Gaucher’s Disease – current state of knowledge and future perspectives?
DOI:
https://doi.org/10.12775/JEHS.2024.64.009Keywords
Gaucher's Disease, lysosomal storage disorder, glucocerebrosidase, enzyme replacement therapy, substrate reduction therapyAbstract
Introduction and purpose: Gaucher's Disease (GD), a rare genetic disorder, is a difficult challenge in genetic and metabolic disorders. The aim of this review is to provide an exploration of GD, spanning its pathophysiology to the latest advancements in diagnostic and therapeutic innovations. In this review we aimed to underscore the challenges it presents and the ongoing efforts to overcome them.
State of knowledge: GD, characterized by the accumulation of glucocerebroside, involves molecular, cellular, and systemic dysfunctions. At the molecular level, mutations in the GBA gene give rise to diverse manifestations, influencing disease severity. Cellular disruptions lead to lysosomal dysfunction, altered calcium homeostasis, and chronic inflammation, impacting various organ systems. Diagnostic approaches involve biomarkers, genetic testing, and imaging studies, each playing a crucial role in confirming the disease type and assessing its grade.
Summary: Management and treatment strategies for GD have evolved, with enzyme replacement therapy and substrate reduction therapy serving as the basics. However, challenges persist, including limited efficacy in treating neurological symptoms and the high cost of treatments. The review highlights ongoing research and future perspectives in GD therapy.
References
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017 Feb 17;18(2):441.
Mistry PK, Lopez G, Schiffmann R, Barton NW, Weinreb NJ, Sidransky E. Gaucher Disease: Progress and Ongoing Challenges. Mol Genet Metab. 2017;120(1–2):8–21.
Brodin L. Parkinson’s disease and Gaucher disease : focus on the GBA1 link [Internet]. Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience; 2024 [cited 2024 Mar 1]. Available from: http://openarchive.ki.se/xmlui/handle/10616/48972
Cormand B, Montfort M, Chabás A, Vilageliu L, Grinberg D. Genetic fine localization of the beta-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease. Hum Genet. 1997 Jul;100(1):75–9.
Dandana A, Ben Khelifa S, Chahed H, Miled A, Ferchichi S. Gaucher Disease: Clinical, Biological and Therapeutic Aspects. Pathobiology. 2015 Nov 21;83(1):13–23.
Pitcairn C, Wani WY, Mazzulli JR. Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson’s disease. Neurobiol Dis. 2019 Feb;122:72–82.
Beutler E. Discrepancies between genotype and phenotype in hematology: an important frontier. Blood. 2001 Nov 1;98(9):2597–602.
Baris HN, Cohen IJ, Mistry PK. Gaucher Disease: The Metabolic Defect, Pathophysiology, Phenotypes And Natural History. Pediatr Endocrinol Rev. 2014 Sep;12(0 1):72–81.
Cox TM. Gaucher disease: clinical profile and therapeutic developments. Biologics: Targets and Therapy. 2010 Dec 6;4:299–313.
Kinghorn KJ, Asghari AM, Castillo-Quan JI. The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson’s disease. Neural Regen Res. 2017 Mar;12(3):380–4.
Aflaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ, et al. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell. 2016 Feb;15(1):77–88.
Arévalo NB, Lamaizon CM, Cavieres VA, Burgos PV, Álvarez AR, Yañez MJ, et al. Neuronopathic Gaucher disease: Beyond lysosomal dysfunction. Frontiers in Molecular Neuroscience [Internet]. 2022 [cited 2024 Mar 4];15. Available from: https://www.frontiersin.org/articles/10.3389/fnmol.2022.934820
Korkotian E, Schwarz A, Pelled D, Schwarzmann G, Segal M, Futerman AH. Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem. 1999 Jul 30;274(31):21673–8.
Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH. Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiology of Disease. 2005 Feb 1;18(1):83–8.
Harmanci O, Bayraktar Y. Gaucher disease: New developments in treatment and etiology. World J Gastroenterol. 2008 Jul 7;14(25):3968–73.
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017 Jul 14;2:17023.
Zelová H, Hošek J. TNF-α signalling and inflammation: interactions between old acquaintances. Inflamm Res. 2013 Jul;62(7):641–51.
Mehta A. Epidemiology and natural history of Gaucher’s disease. European Journal of Internal Medicine. 2006 Nov 1;17:S2–5.
Hughes DA, Pastores GM. Gaucher Disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2024 Mar 2]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1269/
Devigili G, De Filippo M, Ciana G, Dardis A, Lettieri C, Rinaldo S, et al. Chronic pain in Gaucher disease: skeletal or neuropathic origin? Orphanet Journal of Rare Diseases. 2017 Aug 31;12(1):148.
Lutsky KF, Tejwani NC. Orthopaedic manifestations of Gaucher disease. Bull NYU Hosp Jt Dis. 2007;65(1):37–42.
Linari S, Castaman G. Clinical manifestations and management of Gaucher disease. Clin Cases Miner Bone Metab. 2015;12(2):157–64.
Hughes D, Mikosch P, Belmatoug N, Carubbi F, Cox T, Goker‐Alpan O, et al. Gaucher Disease in Bone: From Pathophysiology to Practice. J Bone Miner Res. 2019 Jun;34(6):996–1013.
Hershkop E, Bergman I, Kurolap A, Dally N, Feldman HB. Non-immune Hemolysis in Gaucher Disease and Review of the Literature. Rambam Maimonides Med J. 2021 Jul 20;12(3):e0025.
Hasiński P, Bik-Multanowski M, Koba-Wszędobył M, Walczak M, Bubnowski M, Milewska-Kranc A, et al. Choroba Gauchera – zalecenia dotyczące rozpoznawania, leczenia i monitorowania. Acta Haematologica Polonica. 2017 Oct 1;48(4):222–61.
Ramaswami U, Mengel E, Berrah A, AlSayed M, Broomfield A, Donald A, et al. Throwing a spotlight on under-recognized manifestations of Gaucher disease: Pulmonary involvement, lymphadenopathy and Gaucheroma. Molecular Genetics and Metabolism. 2021 Aug 1;133(4):335–44.
Lo SM, Liu J, Chen F, Pastores GM, Knowles J, Boxer M, et al. Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy. J Inherit Metab Dis. 2011 Jun;34(3):643–50.
Santos DM, Tiscornia G. Induced Pluripotent Stem Cell Modeling of Gaucher’s Disease: What Have We Learned? Int J Mol Sci. 2017 Apr 21;18(4):888.
Weiss K, Gonzalez A, Lopez G, Pedoeim L, Groden C, Sidransky E. The Clinical Management of Type 2 Gaucher Disease. Mol Genet Metab. 2015 Feb;114(2):110–22.
Tsitsi P, Markaki I, Waldthaler J, Machaczka M, Svenningsson P. Neurocognitive profile of adults with the Norrbottnian type of Gaucher disease. JIMD Rep. 2021 Nov 21;63(1):93–100.
Nagral A. Gaucher Disease. J Clin Exp Hepatol. 2014 Mar;4(1):37–50.
Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991 Oct;49(4):855–9.
Charrow J, Scott CR. Long-term treatment outcomes in Gaucher disease. American Journal of Hematology. 2015;90(S1):S19–24.
Dandana A, Ben Khelifa S, Chahed H, Miled A, Ferchichi S. Gaucher Disease: Clinical, Biological and Therapeutic Aspects. Pathobiology. 2015 Nov 21;83(1):13–23.
Mignot C, Doummar D, Maire I, De Villemeur TB, French Type 2 Gaucher Disease Study Group. Type 2 Gaucher disease: 15 new cases and review of the literature. Brain Dev. 2006 Jan;28(1):39–48.
Daykin E, Ryan E, Sidransky E. Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes. Mol Genet Metab. 2021 Feb;132(2):49–58.
Grabowski GA, Zimran A, Ida H. Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. American Journal of Hematology. 2015;90(S1):S12–8.
Sidransky E. Gaucher Disease: Insights from a Rare Mendelian Disorder. Discov Med. 2012 Oct;14(77):273–81.
Park JK, Orvisky E, Tayebi N, Kaneski C, Lamarca ME, Stubblefield BK, et al. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. Pediatr Res. 2003 Mar;53(3):387–95.
Bennett LL, Fellner C. Pharmacotherapy of Gaucher Disease: Current and Future Options. P T. 2018 May;43(5):274–309.
El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Mol Genet Metab. 2017;120(1–2):47–56.
Mistry PK, Sadan S, Yang R, Yee J, Yang M. Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among Hematologists–Oncologists and an opportunity for early diagnosis and intervention. American Journal of Hematology. 2007;82(8):697–701.
Weinreb NJ, Goker-Alpan O, Kishnani PS, Longo N, Burrow TA, Bernat JA, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Molecular Genetics and Metabolism. 2022 May 1;136(1):4–21.
Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest. 1994 Mar;93(3):1288–92.
Kanneganti M, Kamba A, Mizoguchi E. Role of chitotriosidase (chitinase 1) under normal and disease conditions. J Epithel Biol Pharmacol. 2012;5:1–9.
Giuffrida G, Markovic U, Condorelli A, Calafiore V, Nicolosi D, Calagna M, et al. Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review. Orphanet J Rare Dis. 2023 Feb 13;18:27.
Elstein D, Mellgard B, Dinh Q, Lan L, Qiu Y, Cozma C, et al. Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials. Molecular Genetics and Metabolism. 2017 Sep 1;122(1):113–20.
Boot RG, Verhoek M, de Fost M, Hollak CarlaEM, Maas M, Bleijlevens B, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood. 2004 Jan 1;103(1):33–9.
Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, et al. Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1. Orphanet Journal of Rare Diseases [Internet]. 2022 [cited 2024 Mar 4];17. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768924/
Simpson WL, Hermann G, Balwani M. Imaging of Gaucher disease. World J Radiol. 2014 Sep 28;6(9):657–68.
Maas M, Poll LW, Terk MR. Imaging and quantifying skeletal involvement in Gaucher disease. Br J Radiol. 2002;75 Suppl 1:A13-24.
Özdemir GN, Gündüz E. Gaucher Disease for Hematologists. Turk J Haematol. 2022 Jun;39(2):136–9.
Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009 Nov;147(4):561–70.
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 Jan 7;20:18.
Mistry PK, Cappellini MD, Lukina E, Özsan H, Pascual SM, Rosenbaum H, et al. Consensus Conference: A reappraisal of Gaucher disease - diagnosis and disease management algorithms. Am J Hematol. 2011 Jan;86(1):110–5.
Shemesh E, Deroma L, Bembi B, Deegan P, Hollak C, Weinreb NJ, et al. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database Syst Rev. 2015 Mar 27;2015(3):CD010324.
Smith L, Schapira AHV. GBA Variants and Parkinson Disease: Mechanisms and Treatments. Cells. 2022 Apr 8;11(8):1261.
Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother. 2013 Sep;47(9):1182–93.
Torralba-Cabeza MÁ, Olivera-González S, Sierra-Monzón JL. The Importance of a Multidisciplinary Approach in the Management of a Patient with Type I Gaucher Disease. Diseases. 2018 Sep;6(3):69.
Zimran A. How I treat Gaucher disease. Blood. 2011 Aug 11;118(6):1463–71.
Doneda D, Vairo FP, Lopes AL, Reischak-Oliveira Á, Schestatsky P, Bianchin MM, et al. Assessment of Basal Metabolic Rate and Nutritional Status in Patients with Gaucher Disease Type III. JIMD Rep. 2013 Dec 17;14:37–42.
Kałużna M, Trzeciak I, Ziemnicka K, Machaczka M, Ruchała M. Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review. Orphanet J Rare Dis. 2019 Dec 2;14:275.
Nevin SM, McGill BC, Kelada L, Hilton G, Maack M, Elvidge KL, et al. The psychosocial impact of childhood dementia on children and their parents: a systematic review. Orphanet J Rare Dis. 2023 Sep 7;18:277.
Parenti G, Pignata C, Vajro P, Salerno M. New strategies for the treatment of lysosomal storage diseases (Review). International Journal of Molecular Medicine. 2013 Jan 1;31(1):11–20.
Gupta N, Oppenheim I, Kauvar E, Tayebi N, Sidransky E. Type 2 Gaucher disease: phenotypic variation and genotypic heterogeneity. Blood Cells Mol Dis. 2011 Jan 15;46(1):75–84.
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