Abstract
Amaç: Bu çalışmanın temel amacı düzenli tedavinin anahtar hastalık belirteci Lyso-Gb1 üzerindeki etkisini araştırmaktır. Ayrıca bu araştırma, hasta grubunda splenektominin Lyso-Gb1 konsantrasyonları üzerindeki etkisini değerlendirmeyi amaçlamaktadır.
Gereç ve Yöntem: Gaucher Hastalığı (GH) tanısı alan 37 hasta tedavi durumuna göre üç gruba ayrıldı: Tedavilerini tutarlı bir şekilde takip eden düzenli tedavi grubunda 28; düzensiz tedavi grubunda 6 ve henüz tedavi almayan grupta 3 hasta mevcuttu. GH olmayan 33 sağlıklı bireyden oluşan bir kontrol grubu da dahil edildi. Tedavi rejimi olarak enzim replasman tedavisi kullanıldı. Lyso-Gb1 seviyelerinin analizi, ölçümde yüksek hassasiyet sağlayan tandem kütle spektrometresi ile birleştirilmiş sıvı kromatografisi kullanılarak gerçekleştirildi.
Bulgular: Lyso-Gb1 seviyeleri Gaucher hastalarında sağlıklı kontrol grubuyla karşılaştırıldığında anlamlı derecede yüksekti (p<0.05), bu da bunun spesifik bir biyobelirteç olma potansiyelini doğruluyor. Tedavi, Lyso-Gb1 seviyelerinde bir azalma ile ilişkilendirildi (p<0.05). Tedavi edilen Tip 1 ve Tip 3 GH arasında Lyso-Gb1 düzeyleri açısından anlamlı bir fark gözlenmedi (p>0,05). Özellikle splenektomi yapılan hastalarda, yapılmayanlara göre anlamlı derecede daha yüksek Lyso-Gb1 seviyeleri sergilendi (p<0.05).
Sonuç: Bulgularımız Lyso-Gb1'in GH için spesifik bir biyobelirteç olarak kullanımını desteklemektedir. Tedavi edilen grupta tedavi öncesi Lyso-Gb1 seviyeleri bilinmemekle birlikte, sonuçlarımız Lyso-Gb1'in GD'de hastalığın ilerlemesini ve tedavi etkinliğini izlemedeki rolünü daha fazla aydınlatmak için daha büyük, boylamsal çalışmalara olan ihtiyacın altını çiziyor.
References
- Brady R, Kanfer J, Bradley R, Shapiro D. Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease. The Journal of clinical investigation. 1966;45(7):1112-5.
- Beutler E. Gaucher disease. The metabolic and molecular bases of inherited disease. 2001:3635-68.
- Karaca E, Kalkan S, Onay H, Aykut A, Coker M, Ozkinay F. Analysis of the β-glucocerebrosidase gene in Turkish Gaucher disease patients: mutation profile and description of a novel mutant allele. Journal of Pediatric Endocrinology and Metabolism. 2012;25(9-10):957-62.
- Gumus E, Karhan AN, Hizarcioglu-Gulsen H, Demir H, Ozen H, Temizel INS, et al. Clinical-genetic characteristics and treatment outcomes of Turkish children with Gaucher disease type 1 and type 3: A sixteen year single-center experience. European Journal of Medical Genetics. 2021;64(11):104339.
- Bulut FD, Kör D, Şeker-Yılmaz B, Hergüner Ö, Ceylaner S, Özkınay F, et al. Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey. Metabolic Brain Disease. 2018;33:1223-7.
- Biegstraaten M, Cox T, Belmatoug N, Berger M, Collin-Histed T, Vom Dahl S, et al. Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells, Molecules, and Diseases. 2018;68:203-8.
- Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K, Lin H, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. American journal of hematology. 2016;91(11):1082-9.
- Ouyang Y, Chen B, Pan X, Wang Z, Ren H, Xu Y, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease. Experimental and therapeutic medicine. 2018;15(4):3733-42.
- Elstein D, Abrahamov A, Hadas‐Halpern I, Zimran A. Withdrawal of enzyme replacement therapy in Gaucher's disease. British journal of haematology. 2000;110(2):488-92.
- Vom Dahl S, Poll LW, Häussinger D. Clinical monitoring after cessation of enzyme replacement therapy in M. Gaucher. British Journal of Haematology. 2001;113(4):1084-5.
- Czartoryska B, Tylki-Szymańska A, Ługowska A. Changes in serum chitotriosidase activity with cessation of replacement enzyme (cerebrosidase) administration in Gaucher disease. Clinical Biochemistry. 2000;33(2):147-9.
- Schwartz IVD, Karam S, Ashton-Prolla P, Michelin K, Coelho J, Pires RF, et al. Effects of imilglucerase withdrawal on an adult with Gaucher disease. British Journal of Haematology. 2001;113(4).
- Dinur T, Bauer P, Beetz C, Cozma C, Becker-Cohen M, Istaiti M, et al. Contribution of Glucosylsphingosine (Lyso-Gb1) to Treatment Decisions in Patients with Gaucher Disease. International Journal of Molecular Sciences. 2023;24(4):3945.
- Elstein D, Abrahamov A, Hadas-Halpern I, Meyer A, Zimran A. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM: monthly journal of the Association of Physicians. 1998;91(7):483-8.
- Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. Journal of human genetics. 2007;52(5):391-6.
- Mao X-Y, Burgunder J-M, Zhang Z-J, An X-K, Zhang J-H, Yang Y, et al. Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China. Neuroscience letters. 2010;469(2):256-9.
- Ida H, Watanabe Y, Sagara R, Inoue Y, Fernandez J. An observational study to investigate the relationship between plasma glucosylsphingosine (lyso-Gb1) concentration and treatment outcomes of patients with Gaucher disease in Japan. Orphanet Journal of Rare Diseases. 2022;17(1):401.
- Saville JT, McDermott BK, Chin SJ, Fletcher JM, Fuller M. Expanding the clinical utility of glucosylsphingosine for Gaucher disease. Journal of Inherited Metabolic Disease. 2020;43(3):558-63.
- Tylki-Szymańska A, Szymańska-Rożek P, Hasiński P, Ługowska A. Plasma chitotriosidase activity versus plasma glucosylsphingosine in wide spectrum of Gaucher disease phenotypes–A statistical insight. Molecular Genetics and Metabolism. 2018;123(4):495-500.
- Chipeaux C, de Person M, Burguet N, de Villemeur TB, Rose C, Belmatoug N, et al. Optimization of ultra high pressure liquid chromatography–tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher’s disease. Journal of Chromatography a. 2017;1525:116-25.
Abstract
Aim/Objective: The primary goal of this study is to explore the impact of consistent treatment on key disease marker, Lyso-Gb1. Additionally, this research aims to evaluate the influence of splenectomy on Lyso-gb1 concentrations within the patient group.
Materials and Methods: 37 patients diagnosed with GD were categorized based on treatment compliance into three groups: 28 in the regular treatment group, who consistently followed their treatment; 6 in the irregular treatment group, with inconsistent treatment adherence; and 3 in the untreated group. A control group of 33 healthy individuals without GD was also included. Enzyme replacement therapy was utilized as the treatment regimen. The analysis of Lyso-Gb1 levels was performed using liquid chromatography coupled with tandem mass spectrometry, ensuring high precision in measurement.
Results: Lyso-Gb1 levels were significantly higher in GD patients compared to the healthy control group (p<0.05), affirming its potential as a specific biomarker. Treatment was associated with a reduction in Lyso-Gb1 levels (p<0.05). No significant difference in Lyso-Gb1 levels was observed between treated patients with Type 1 and Type 3 GD (p>0.05). Notably, patients who underwent splenectomy exhibited significantly higher Lyso-Gb1 levels than those who did not (p<0.05).
Conclusion: Our findings support the utility of Lyso-Gb1 as a specific biomarker for GD. While pre-treatment Lyso-Gb1 levels in the treated group remain unknown, our results underscore the need for larger, longitudinal studies to further elucidate Lyso-Gb1's role in monitoring disease progression and treatment efficacy in GD.
Ethical Statement
Ethics approval and consent to participate: The study was approved by the Medical Research Ethics Committee of Ege University Faculty of Medicine (Document Number: 19-12T/14). Written informed consent was obtained from the participants or the parents of participants under 18 to include in the study. The study was done by the principles outlined in the Helsinki Declaration (1964). Consent for publication: A written informed consent for the publication of this manuscript, including identifying images and other personal and clinical details, was obtained from the participants and parents or legal guardians of all participants under the age of 18. Competing interests: None of the authors has any competing interests in the manuscript.
Supporting Institution
This research was supported by Pfizer. The sponsor had no role in the design, writing, execution, or interpretation of the results.
Thanks
The authors thank the patients and/or their parents for helping us improve the care of the GD patients through the blood samples and the use of information collected through our electronic health record systems.
References
- Brady R, Kanfer J, Bradley R, Shapiro D. Demonstration of a deficiency of glucocerebroside-cleaving enzyme in Gaucher's disease. The Journal of clinical investigation. 1966;45(7):1112-5.
- Beutler E. Gaucher disease. The metabolic and molecular bases of inherited disease. 2001:3635-68.
- Karaca E, Kalkan S, Onay H, Aykut A, Coker M, Ozkinay F. Analysis of the β-glucocerebrosidase gene in Turkish Gaucher disease patients: mutation profile and description of a novel mutant allele. Journal of Pediatric Endocrinology and Metabolism. 2012;25(9-10):957-62.
- Gumus E, Karhan AN, Hizarcioglu-Gulsen H, Demir H, Ozen H, Temizel INS, et al. Clinical-genetic characteristics and treatment outcomes of Turkish children with Gaucher disease type 1 and type 3: A sixteen year single-center experience. European Journal of Medical Genetics. 2021;64(11):104339.
- Bulut FD, Kör D, Şeker-Yılmaz B, Hergüner Ö, Ceylaner S, Özkınay F, et al. Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey. Metabolic Brain Disease. 2018;33:1223-7.
- Biegstraaten M, Cox T, Belmatoug N, Berger M, Collin-Histed T, Vom Dahl S, et al. Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells, Molecules, and Diseases. 2018;68:203-8.
- Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K, Lin H, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. American journal of hematology. 2016;91(11):1082-9.
- Ouyang Y, Chen B, Pan X, Wang Z, Ren H, Xu Y, et al. Clinical significance of plasma globotriaosylsphingosine levels in Chinese patients with Fabry disease. Experimental and therapeutic medicine. 2018;15(4):3733-42.
- Elstein D, Abrahamov A, Hadas‐Halpern I, Zimran A. Withdrawal of enzyme replacement therapy in Gaucher's disease. British journal of haematology. 2000;110(2):488-92.
- Vom Dahl S, Poll LW, Häussinger D. Clinical monitoring after cessation of enzyme replacement therapy in M. Gaucher. British Journal of Haematology. 2001;113(4):1084-5.
- Czartoryska B, Tylki-Szymańska A, Ługowska A. Changes in serum chitotriosidase activity with cessation of replacement enzyme (cerebrosidase) administration in Gaucher disease. Clinical Biochemistry. 2000;33(2):147-9.
- Schwartz IVD, Karam S, Ashton-Prolla P, Michelin K, Coelho J, Pires RF, et al. Effects of imilglucerase withdrawal on an adult with Gaucher disease. British Journal of Haematology. 2001;113(4).
- Dinur T, Bauer P, Beetz C, Cozma C, Becker-Cohen M, Istaiti M, et al. Contribution of Glucosylsphingosine (Lyso-Gb1) to Treatment Decisions in Patients with Gaucher Disease. International Journal of Molecular Sciences. 2023;24(4):3945.
- Elstein D, Abrahamov A, Hadas-Halpern I, Meyer A, Zimran A. Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease. QJM: monthly journal of the Association of Physicians. 1998;91(7):483-8.
- Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. Journal of human genetics. 2007;52(5):391-6.
- Mao X-Y, Burgunder J-M, Zhang Z-J, An X-K, Zhang J-H, Yang Y, et al. Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China. Neuroscience letters. 2010;469(2):256-9.
- Ida H, Watanabe Y, Sagara R, Inoue Y, Fernandez J. An observational study to investigate the relationship between plasma glucosylsphingosine (lyso-Gb1) concentration and treatment outcomes of patients with Gaucher disease in Japan. Orphanet Journal of Rare Diseases. 2022;17(1):401.
- Saville JT, McDermott BK, Chin SJ, Fletcher JM, Fuller M. Expanding the clinical utility of glucosylsphingosine for Gaucher disease. Journal of Inherited Metabolic Disease. 2020;43(3):558-63.
- Tylki-Szymańska A, Szymańska-Rożek P, Hasiński P, Ługowska A. Plasma chitotriosidase activity versus plasma glucosylsphingosine in wide spectrum of Gaucher disease phenotypes–A statistical insight. Molecular Genetics and Metabolism. 2018;123(4):495-500.
- Chipeaux C, de Person M, Burguet N, de Villemeur TB, Rose C, Belmatoug N, et al. Optimization of ultra high pressure liquid chromatography–tandem mass spectrometry determination in plasma and red blood cells of four sphingolipids and their evaluation as biomarker candidates of Gaucher’s disease. Journal of Chromatography a. 2017;1525:116-25.
Details
| Primary Language | English |
|---|---|
| Subjects | Pediatric Metabolism Diseases |
| Journal Section | Research Articles |
| Authors | |
| Publication Date | December 9, 2024 |
| Submission Date | May 6, 2024 |
| Acceptance Date | July 19, 2024 |
| Published in Issue | Year 2024 |