Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta: Data from the Fabry Registry

  • William R. Wilcox
  • Ulla Feldt-Rasmussen
  • Ana Maria Martins
  • Alberto Ortiz
  • Roberta M. Lemay
  • Ana Jovanovic
  • Dominique P. Germain
  • Carmen Varas
  • Katherine Nicholls
  • Frank Weidemann
  • Robert J. Hopkin
Research Report
Part of the JIMD Reports book series (JIMD, volume 38)

Abstract

Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal symptoms (abdominal pain, diarrhea). Outcomes at baseline and last follow-up, and their change from baseline to last follow-up, were assessed. Relevant data were available for 168 female patients. Mean age at the start of ERT was 43 years and mean treatment duration 5.7 years. Baseline pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31% reported abdominal pain (p < 0.01) and 27% diarrhea (p < 0.01). The results of this Fabry Registry analysis suggest that while on sustained treatment with agalsidase beta (1.0 mg/kg every 2 weeks), both abdominal pain and diarrhea improved in many female patients with Fabry disease.

Keywords

Abdominal pain Agalsidase beta Diarrhea Enzyme replacement therapy Fabry disease Fabry registry Gastrointestinal symptoms 

Notes

Acknowledgments

The authors would like to thank the many patients who have agreed to participate in the Fabry Registry as well as the physicians and research coordinators who have entered clinical data on behalf of these patients.

Supplementary material

464154_1_En_28_MOESM1_ESM.docx (39 kb)
Supplementary Table S1 Analysis of possible risk factors for lack of ERT response and occurrence of new abdominal pain (DOCX 39 kb)
464154_1_En_28_MOESM2_ESM.docx (39 kb)
Supplementary Table S2 Analyses of possible risk factors for lack of ERT response and occurrence of new diarrhea (DOCX 38 kb)

References

  1. Banikazemi M, Ullman T, Desnick RJ (2005) Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab 85:255–259CrossRefPubMedGoogle Scholar
  2. Bernstein MT, Graff LA, Avery L, Palatnick C, Parnerowski K, Targownik LE (2014) Gastrointestinal symptoms before and during menses in healthy women. BMC Womens Health 14:14CrossRefPubMedCentralPubMedGoogle Scholar
  3. Buda P, Książyk J, Tylki-Szymanska A (2013) Gastroenterological complications of Anderson-Fabry disease. Curr Pharm Des 19:6009–6013CrossRefPubMedGoogle Scholar
  4. Echevarria L, Benistan K, Toussaint A et al (2016) X-chromosome inactivation in female patients with Fabry disease. Clin Genet 89:44–54CrossRefPubMedGoogle Scholar
  5. Eng CM, Fletcher J, Wilcox WR et al (2007) Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 30:184–192CrossRefPubMedGoogle Scholar
  6. Eng CM, Guffon N, Wilcox WR et al (2001) Safety and efficacy of recombinant human alpha-galactosidase A – replacement therapy in Fabry’s disease. N Engl J Med 345:9–16CrossRefPubMedGoogle Scholar
  7. Fabry disease mutation database (H. Sakuraba). http://fabry-database.org/mutants/old.cgi. Accessed 7 Apr 2016
  8. Germain DP (2010) Fabry disease. Orphanet J Rare Dis 5:30CrossRefPubMedCentralPubMedGoogle Scholar
  9. Germain DP, Waldek S, Banikazemi M et al (2007) Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol 18:1547–1557CrossRefPubMedGoogle Scholar
  10. Hilz MJ, Brys M, Marthol H, Stemper B, Dütsch M (2004) Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 62:1066–1072CrossRefPubMedGoogle Scholar
  11. Hoffmann B, Schwarz M, Mehta A, Keshav S (2007) Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol 5:1447–1453CrossRefPubMedGoogle Scholar
  12. Hopkin RJ, Bissler J, Banikazemi M et al (2008) Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res 64:550–555CrossRefPubMedGoogle Scholar
  13. Hopkin RJ, Cabrera G, Charrow J et al (2016) Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: data from the Fabry Registry. Mol Genet Metab 119:151–159CrossRefPubMedGoogle Scholar
  14. Kay L, Jørgensen T, Jensen KH (1994) Epidemiology of abdominal symptoms in a random population: prevalence, incidence, and natural history. Eur J Epidemiol 10:559–566CrossRefPubMedGoogle Scholar
  15. Lenders M, Canaan-Kühl S, Krämer J et al (2016) Patients with Fabry disease after enzyme replacement therapy dose reduction and switch-2-year follow-up. J Am Soc Nephrol 27:952–962CrossRefPubMedGoogle Scholar
  16. MacDermot KD, Holmes A, Miners AH (2001) Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38:769–775CrossRefPubMedCentralPubMedGoogle Scholar
  17. Pensabene L, Sestito S, Nicoletti A, Graziano F, Strisciuglio P, Concolino D (2016) Gastrointestinal symptoms of patients with Fabry disease. Gastroenterol Res Pract 2016:9712831CrossRefPubMedGoogle Scholar
  18. Politei J, Thurberg BL, Wallace E, Warnock D, Serebrinsky G, Durand C, Schenone AB (2016) Gastrointestinal involvement in Fabry disease. So important, yet often neglected. Clin Genet 89:5–9CrossRefPubMedGoogle Scholar
  19. Ramaswami U, Whybra C, Parini R et al (2006) Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr 95:86–92CrossRefPubMedGoogle Scholar
  20. Ramaswami U, Parini R, Pintos-Morell G, Kalkum G, Kampmann C, Beck M (2012) Fabry disease in children and response to enzyme replacement therapy: results from the Fabry Outcome Survey. Clin Genet 81:485–490CrossRefPubMedGoogle Scholar
  21. Ries M, Gupta S, Moore DF et al (2005) Pediatric Fabry disease. Pediatrics 115:e344–e355CrossRefPubMedGoogle Scholar
  22. Schiffmann R, Kopp JB, Austin HA 3rd et al (2001) Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285:2743–2749CrossRefPubMedGoogle Scholar
  23. Watt T, Burlina AP, Cazzorla C et al (2010) Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: findings from the Fabry Registry. Genet Med 12:703–712CrossRefPubMedGoogle Scholar
  24. Wilcox WR, Oliveira JP, Hopkin RJ et al (2008) Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 93:112–128CrossRefPubMedGoogle Scholar
  25. Wraith JE, Tylki-Szymanska A, Guffon N et al (2008) Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr 152:563–570CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • William R. Wilcox
    • 1
  • Ulla Feldt-Rasmussen
    • 2
  • Ana Maria Martins
    • 3
  • Alberto Ortiz
    • 4
  • Roberta M. Lemay
    • 5
  • Ana Jovanovic
    • 6
  • Dominique P. Germain
    • 7
  • Carmen Varas
    • 8
  • Katherine Nicholls
    • 9
    • 10
  • Frank Weidemann
    • 11
  • Robert J. Hopkin
    • 12
  1. 1.Department of Human GeneticsEmory University School of MedicineAtlantaUSA
  2. 2.Department of Medical Endocrinology, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  3. 3.Reference Center for Inborn Errors of MetabolismFederal University of São PauloSão PauloBrazil
  4. 4.Unidad de Dialisis, IIS-Fundacion Jimenez DiazUniversidad Autonoma de MadridMadridSpain
  5. 5.Strategic Epidemiology and Biostatistics, Rare Diseases, Sanofi GenzymeCambridgeUSA
  6. 6.Mark Holland Metabolic Unit, Salford Royal NHS Foundation TrustSalfordUK
  7. 7.Division of Medical GeneticsUniversity of Versailles – St Quentin en Yvelines, Paris-Saclay UniversityMontignyFrance
  8. 8.Fabry Disease Multidisciplinary Team, Departamento Dermatología y ETSHospital San Pablo de CoquimboCoquimboChile
  9. 9.Department of NephrologyRoyal Melbourne HospitalParkvilleAustralia
  10. 10.University of MelbourneParkvilleAustralia
  11. 11.Department of Internal Medicine IIKatharinen-Hospital UnnaUnnaGermany
  12. 12.Division of Human GeneticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA

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