2019] [Accepted: 05/11/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD.
CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient).
CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.
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Affiliation(s)
- Snezana Vujosevic
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Sanja Medenica
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Vesko Vujicic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Milena Dapcevic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Nikola Bakic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Ruhua Yang
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Jun Liu
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Pramod K Mistry
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
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Davari M, Nabizadeh A, Kadivar M, Asl AA, Sarkheil P. Healthcare resource utilization and cost of care for Gaucher patients in Iran. J Diabetes Metab Disord 2019; 18:127-132. [PMID: 31275883 DOI: 10.1007/s40200-019-00399-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 03/14/2019] [Indexed: 10/27/2022]
Abstract
Introduction Gaucher disease (GD) is an inherited recessive enzyme deficiency with a multisystem condition. The Iranian government covers the therapeutic expenditure of GD patients as it is not affordable for the patients. The aim of this study is to identify the main components of the cost of care in Gaucher patients (GPs) in Iran. Methods The Gaucher patients were identified from the Iran Food and Drug Administration (IFDA) national registry database. The direct medical costs, including medication, diagnostic services, and physician visits were considered. The prices of therapeutic and diagnostic services were extracted from Iranian medical tariff book 2014-15. Iran Food and Drug Administration determined the cost of medications. Results 164 Gaucher patients have been registered in Iran. A valid and reliable diagnostic tests are not used to identify the type of GD. The average health care cost per annum was 20,758 USD per patient, which is higher than 4 GDP per capita in Iran. Medication cost constitutes 95.2% of the total cost. The average cost of each GP was $1,473,818 in his/her total life. Conclusion GD is amongst the high-cost diseases and should be managed effectively. The application of oral medication for eligible GPs could improve allocative efficiency in GD management significantly. A sound, valid and reliable national clinical guideline could improve the efficiency of healthcare resources effectively. Selecting appropriate strategies for reducing the birth of a child with Gaucher, could support allocative efficiency of the limited resources effectively.
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Affiliation(s)
- Majid Davari
- 1Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Azita Nabizadeh
- 1Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Maliheh Kadivar
- 2Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Akbar Abdollahi Asl
- 1Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Peymaneh Sarkheil
- 3Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Jaffe DH, Flaks-Manov N, Benis A, Gabay H, DiBonaventura M, Rosenbaum H, Joseph A, Bachrach A, Leventer-Roberts M. Population-based cohort of 500 patients with Gaucher disease in Israel. BMJ Open 2019; 9:e024251. [PMID: 30670517 PMCID: PMC6347887 DOI: 10.1136/bmjopen-2018-024251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE To characterise a population-based cohort of patients with Gaucher disease (GD) in Israel relative to the general population and describe sociodemographic and clinical differences by disease severity (ie, enzyme replacement therapy [ERT] use). DESIGN A cross-sectional study was conducted. SETTING Data from the Clalit Health Services electronic health record (EHR) database were used. PARTICIPANTS The study population included all patients in the Clalit EHR database identified as having GD as of 30 June 2014. RESULTS A total of 500 patients with GD were identified and assessed. The majority were ≥18 years of age (90.6%), female (54.0%), Jewish (93.6%) and 34.8% had high socioeconomic status, compared with 19.0% in the general Clalit population. Over half of patients with GD with available data (51.0%) were overweight/obese and 63.5% had a Charlson Comorbidity Index ≥1, compared with 46.6% and 30.4%, respectively, in the general Clalit population. The majority of patients with GD had a history of anaemia (69.6%) or thrombocytopaenia (62.0%), 40.4% had a history of bone events and 22.2% had a history of cancer. Overall, 41.2% had received ERT. CONCLUSIONS Establishing a population-based cohort of patients with GD is essential to understanding disease progression and management. In this study, we highlight the need for physicians to monitor patients with GD regardless of their ERT status.
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Affiliation(s)
- Dena H Jaffe
- Health Outcomes Practice, Kantar Health, Tel Aviv, Israel
| | | | - Arriel Benis
- Clalit Research Institute, Clalit Health Services, Tel Aviv, Israel
| | - Hagit Gabay
- Clalit Research Institute, Clalit Health Services, Tel Aviv, Israel
| | | | - Hanna Rosenbaum
- Department of Oncology, Clalit Medical Center, Nazareth, Israel
| | - Alain Joseph
- Health Economics and Health Outcomes, Shire GmbH Zug, Zug, Switzerland
| | - Asaf Bachrach
- Clalit Research Institute, Clalit Health Services, Tel Aviv, Israel
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Russell SA, Sholzberg M, Mangel J, Keeney M, Hedley B, Bode M, Gob A, Lam S, Phua C, Hsia CC. Gaucher disease screening at a general adult hematology tertiary care centre: A prospective study. Int J Lab Hematol 2018; 41:e66-e69. [DOI: 10.1111/ijlh.12960] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/05/2018] [Accepted: 11/12/2018] [Indexed: 11/28/2022]
Affiliation(s)
- Steven A. Russell
- Department of Internal Medicine Western University London Ontario Canada
| | - Michelle Sholzberg
- Department of Medicine and Laboratory Medicine & Pathobiology St. Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto London Ontario Canada
| | - Joy Mangel
- Division of Hematology, Department of Medicine Western University London Ontario Canada
| | - Michael Keeney
- MLT London Laboratory Services Group London Ontario Canada
| | - Ben Hedley
- MLT London Laboratory Services Group London Ontario Canada
| | - Margo Bode
- MLT London Laboratory Services Group London Ontario Canada
| | - Alan Gob
- Division of Hematology, Department of Medicine Western University London Ontario Canada
| | - Selay Lam
- Division of Hematology, Department of Medicine Western University London Ontario Canada
| | - Chai Phua
- Division of Hematology, Department of Medicine Western University London Ontario Canada
| | - Cyrus C. Hsia
- Division of Hematology, Department of Medicine Western University London Ontario Canada
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21
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Mistry PK, Balwani M, Baris HN, Turkia HB, Burrow TA, Charrow J, Cox GF, Danda S, Dragosky M, Drelichman G, El-Beshlawy A, Fraga C, Freisens S, Gaemers S, Hadjiev E, Kishnani PS, Lukina E, Maison-Blanche P, Martins AM, Pastores G, Petakov M, Peterschmitt MJ, Rosenbaum H, Rosenbloom B, Underhill LH, Cox TM. Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1. Blood Cells Mol Dis 2018; 71:71-74. [PMID: 29680197 DOI: 10.1016/j.bcmd.2018.04.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/04/2018] [Accepted: 04/04/2018] [Indexed: 01/15/2023]
Affiliation(s)
| | | | - Hagit N Baris
- The Genetics Institute, Rambam Health Care Campus, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, - Israel Institute of Technology, Haifa, Israel
| | | | - T Andrew Burrow
- College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Joel Charrow
- Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Gerald F Cox
- Editas, Cambridge, MA, USA (formerly Sanofi Genzyme, Cambridge, MA, USA)
| | | | | | | | | | | | | | | | | | - Priya S Kishnani
- Duke University School of Medicine, Department of Pediatrics, Durham, NC, USA
| | - Elena Lukina
- National Research Center for Hematology, Moscow, Russia
| | | | | | | | - Milan Petakov
- Clinical Center of Serbia, University of Belgrade School of Medicine, Belgrade, Serbia
| | | | | | | | | | - Timothy M Cox
- University of Cambridge, Department of Medicine, Box 157, Level 5, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
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22
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Energy balance, glucose and lipid metabolism, cardiovascular risk and liver disease burden in adult patients with type 1 Gaucher disease. Blood Cells Mol Dis 2018; 68:74-80. [DOI: 10.1016/j.bcmd.2016.10.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 10/19/2016] [Indexed: 01/14/2023]
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23
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Weinreb NJ, Barbouth DS, Lee RE. Causes of death in 184 patients with type 1 Gaucher disease from the United States who were never treated with enzyme replacement therapy. Blood Cells Mol Dis 2018; 68:211-217. [DOI: 10.1016/j.bcmd.2016.10.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 10/17/2016] [Indexed: 11/26/2022]
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24
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Ibrahim J, Call R. Letter to the Editor on “Enzyme Replacement or Substrate Reduction? A Review of Gaucher Disease Treatment Options”. Hosp Pharm 2017; 52:725-726. [DOI: 10.1177/0018578717735641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Jennifer Ibrahim
- Senior US Medical Director, Rare Disease Sanofi Genzyme, Cambridge, MA, USA
| | - Rebecca Call
- Medical Affairs/Medical Science Liaison (MSL): Rare Disease Fellow Sanofi Genzyme, Cambridge, MA, USA
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25
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Beaton B, Monzón JLS, Hughes DA, Pastores GM. Gaucher disease: risk stratification and comorbidities. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1385455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Brendan Beaton
- Lysosomal Storage Disorder Unit, Royal Free NHS FT and University College London, London, UK
| | | | - Derralynn A. Hughes
- Lysosomal Storage Disorder Unit, Royal Free NHS FT and University College London, London, UK
- Department of Haematology and Palliative Care, Royal Free NHS FT, University College London, London, UK
| | - Gregory M. Pastores
- Department of Medicine/National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital and University College Dublin, Dublin, Ireland
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26
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Holubar J, Bres V, Costes-Martineau V, Pers YM. Cholangiocarcinoma occurring in a patient with type 1 Gaucher disease treated with velaglucerase alfa enzyme replacement therapy: First case report. Blood Cells Mol Dis 2017; 68:112-114. [PMID: 28559130 DOI: 10.1016/j.bcmd.2017.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/22/2017] [Accepted: 05/23/2017] [Indexed: 11/19/2022]
Affiliation(s)
- Jan Holubar
- Clinical immunology and osteoarticular diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France
| | - Virginie Bres
- Pharmacovigilance Regional Center, Medical Pharmacology and Toxicology Department, CHU, Montpellier, France
| | | | - Yves-Marie Pers
- Clinical immunology and osteoarticular diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France; IRMB, INSERM U1183, Saint-Eloi University Hospital, Montpellier, France.
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27
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Ganz ML, Stern S, Ward A, Nalysnyk L, Selzer M, Hamed A, Weinreb N. A new framework for evaluating the health impacts of treatment for Gaucher disease type 1. Orphanet J Rare Dis 2017; 12:38. [PMID: 28219443 PMCID: PMC5319149 DOI: 10.1186/s13023-017-0592-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/08/2017] [Indexed: 12/25/2022] Open
Abstract
Background The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5 < DS3 ≤ 6.5) without SSC; moderate with SSC; marked (6.5 < DS3 ≤ 9.5) without SSC; marked with SSC; severe (9.5 < DS3 ≤ 19) without SSC; and severe with SSC. Health-state transition probabilities and utilities were estimated from a longitudinal sample of patients with GD1 who started enzyme replacement therapy (the DS3 Score Study). Age dependent GD1-specific mortality was derived from published data. We used a Markov state-transition model to illustrate how to estimate time spent in each health state. Results The average predicted utilities for each health state ranged from 0.76 for mild disease with no clinical symptoms of bone disease to 0.52 with severe disease with SSC. Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. Patients who started treatment with intact or residual spleens spent more time in better health states than those who started treatment with total splenectomy. Conclusions This new framework, which is based on the DS3, can be used to project the long-term outcomes of GD1 patients starting treatment. The framework could also be used to compare the long-term outcomes of different GD1 treatment options. Trial registration NCT01136304. Registered: May 31, 2010 (retrospectively registered). Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0592-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Michael L Ganz
- Evidera, 500 Totten Pond Road, 5th Floor, Waltham, MA, 02451, USA.
| | - Sean Stern
- Evidera, 7101 Wisconsin Avenue, Suite 600, Bethesda, MD, 20814, USA
| | - Alex Ward
- Evidera, 500 Totten Pond Road, 5th Floor, Waltham, MA, 02451, USA
| | - Luba Nalysnyk
- Sanofi Genzyme, 500 Kendall Street, Cambridge, MA, 02142, USA
| | | | - Alaa Hamed
- Sanofi Genzyme, 500 Kendall Street, Cambridge, MA, 02142, USA
| | - Neal Weinreb
- University Research Foundation for Lysosomal Storage Diseases Inc., 7367 Wexford Terrace, Boca Raton, FL, 33433, USA
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28
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Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. ACTA ACUST UNITED AC 2016; 22:65-73. [PMID: 27762169 DOI: 10.1080/10245332.2016.1240391] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVES The objectives of this research were: (1) to heighten awareness of Gaucher disease (GD), a rare lysosomal storage disorder with highly heterogeneous patterns of organ involvement and disease severity, to clinicians most likely to encounter these patients, and; (2) to summarize the published evidence on GD epidemiology which is essential to accurately depict the total societal burden of this rare worldwide disorder. METHODS A comprehensive literature review was undertaken to summarize the published evidence on the epidemiology of GD. MEDLINE, EMBASE, CENTRAL, and 'grey' literature sources published in English between January 1990 and March 2015 were searched to identify relevant publications. RESULTS In total, 188 full-text articles were reviewed and findings from 49 studies are summarized herein. The standardized birth incidence of GD in the general population varied from 0.39 to 5.80 per 100 000, and prevalence ranged from 0.70 to 1.75 per 100 000, respectively. Time from onset of GD symptoms to clinical diagnosis was highly variable, with median delays of up to 7 years reported. DISCUSSION The incidence and prevalence of GD is substantially higher among the Ashkenazi Jewish population than the general population. Limited epidemiologic information was available from Latin America, Africa, Asia, and developed nations such as the United States, Germany, and the United Kingdom. CONCLUSIONS Signs and symptoms of GD frequently mimic more common hematologic conditions resulting in missed or delayed diagnosis. Early diagnosis and prompt initiation of treatment when indicated is crucial to prevent or minimize life-altering or life-threatening liver and skeletal complications.
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Affiliation(s)
| | | | | | | | - Neal Weinreb
- c University Research Foundation for Lysosomal Storage Disorders , Coral Springs , FL , USA
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29
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Cassiman D, Packman S, Bembi B, Turkia HB, Al-Sayed M, Schiff M, Imrie J, Mabe P, Takahashi T, Mengel KE, Giugliani R, Cox GF. Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases. Mol Genet Metab 2016; 118:206-213. [PMID: 27198631 DOI: 10.1016/j.ymgme.2016.05.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/04/2016] [Accepted: 05/05/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND Acid sphingomyelinase deficiency (ASMD), [Niemann-Pick Disease Types A and B (NPD A and B)], is an inherited metabolic disorder resulting from deficiency of the lysosomal enzyme acid sphingomyelinase. Accumulation of sphingomyelin in hepatocytes, reticuloendothelial cells, and in some cases neurons, results in a progressive multisystem disease that encompasses a broad clinical spectrum of neurological and visceral involvement, including: infantile neurovisceral ASMD (NPD A) that is uniformly fatal by 3years of age; chronic neurovisceral ASMD (intermediate NPD A/B; NPD B variant) that has later symptom onset and slower neurological and visceral disease progression; and chronic visceral ASMD (NPD B) that lacks neurological symptoms but has significant disease-related morbidities in multiple organ systems. The purpose of this study was to characterize disease-related morbidities and causes of death in patients with the chronic visceral and chronic neurovisceral forms of ASMD. METHODS Data for 85 patients who had died or received liver transplant were collected by treating physicians (n=27), or abstracted from previously published case studies (n=58). Ages at symptom onset, diagnosis, and death; cause of death; organ involvement, and morbidity were analyzed. RESULTS Common disease-related morbidities included splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%). The overall leading causes of death were respiratory failure and liver failure (27.7% each) irrespective of age. For patients with chronic neurovisceral ASMD (31.8%), progression of neurodegenerative disease was a leading cause of death along with respiratory disease (both 23.1%) and liver disease (19.2%). Patients with chronic neurovisceral disease died at younger ages than those with chronic visceral disease (median age at death 8 vs. 23.5years). CONCLUSIONS The analysis emphasizes that treatment goals for patients with chronic visceral and chronic neurovisceral ASMD should include reducing splenomegaly and improving liver function and respiratory status, with the ultimate goal of decreasing serious morbidity and mortality.
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Affiliation(s)
| | - Seymour Packman
- University of California San Francisco, San Francisco, CA, United States
| | - Bruno Bembi
- Academic Medical Centre Hospital of Udine, Udine, Italy
| | | | | | - Manuel Schiff
- University of Paris-Diderot, APHP and INSERM U1141, Reference Center for Inborn Errors of Metabolism, Robert-Debré Hospital, Paris, France
| | - Jackie Imrie
- Niemann-Pick Disease Group (UK), Tyne and Wear, UK
| | - Paulina Mabe
- Hospital Dr. Exequiel González Cortés, Santiago, Chile
| | | | - Karl Eugen Mengel
- Villa Metabolica, Center of Pediatric and Adolescents Medicine, University Medical Center, Mainz, Germany
| | - Roberto Giugliani
- Medical Genetics Service, HCPA, Dep. Genetics, UFRGS and INAGEMP, Porto Alegre, Brazil
| | - Gerald F Cox
- Clinical Development, Sanofi Genzyme, Cambridge, MA, United States.
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Ilan Y. Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1102-17. [PMID: 27173510 DOI: 10.1152/ajpgi.00095.2016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 05/04/2016] [Indexed: 01/31/2023]
Abstract
The compounds of sphingomyelin-ceramide-glycosphingolipid pathways have been studied as potential secondary messenger molecules in various systems, along with liver function and insulin resistance. Secondary messenger molecules act directly or indirectly to affect cell organelles and intercellular interactions. Their potential role in the pathogenesis of steatohepatitis and diabetes has been suggested. Data samples collected from patients with Gaucher's disease, who had high levels of glucocerebroside, support a role for compounds from these pathways as a messenger molecules in the pathogenesis of fatty liver disease and diabetes. The present review summarizes some of the recent data on the role of glycosphingolipid molecules as messenger molecules in various physiological and pathological conditions, more specifically including insulin resistance and fatty liver disease.
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Affiliation(s)
- Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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31
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Weinreb NJ, Kaplan P. The history and accomplishments of the ICGG Gaucher registry. Am J Hematol 2015; 90 Suppl 1:S2-5. [PMID: 26096743 DOI: 10.1002/ajh.24054] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Neal J. Weinreb
- University Research Foundation for Lysosomal Storage Disorders; Coral Springs, Florida, USA
| | - Paige Kaplan
- Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, Pennsylvania, USA
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32
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Mistry PK, Belmatoug N, vom Dahl S, Giugliani R. Understanding the natural history of Gaucher disease. Am J Hematol 2015; 90 Suppl 1:S6-11. [PMID: 26096746 DOI: 10.1002/ajh.24055] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Gaucher disease is a rare and extraordinarily heterogeneous inborn error of metabolism that exhibits diverse manifestations, a broad range of age of onset of symptoms, and a wide clinical spectrum of disease severity, from lethal disease during infancy to first age of onset of symptoms in octogenarians. Before the advent of the International Collaborative Gaucher Group (ICGG) Gaucher Registry, the understanding of the natural history and phenotypic range of Gaucher disease was based on isolated case reports and small case series. Limited data hindered understanding of the full spectrum of the disease leading to some early misconceptions about Gaucher disease, notably, that nonneuronopathic (type 1) disease was a disease of adults only. The global scope of the ICGG Gaucher Registry, with its vast body of longitudinal data, has enabled a real appreciation of both the phenotypic spectrum of Gaucher disease and its natural history. This body of evidence represents the foundation for accurate assessment of the response to specific therapies for Gaucher disease and to the development of standard-of-care to monitor disease activity. Here, we outline the key developments in delineating the natural history of this highly complex disease and role of the ICGG Gaucher Registry in this effort.
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Affiliation(s)
- Pramod K. Mistry
- Department of Internal Medicine Yale University School of Medicine; New Haven Connecticut, USA
| | - Nadia Belmatoug
- Department of Internal Medicine; Reference Center for Lysosomal Diseases; Beaujon Hospital, Clichy, Assistance Publique-Hôpitaux De Paris France
| | - Stephan vom Dahl
- Department of Gastroenterology, Hepatology and Infectious Diseases; University Hospital, University of Düesseldorf; Düsseldorf Germany
| | - Roberto Giugliani
- Department of Genetics/UFRGS and INAGEMP; Medical Genetics Service/HCPA; Porto Alegre Rio Grande do Sul Brazil
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Essabar L, Meskini T, Lamalmi N, Ettair S, Erreimi N, Mouane N. Gaucher's disease: report of 11 cases with review of literature. Pan Afr Med J 2015; 20:18. [PMID: 25995815 PMCID: PMC4431408 DOI: 10.11604/pamj.2015.20.18.4112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 10/09/2014] [Indexed: 12/16/2022] Open
Abstract
Gaucher's disease (GD) is a lysosomal storage disorder due to glucocerebrosidase deficiency; it's one of the rare genetic diseases for which therapy is now available. The purpose of this work is to study the epidemiological features of the disease and to highlight the diagnostic difficulties. We performed an 11-year retrospective study of 11 patients with GD followed-up in the department of paediatric hepatology gastroenterology and nutrition of Rabat children's Hospital. We observed 11 patients with GD: 6 males and 5 females. Age at onset ranged from 3 months to 10 years with an average of 3.41 years. Mean age at diagnosis was 4 years (range 3months-14years). Parental consanguinity was noted in 85% cases. According to the clinical presentation, we classified our patients into: 9 cases of type 1 (81%) and two cases of type 2 (19%), none of the patients presented GD type 3. GD type 1: The age at diagnosis ranged from 2 years to 14 year with an average of 6 years. Main symptoms were: splenomegaly, hepatomegaly, pallor, haemorrhagic appearance (40%), bone pain (40%). The diagnosis was based on histology showing the Gaucher's cells in various tissues (100%). Enzymatic activity dosage confirmed the diagnosis of GD for 4 patients (44.5%). The treatment was always symptomatic (analgesics, transfusion). A splenectomy was performed in one case presenting with multiple splenic abscesses and high transfusion requirements. None of the patients received a specific treatment (substitutive enzymotherapy). The follow-up period ranged from 3 months to 6 years with an average follow-up of 4 years. We noticed stability in 4 cases, 2 worsening cases with bone and spleen complications. Three patients were lost to follow-up. GD type 2: we observed two cases of GD type 2 diagnosed at 3 and 18 months. The visceral symptoms were serious and the neurological features included seizures, hypertony, squint, physical developmental milestones delay. Both of them died. Gaucher's disease is not exceptional in Morocco. Type 1 is the most common type. We noted through this study some diagnostic difficulties as the diagnosis was delayed and the enzymatic dosage was performed in only 42% of the cases as well as therapeutic difficulty with no prescription of the specific treatment given the high cost of the enzyme.
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Affiliation(s)
- Laila Essabar
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Toufik Meskini
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Najat Lamalmi
- FMPR, University Mohammed V Souissi, Department of Anatomo-Pathology, Rabat Children's Hospital
| | - Said Ettair
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Naima Erreimi
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
| | - Nezha Mouane
- FMPR, University Mohammed V Souissi, Department of Pediatric Hepatology Gastroenterology and Nutrition - P III, Rabat Children's Hospital, Morocco
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Zimran A, Gonzalez-Rodriguez DE, Abrahamov A, Elstein D, Paz A, Brill-Almon E, Chertkoff R. Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease. Blood Cells Mol Dis 2014; 54:9-16. [PMID: 25453586 DOI: 10.1016/j.bcmd.2014.10.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 09/23/2014] [Accepted: 09/23/2014] [Indexed: 12/18/2022]
Abstract
Taliglucerase alfa is a plant cell-expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n=6) or 60U/kg (n=5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690.
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Affiliation(s)
- Ari Zimran
- Gaucher Clinic, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 01931, Israel; Hadassah Medical School - Hebrew University, Jerusalem, Israel.
| | | | - Aya Abrahamov
- Gaucher Clinic, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 01931, Israel; Hadassah Medical School - Hebrew University, Jerusalem, Israel.
| | - Deborah Elstein
- Gaucher Clinic, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 01931, Israel; Hadassah Medical School - Hebrew University, Jerusalem, Israel.
| | - Alona Paz
- Protalix BioTherapeutics, 2 Snunit Street, Science Park, POB 455, Carmiel 20100, Israel.
| | - Einat Brill-Almon
- Protalix BioTherapeutics, 2 Snunit Street, Science Park, POB 455, Carmiel 20100, Israel.
| | - Raul Chertkoff
- Protalix BioTherapeutics, 2 Snunit Street, Science Park, POB 455, Carmiel 20100, Israel.
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Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology, phenotypes and natural history. PEDIATRIC ENDOCRINOLOGY REVIEWS : PER 2014; 12 Suppl 1:72-81. [PMID: 25345088 PMCID: PMC4520262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Gaucher disease (GD), a prototype lysosomal storage disorder, results from inherited deficiency of lysosomal glucocerebrosidase due to biallelic mutations in GBA. The result is widespread accumulation of macrophages engorged with predominantly lysosomal glucocerebroside. A complex multisystem phenotype arises involving the liver, spleen, bone marrow and occasionally the lungs in type 1 Gaucher disease; in neuronopathic fulminant type 2 and chronic type 3 disease there is in addition progressive neurodegenerative disease. Manifestations of Gaucher disease type 1 (GD1) include hepatosplenomegaly, cytopenia, a complex pattern of bone involvement with avascular osteonecrosis (AVN), osteoporosis, fractures and lytic lesions. Enzyme replacement therapy became the standard of care in 1991, and this has transformed the natural history of GD1. This article reviews the clinical phenotypes of GD, diagnosis, pathophysiology and its natural history. A subsequent chapter discusses the treatment options.
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Mistry PK, Taddei T, vom Dahl S, Rosenbloom BE. Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog 2013; 18:235-46. [PMID: 23510066 DOI: 10.1615/critrevoncog.2013006145] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Clinical observations spanning almost half a century have demonstrated a consistent association of type 1 Gaucher disease (GD1) and cancers. However, the cellular and molecular bases of the association are not understood. Gaucher disease (GD) is a lysosomal storage disorder due to an inherited deficiency of acid β-glucosidase that underlies the accumulation of glucosylceramide in lysosomes of mononuclear phagocytes and immune dysregulation. The overall cancer risk is markedly increased in GD, and the determinants of malignancy in a subset of patients with GD1 are not known. The association of GD and cancer is most striking for hematological malignancies, with the risk for multiple myeloma estimated at almost 37-fold compared to the general population; some studies have also suggested increased cancer risk for non-hematological malignancies. There is no association of overall severity of GD to risk of cancer, although there is an increased prevalence of splenectomy among patients exhibiting the GD/cancer phenotype. Moreover, there appears to be an increased incidence of multiple consecutive cancers in individual patients. Several factors could contribute to cancer development in GD, including polarization of macrophages to the alternatively activated phenotype, chronic inflammation, chronic B-cell stimulation, splenectomy, hyperferritinemia, lysosomal dysfunction, and endoplasmic reticulum stress. Recent studies have highlighted T-cell dysfunction and modifier genes contributing to an increased cancer risk in GD. Macrophage-targeted enzyme replacement therapy (ERT) reverses systemic features of GD1; while cancer risk appears to be reduced in the era of ERT, it is not known whether this is a direct effect of therapy. Delineation of the mechanisms underlying the increased cancer risk in GD will provide additional novel insights into the role of lipids and macrophages in cancer pathogenesis and, moreover, have the potential to reveal novel therapeutic targets.
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Affiliation(s)
- Pramod K Mistry
- Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520-8064, USA.
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Morbidity and mortality in type B Niemann-Pick disease. Genet Med 2013; 15:618-23. [PMID: 23412609 DOI: 10.1038/gim.2013.4] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 01/07/2013] [Indexed: 01/27/2023] Open
Abstract
PURPOSE The purpose of this study was to perform a systematic evaluation of morbidity and mortality in type B Niemann-Pick disease. METHODS A total of 103 patients with Niemann-Pick disease (49 males, 54 females, age range: 1-72 years) participated in natural history studies through Mount Sinai's International Center for Types A and B Niemann-Pick Disease between 1992 and 2012. RESULTS Serious morbidities included significant neurological, hepatic, and cardiac disease. Thirteen patients had some degree of neurological impairment. Nine patients had cirrhosis or liver failure requiring transplantation. Coronary artery and valvular heart disease were present in nine patients. Of note, only four patients were oxygen dependent, although progressive pulmonary disease is a well-described feature of Niemann-Pick disease. During the follow-up period, 18 deaths occurred. The median age of death was 15.5 years (range 1-72). Causes of death included pneumonia, liver failure, and hemorrhage. The majority of deaths (12 of 18) occurred in patients <21 years, yielding a mortality rate of 19% in the pediatric population. CONCLUSION This study demonstrates that Niemann-Pick disease is a life-threatening disorder with significant morbidity and mortality, especially in the pediatric population. The information collected in this series highlights the need for safe, effective therapy for Niemann-Pick disease.
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Barth BM, Shanmugavelandy SS, Tacelosky DM, Kester M, Morad SAF, Cabot MC. Gaucher's disease and cancer: a sphingolipid perspective. Crit Rev Oncog 2013; 18:221-234. [PMID: 23510065 PMCID: PMC3604879 DOI: 10.1615/critrevoncog.2013005814] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Gaucher's disease is a sphingolipidosis characterized by a specific deficiency in an acidic glucocerebrosidase, which results in aberrant accumulation of glucosylceramide primarily within the lysosome. Gaucher's disease has been correlated with cases of myeloma, leukemia, glioblastoma, lung cancer, and hepatocellular carcinoma, although the reasons for the correlation are currently being debated. Some suggest that the effects of Gaucher's disease may be linked to cancer, while others implicate the therapies used to treat Gaucher's disease. This debate is not entirely surprising, as the speculations linking Gaucher's disease with cancer fail to address the roles of ceramide and glucosylceramide in cancer biology. In this review, we will discuss, in the context of cancer biology, ceramide metabolism to glucosylceramide, the roles of glucosylceramide in multidrug-resistance, and the role of ceramide as an anticancer lipid. This review should reveal that it is most practical to associate elevated glucosylceramide, which accompanies Gaucher's disease, with the progression of cancer. Furthermore, this review proposes that the therapies used to treat Gaucher's disease, which augment ceramide accumulation, are likely not linked to correlations with cancer.
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Affiliation(s)
- Brian M. Barth
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | | | - Diana M. Tacelosky
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Mark Kester
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Samy A. F. Morad
- Experimental Therapeutics Program, John Wayne Cancer Institute, Santa Monica, CA, USA
| | - Myles C. Cabot
- Experimental Therapeutics Program, John Wayne Cancer Institute, Santa Monica, CA, USA
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Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, Rose C, Camou F, de Roux-Serratrice C, Grosbois B, Kaminsky P, Robert A, Caillaud C, Froissart R, Levade T, Masseau A, Mignot C, Sedel F, Dobbelaere D, Vanier MT, Valayanopoulos V, Fain O, Fantin B, de Villemeur TB, Mentré F, Belmatoug N. The French Gaucher's disease registry: clinical characteristics, complications and treatment of 562 patients. Orphanet J Rare Dis 2012; 7:77. [PMID: 23046562 PMCID: PMC3526516 DOI: 10.1186/1750-1172-7-77] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Accepted: 10/07/2012] [Indexed: 02/02/2023] Open
Abstract
Background Clinical features, complications and treatments of Gaucher’s disease (GD), a rare autosomal–recessive disorder due to a confirmed lysosomal enzyme (glucocerebrosidase) deficiency, are described. Methods All patients with known GD, living in France, with ≥1 consultations (1980–2010), were included in the French GD registry, yielding the following 4 groups: the entire cohort, with clinical description; and its subgroups: patients with ≥1 follow-up visits, to investigate complications; recently followed (2009–2010) patients; and patients treated during 2009–2010, to examine complications before and during treatment. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables. Results Among the 562 registry patients, 265 (49.6%) were females; 454 (85.0%) had type 1, 22 (4.1%) type 2, 37 (6.9%) perinatal–lethal type and 21 (3.9%) type 3. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0–77) and 22 (0–84) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (37.6% and 26.3%, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 54.7% of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. For the 378 followed patients, median follow-up was 16.2 (0.1–67.6) years. Major clinical complications were bone events (BE; avascular necrosis, bone infarct or pathological fracture) for 109 patients, splenectomy for 104, and Parkinson’s disease for 14; 38 patients died (neurological complications for 15 type-2 and 3 type-3 patients, GD complications for 11 type-1 and another disease for 9 type-1 patients). Forty-six had monoclonal gammopathy. Among 283 recently followed patients, 36 were untreated and 247 had been treated during 2009–2010; 216 patients received treatment in December 2010 (126 with imiglucerase, 45 velaglucerase, 24 taliglucerase, 21 miglustat). BE occurred before (130 in 67 patients) and under treatment (60 in 41 patients) with respective estimated frequencies (95% CI) of first BE at 10 years of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%). Conclusion This registry enabled the epidemiological description of GD in France and showed that BE occur even during treatment.
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Affiliation(s)
- Jérôme Stirnemann
- INSERM, UMR 738, Laboratoire de Biostatistiques Hôpital Bichat, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
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Abstract
The scientific and therapeutic development of imiglucerase (Cerezyme(®)) by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease.
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Affiliation(s)
- Patrick B Deegan
- Department of Medicine, University of Cambridge, Lysosomal Disorders Unit, Addenbrooke's NHS Foundation Hospitals Trust, Cambridge, UK.
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Capablo Liesa JL, de Cabezón AS, Alarcia Alejos R, Ara Callizo JR. [Clinical characteristics of the neurological forms of Gaucher's disease]. Med Clin (Barc) 2012; 137 Suppl 1:6-11. [PMID: 22230119 DOI: 10.1016/s0025-7753(11)70010-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Gaucher's disease is the most prevalent disease of accumulation of glycosphingolipids. Neurological involvement is used to classify the different types of the disease. Type 1 affects approximately 90% of patients, and visceral manifestations and bone marrow, without affecting the nervous system. Type 2 is considered a severe form of disease with severe nervous system and death within two years. Type 3 is late, slowly progressive neurological symptoms and survival until the third decade. Besides these classical syndromes, the best knowledge of the disease related to the existence of national registries, the increased survival of patients resulting from replacement therapy, and demonstration of the behavior of glucocerebrosidase mutations as a risk factor of neurodegenerative diseases, has expanded the clinical phenotype and altered the traditional classification of the disease.
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Abstract
Abstract
This review presents a cohesive approach to treating patients with Gaucher disease. The spectrum of the clinical presentation of the disease is broad, yet heretofore there was only one disease-specific treatment. In the past 2 years, a global shortage of this product has resulted in reassessment of the “one enzyme–one disease–one therapy” mantra. It has also showcased the multiple levels that engage the patient, the treating physician, and the third-party insurer in providing adequate treatment to all symptomatic patients. The key points summarizing the way I manage my patients include accurate enzymatic diagnosis with mutation analysis (for some prognostication and better carrier detection in the family), a detailed follow-up every 6-12 months (with an option to see consultants and attention to comorbidities), and initiation of enzyme replacement therapy according to symptoms or deterioration in clinically significant features or both. I do not treat patients with very mild disease, but I consider presymptomatic therapy for patients at risk, including young women with poor obstetric history. I prefer the minimal-effective dose rather than the maximally tolerated dose, and when the difference between high-dose and lower-dose regimens is (merely statistically significant but) clinically meaningless, minimizing the burden on society by advocating less-expensive treatments is ethically justified.
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D-dimer assay in Egyptian patients with Gaucher disease: correlation with bone and lung involvement. Blood Coagul Fibrinolysis 2011; 22:176-84. [PMID: 21346558 DOI: 10.1097/mbc.0b013e3283424809] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Gaucher disease is the most frequent lysosomal storage disorder. Bone and lung involvement are two major causes of morbidity in this disease. D-dimer is a reliable indicator of active microvascular thrombosis, even in patients without overt hypercoagulation. This study aimed to assess D-dimer levels in Gaucher disease, correlating this marker to clinical characteristics and radiological parameters to investigate its role as a potential predictor for the occurrence and severity of skeletal and pulmonary manifestations. The study population consisted of 56 Egyptian patients with Gaucher disease, 36 had type 1 Gaucher disease (64.3%) and 20 had type 3 Gaucher disease (35.7%). Thirty healthy individuals were enrolled as a control group. D-dimer levels were significantly higher in all patients with Gaucher disease compared with controls (P < 0.001). Patients with type 3 showed significantly higher D-dimer concentrations compared with type 1 (P < 0.001). Pulmonary involvement was present in a significant proportion among type 3 Gaucher patients (P < 0.05), whereas bone changes were present in a higher percentage in type 1 compared with type 3 Gaucher patients. D-dimers were significantly higher in patients with abnormal MRI findings of the long bones and in those with ground glass appearance on high-resolution computerized tomography of the chest compared with patients with normal radiology (P < 0.001). Splenectomized patients displayed significantly higher D-dimer levels compared with nonsplenectomized patients (P < 0.001). Our results suggest that D-dimer is significantly elevated in Gaucher disease, particularly type 3, and may be considered as a potential marker of risk prediction of bone and lung involvement that could be used to monitor treatment response.
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Mistry PK, Cappellini MD, Lukina E, Ozsan H, Mach Pascual S, Rosenbaum H, Helena Solano M, Spigelman Z, Villarrubia J, Watman NP, Massenkeil G. A reappraisal of Gaucher disease-diagnosis and disease management algorithms. Am J Hematol 2011; 86:110-5. [PMID: 21080341 DOI: 10.1002/ajh.21888] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease.
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Affiliation(s)
- Pramod K Mistry
- Department of Pediatrics and Medicine, Yale University, New Haven, Connecticut 06562, USA.
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Osteopenia in Gaucher disease develops early in life: response to imiglucerase enzyme therapy in children, adolescents and adults. Blood Cells Mol Dis 2010; 46:66-72. [PMID: 21112800 DOI: 10.1016/j.bcmd.2010.10.011] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2010] [Revised: 10/10/2010] [Accepted: 10/10/2010] [Indexed: 11/22/2022]
Abstract
BACKGROUND In Gaucher disease (GD), acid-β-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to imiglucerase enzyme therapy, differs by the age of the patient. OBJECTIVE We hypothesized that osteopenia develops early in life, during the natural course of type 1 Gaucher disease (GD1), and that its response to treatment is maximal during this period. METHODS We examined data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry of patients treated with imiglucerase between the ages of 5 and 50 years. Lumbar spine bone mineral density (BMD) (determined by dual-energy X-ray absorptiometry (DXA) and expressed as Z-scores) at baseline and for up to 10 years on imiglucerase were analyzed in children (ages ≥ 5 to <12 years), adolescents (≥ 12 to <20 years), young adults (≥ 20 to < 30 years), and older adults (≥ 30 to < 50 years). BMD was correlated with other disease characteristics. Pre-treatment, descriptive statistics were applied to 5-year age categories. Non-linear mixed effects regression models were used to analyze DXA Z-scores over time after treatment with imiglucerase. RESULTS Pre-treatment, low BMD was prevalent in all age groups, most strikingly in adolescents. DXA Z-scores were at or below -1 in 44% of children (n=43), 76% of adolescents (n=41), 54% of young adults (n=56) and 52% of older adults (n=171). The most common GBA1 genotype was N370S heteroallelic. Baseline hematological and visceral manifestations in the 4 age groups were similar. In children with DXA Z-scores ≤-1 at baseline, imiglucerase therapy for 6 years resulted in improvement of mean DXA Z-scores from -1.38 (95% CI -1.73 to -1.03) to -0.73 (95% CI -1.25 to -0.21); in young adults DXA Z-scores improved from -1.95 (95% CI -2.26 to -1.64) to -0.67 (95% CI -1.09 to -0.26). BMD also improved in older adults, but the magnitude of the improvement was lower compared to younger patients. CONCLUSIONS Low bone density is common in GD1 with the highest prevalence rate in adolescence, a developmental period critical to attainment of peak bone mass. Imiglucerase results in amelioration of osteopenia in all age groups, with the greatest improvements in younger patients.
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The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry. Blood Cells Mol Dis 2010; 46:95-102. [PMID: 21067946 DOI: 10.1016/j.bcmd.2010.10.006] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Accepted: 10/07/2010] [Indexed: 02/07/2023]
Abstract
PURPOSE Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients. METHODS STUDY TYPE Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier). DATA SOURCE The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism. RESULTS The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years. CONCLUSIONS The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.
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vom Dahl S, Mengel E. Lysosomal storage diseases as differential diagnosis of hepatosplenomegaly. Best Pract Res Clin Gastroenterol 2010; 24:619-28. [PMID: 20955964 DOI: 10.1016/j.bpg.2010.09.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 08/27/2010] [Accepted: 09/01/2010] [Indexed: 01/31/2023]
Abstract
In adults, elevated transaminases and hepatomegaly, often mild, with moderate to massive idiopathic splenomegaly might hint to a lysosomal storage disease (LSD). In most of these cases, hepatosplenomegaly does not eventually lead to cirrhosis, hepatocellular carcinoma or cholestasis. Nevertheless, the hepatic clinical findings might be the incentive for the patient to present at the physician's office. Many of the currently known >50 lysosomal storage diseases might manifest in liver: out of these, the most important ones in adults are: Gaucher disease, cholesterol ester storage disease (CESD) and the Niemann-Pick diseases. An increase of plasma chitotriosidase should alert the physician for the presence of an LSD. For Gaucher's disease, enzyme supplementation and substrate deprivation constitute effective therapeutic options. Fabry's disease, the most prevalent lysosomal storage disease, does usually not affect the liver, but causes painful episodes of hands' or feet pain (acroparesthesias), left ventricular hypertrophy, renal failure, early stroke and decreased life expectancy. The emerging advent of effective therapeutic options and the cumulative prevalence of lysosomal storage diseases urge the hepatologist to add these diagnostic pathways to the clinical repertoire.
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Affiliation(s)
- Stephan vom Dahl
- Dept. of Internal Medicine/Gastroenterology, St. Franziskus-Hospital, Academic Teaching Hospital, University of Cologne, Schoensteinstrasse 63, 50825 Cologne, Germany.
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Abstract
Ashkenazi Jewish genetic screening has expanded significantly in the past 4 decades. Individuals of Eastern European (Ashkenazi) Jewish (AJ) descent are at increased risk of having offspring with particular genetic diseases that have significant morbidity and mortality. In addition, there are some disorders, such as cystic fibrosis, for which northern European Caucasians are at comparable risk with those of an AJ background. Carrier screening for many of these Jewish genetic disorders has become standard of care. As technology advances, so does the number of disorders for which screening is available. Thus, we need to continue to be cognizant of informed consent, test sensitivity, confidentiality, prenatal diagnosis, preimplantation genetic screening, and public health concerns regarding testing.
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Puzo J, Alfonso P, Irun P, Gervas J, Pocovi M, Giraldo P. Changes in the atherogenic profile of patients with type 1 Gaucher disease after miglustat therapy. Atherosclerosis 2010; 209:515-9. [DOI: 10.1016/j.atherosclerosis.2009.10.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 10/06/2009] [Accepted: 10/07/2009] [Indexed: 11/30/2022]
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Best practices: antenatal screening for common genetic conditions other than aneuploidy. Curr Opin Obstet Gynecol 2010; 22:139-45. [DOI: 10.1097/gco.0b013e3283372379] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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