Endocrinological, immunological and metabolic features of patients with Fabry disease under therapy

Merve Emecen Sanli; Ayse Kilic; Asli Inci; Ilyas Okur; Fatih Ezgu; Leyla Tumer

doi:10.1515/jpem-2023-0105

Article

Endocrinological, immunological and metabolic features of patients with Fabry disease under therapy

Merve Emecen Sanli , Ayse Kilic , Asli Inci , Ilyas Okur , Fatih Ezgu and Leyla Tumer

Published/Copyright: May 31, 2023

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Journal of Pediatric Endocrinology and Metabolism Volume 36 Issue 7

Abstract

Objectives

Fabry disease is an X-linked lysosomal disorder caused by decreased or absent alpha galactosidase enzyme. The enzyme deficiency leads to progressive accumulation of globotriaosylceramide (Gb-3) and its deacetylated form lyso-Gb3 in various tissue lysosomes that results in primarily lysosomal deterioration and subsequently mitochondrial, endothelial, and immunologic dysfunctions.

Methods

The endocrinological, metabolic, immunological and HLA status of 12 patients were evaluated.

Results

A total of 11 patients (91.6 %) had immunologic and/or endocrinologic abnormalities. fT4, anti-TPO, and anti-TG levels were increased in 1, 2, and 2 patients, respectively. Three patients had elevated proinflammatory cytokines. ANA profile, p-ANCA and c-ANCA were positive in 1, 1, and 2 patients, respectively. Tissue transglutaminase antibody was negative in all patients however P5 was diagnosed with Celiac disease at the age of 12 and on gluten free diet. All patients had distinct types of HLA apart from 2 patients with anti-TG and anti-TPO positive and there was no relationship between the HLA types and the autoimmunity biomarkers.

Conclusions

FD may have impact on endocrinologic and immunologic abnormalities even in the patients under ERT, therefore prevalence of these abnormalities may be higher in ERT naïve patients. However, apparently, they are less likely to cause clinical symptoms. Certain HLA alleles may contribute to the direct impact of immunological pathogenesis in FD by developing abnormal autoimmune biomarkers. To the best of our knowledge, this is the first study investigating HLA status of FD patients; therefore further studies are needed to elucidate the underlying mechanism of action.

Keywords: endocrinopathy; Fabry disease; hla typing; immunopathy

Corresponding author: Merve Emecen Sanli, Department of Pediatrics, Division of Inborn Errors of Metabolism, Gazi University Medical Faculty, Ankara, Türkiye, Phone: +902129096000, E-mail: merveemecan@gmail.com

Research funding: Gazi University scientific research fund.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from parents of all individuals included in this study.
Ethical approval: The local Institutional Review Board deemed the study exempt from review.

References

1. Zarate, YA, Hopkin, RJ. Fabry’s disease. Lancet 2008;372:1427–35. https://doi.org/10.1016/s0140-6736(08)61589-5.Search in Google Scholar

2. Kok, K, Zwiers, KC, Boot, RG, Overkleeft, HS, Aerts, JMFG, Artola, M. Fabry disease: molecular basis, pathophysiology, diagnostics and potential therapeutic directions. Biomolecules 2021;11:271. https://doi.org/10.3390/biom11020271.Search in Google Scholar PubMed PubMed Central

3. Tuttolomondo, A, Pecoraro, R, Simonetta, I, Miceli, S, Pinto, A, Licata, G. Anderson-Fabry disease: a multiorgan disease. Curr Pharmaceut Des 2013;19:5974–96. https://doi.org/10.2174/13816128113199990352.Search in Google Scholar PubMed

4. Martinez, P, Aggio, M, Rozenfeld, P. High incidence of autoantibodies in Fabry disease patients. J Inherit Metab Dis 2007;30:365–9. https://doi.org/10.1007/s10545-007-0513-2.Search in Google Scholar PubMed

5. Faggiano, A, Pisani, A, Milone, F, Gaccione, M, Filippella, M, Santoro, A, et al.. Endocrine dysfunction in patients with Fabry disease. J Clin Endocrinol Metab 2006;91:4319–25. https://doi.org/10.1210/jc.2006-0858.Search in Google Scholar PubMed

6. Tümer, L, Ezgü, FS, Hasanoğlu, A, Dalgiç, B, Bakkaloğlu, SA, Memiş, L, et al.. The co-existence of Fabry and celiac diseases: a case report. Pediatr Nephrol 2004;19:679–81. https://doi.org/10.1007/s00467-004-1462-8.Search in Google Scholar PubMed

7. Afruza, R, Islam, LN, Banerjee, S, Hassan, MM, Suzuki, F, Nabi, AN. Renin gene polymorphisms in bangladeshi hypertensive population. J Genom 2014;2:45–53. https://doi.org/10.7150/jgen.5193.Search in Google Scholar PubMed PubMed Central

8. Surks, MI, Ortiz, E, Daniels, GH, Sawin, CT, Col, NF, Cobin, RH, et al.. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228–38. https://doi.org/10.1001/jama.291.2.228.Search in Google Scholar PubMed

9. Tuttolomondo, A, Simonetta, I, Riolo, R, Todaro, F, Di Chiara, T, Miceli, S, et al.. Pathogenesis and molecular mechanisms of anderson-fabry disease and possible new molecular addressed therapeutic strategies. Int J Mol Sci 2021;22:10088. https://doi.org/10.3390/ijms221810088.Search in Google Scholar PubMed PubMed Central

10. Nistal, M, Paniagua, R, Picazo, ML. Testicular and epididymal involvement in Fabry’s disease. J Pathol 1983;141:113–24. https://doi.org/10.1002/path.1711410203.Search in Google Scholar PubMed

11. Tojo, K, Oota, M, Honda, H, Shibasaki, T, Sakai, O. Possible thyroidal involvement in a case of Fabry disease. Intern Med 1994;33:172–6. https://doi.org/10.2169/internalmedicine.33.172.Search in Google Scholar PubMed

12. Murugesan, V, Chuang, WL, Liu, J, Lischuk, A, Kacena, K, Lin, H, et al.. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol 2016;91:1082–9. https://doi.org/10.1002/ajh.24491.Search in Google Scholar PubMed PubMed Central

13. Hauser, AC, Gessl, A, Harm, F, Wiesholzer, M, Kleinert, J, Wallner, M, et al.. Hormonal profile and fertility in patients with Anderson– Fabry disease. Int J Clin Pract 2005;59:1025–8. https://doi.org/10.1111/j.1742-1241.2005.00620.x.Search in Google Scholar PubMed

14. Hauser, AC, Gessl, A, Lorenz, M, Voigtländer, T, Födinger, M, Sunder-Plassmann, G. High prevalence of subclinical hypothyroidism in patients with Anderson-Fabry disease. J Inherit Metab Dis 2005;28:715–22. https://doi.org/10.1007/s10545-005-0003-3.Search in Google Scholar PubMed

15. Glaros, EN, Kim, WS, Quinn, CM, Wong, J, Gelissen, I, Jessup, W, et al.. Glycosphingolipid accumulation inhibits cholesterol efflux via the ABCA1/apolipoprotein A-I pathway: 1-phenyl-2-decanoylamino-3-morpholino-1-propanol is a novel cholesterol efflux accelerator. J Biol Chem 2005;280:24515–23. https://doi.org/10.1074/jbc.m413862200.Search in Google Scholar

16. Schueler, U, Kaneski, C, Remaley, A, Demosky, S, Dwyer, N, Blanchette-Mackie, J, et al.. A short synthetic peptide mimetic of apolipoprotein A1 mediates cholesterol and globotriaosylceramide efflux from fabry fibroblasts. JIMD Rep 2016;29:69–75. https://doi.org/10.1007/8904_2015_507.Search in Google Scholar PubMed PubMed Central

17. Thurberg, BL, Fallon, T, Mitchell, R, Aretz, T, Gordon, RE, O’Callaghan, MW. Cardiac microvascular pathology in Fabry disease evaluation of endomyocardial biopsies before and after enzyme replacement therapy. Circulation 2009;119:2561–7. https://doi.org/10.1161/circulationaha.108.841494.Search in Google Scholar

18. Stepien, KM, Hendriksz, CJ. Lipid profile in adult patients with Fabry disease – ten-year follow up. Mol Genet Metab Rep 2017;13:3–6. https://doi.org/10.1016/j.ymgmr.2017.06.010.Search in Google Scholar PubMed PubMed Central

19. Katsuta, H, Tsuboi, K, Yamamoto, H, Goto, H. Correlations between serum cholesterol and vascular lesions in fabry disease patients. Circ J 2018;82:3058–63. https://doi.org/10.1253/circj.cj-18-0378.Search in Google Scholar

20. Ersoy, M, Pişkinpaşa, H. Evaluation of endocrinological involvement and metabolic status in patients with Gaucher disease type 1 and Fabry disease under enzyme replacement therapy. J Pediatr Endocrinol Metab 2022;35:519–27. https://doi.org/10.1515/jpem-2021-0664.Search in Google Scholar PubMed

21. Rozenfeld, P, Feriozzi, S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metabol 2017;122:19–27. https://doi.org/10.1016/j.ymgme.2017.09.004.Search in Google Scholar PubMed

22. Mauhin, W, Lidove, O, Masat, E, Mingozzi, F, Mariampillai, K, Ziza, JM, et al.. Innate and adaptive immune response in Fabry disease. JIMD Rep 2015;22:1–10. https://doi.org/10.1007/8904_2014_371.Search in Google Scholar PubMed PubMed Central

23. De Francesco, PN, Mucci, JM, Ceci, R, Fossati, CA, Rozenfeld, PA. Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide. Mol Genet Metabol 2013;109:93–9. https://doi.org/10.1016/j.ymgme.2013.02.003.Search in Google Scholar PubMed

24. Shen, JS, Meng, XL, Moore, DF, Quirk, JM, Shayman, JA, Schiffmann, R, et al.. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metabol 2008;95:163–8. https://doi.org/10.1016/j.ymgme.2008.06.016.Search in Google Scholar PubMed PubMed Central

25. DeGraba, T, Azhar, S, Dignat-George, F, Brown, E, Boutière, B, Altarescu, G, et al.. Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol 2000;47:229–33. https://doi.org/10.1002/1531-8249(200002)47:2<229::aid-ana13>3.0.co;2-t.10.1002/1531-8249(200002)47:2<229::AID-ANA13>3.0.CO;2-TSearch in Google Scholar

26. Biancini, GB, Vanzin, CS, Rodrigues, DB, Deon, M, Ribas, GS, Barschak, AG, et al.. Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochim Biophys Acta 2012;1822:226–32. https://doi.org/10.1016/j.bbadis.2011.11.001.Search in Google Scholar

27. Puszczewicz, M, Iwaszkiewicz, C. Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis. Arch Med Sci 2011;7:189–94. https://doi.org/10.5114/aoms.2011.22067.Search in Google Scholar

28. Paim-Marques, L, Cavalcante, AV, Verçosa, I, Carneiro, P, Souto-Maior, M, Marques, E, et al.. Frequency of Fabry disease in a juvenile idiopathic arthritis cohort. Pediatr Rheumatol Online J 2021;19:91. https://doi.org/10.1186/s12969-021-00563-9.Search in Google Scholar

29. Whybra, C, Schwarting, A, Kriegsmann, J, Gal, A, Mengel, E, Kampmann, C, et al.. IgA nephropathy in two adolescent sisters heterozygous for Fabry disease. Pediatr Nephrol 2006;21:1251–6. https://doi.org/10.1007/s00467-006-0176-5.Search in Google Scholar

30. Halsted, CH, Rowe, JW. Occurrence of celiac sprue in a patient with Fabry’s disease. Ann Intern Med 1975;83:524–5. https://doi.org/10.7326/0003-4819-83-4-524.Search in Google Scholar

31. Garcia-Quintanilla, A, Miranzo-Navarro, D. Extraintestinal manifestations of celiac disease: 33-mer gliadin binding to glutamate receptor GRINA as a new explanation. Bioessays 2016;38:427–39. https://doi.org/10.1002/bies.201500143.Search in Google Scholar PubMed

32. Yamaji, T, Nishikawa, K, Hanada, K. Transmembrane BAX inhibitor motif containing (TMBIM) family proteins perturbs a trans-golgi network enzyme, Gb3 synthase, and reduces Gb3 biosynthesis. J Biol Chem 2010;285:35505–18. https://doi.org/10.1074/jbc.m110.154229.Search in Google Scholar PubMed PubMed Central

33. Gough, SC, Simmonds, MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genom 2007;8:453–65. https://doi.org/10.2174/138920207783591690.Search in Google Scholar PubMed PubMed Central

34. Sciurti, M, Fornaroli, F, Gaiani, F, Bonaguri, C, Leandro, G, Di Mario, F, et al.. Genetic susceptibility and celiac disease: what role do HLA haplotypes play? Acta Biomed 2018;89:17–21. https://doi.org/10.23750/abm.v89i9-S.7953.Search in Google Scholar PubMed PubMed Central

35. Alsaeid, KM, Haider, MZ, al-Awadhi, AM, Srivastva, BS, Ayoub, EM. Role of human leukocyte antigen DRB1*0307 and DRB1*0308 in susceptibility to juvenile rheumatoid arthritis. Clin Exp Rheumatol 2003;21:399–402.10.1046/j.1365-2370.2002.00253.xSearch in Google Scholar PubMed

36. Tandon, N, Zhang, L, Weetman, AP. HLA associations with Hashimoto’s thyroiditis. Clin Endocrinol 1991;34:383–6. Erratum in: Clin Endocrinol (Oxf) 1994 May;40(5):702. https://doi.org/10.1111/j.1365-2265.1991.tb00309.x.Search in Google Scholar PubMed

Received: 2023-03-09

Accepted: 2023-04-20

Published Online: 2023-05-31

Published in Print: 2023-07-26

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/jpem-2023-0105

Keywords for this article

endocrinopathy; Fabry disease; hla typing; immunopathy