- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01165697
Establishment of Biomarkers for Fabry Disease
Fabry disease, an x-linked recessive lysosomal storage disease (LSD) is commonly recognized as a cause of renal failure in involved men and more recently recognized in women too. Women are involved in significant numbers and with complications, as are men, of vascular disease. This manifests as unexpected strokes in young adults. We have morphologic evidence that storage-endotheliopathy induced microvascular disease is the cause of cardiopathy and of cryptogenic strokes, and that storage endotheliopathy starts in early life, probably before birth. Based on our earlier work with other endotheliopathies such as diabetes mellitus, Susac syndrome, and hypertension, we will find and study patients using unique methods, neuro-retinal fluorescein angiography (NRFA), that we have developed for this purpose. These methods include NRFA to demonstrate capillary perfusion in the optic nerve head and retinal quadrants. We anticipate, based on our earlier experience with other endotheliopathies, that we will show more vascular pathology earlier than previously reported. Using epidemiologic and genetic tools we will find more patients than previously known or expected. It will offer opportunity for earlier diagnosis, prognosis, and response to enzyme replacement therapy.
We hypothesize that Fabry disease is a poorly recognized and poorly characterized cause of microvascular disease and cryptogenic strokes in young women and men. Neuroretinal capillary perfusion abnormalities in Fabry disease will be predictive of equivalent vascular disease in kidney, heart, brain and other organs, and further that it will be responsive to change induced by enzyme replacement therapy treatment.
Study Overview
Detailed Description
Specific Aims
Specific Aim 1. To demonstrate the specificity and sensitivity of the diagnostic capabilities of a neuroretinal examination which includes slit lamp and fundoscopy, and NRFA for the diagnosis of Fabry disease on a subject population of identified FD patients.
Specific Aim 2. To show capillary perfusion abnormalities in optic nerve and retina using neuroretinal fluorescein angiography in patients with Fabry disease and compare these to renal (measured by GFR).
Specific Aim 3. To show that the change in capillary perfusion studies when compared to baseline in response to enzyme replacement therapy treatment over time, as a manifestation of tissue burden and prognosis is a more sensitive biomarker of the extent of patient disease than corneal keratopathy.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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Ohio
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Columbus, Ohio, United States, 43212
- Eye and Ear Institute
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- Fabry patient
- evidence of angiopathy (renal, cardiac, or ocular)
- Patients above the age of 18
Exclusion Criteria:
- Patients unable or unwilling to provide written informed consent will not be recruited
- Patients who are below the age of 18
- Patients who have not or will not be undergoing Fluorescein angiography
- Allergy to fluorescein
- Pregnant women and fetuses are exclude from the study due to risks related to fluorescein and no direct benefit to the pregnant woman and fetus
Study Plan
How is the study designed?
Design Details
- Observational Models: Case-Only
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
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Fabry disease biomarker
Neuro-retinal fluorescein angiography (NRFA) exam will be administered once every 6 months for up to 3 years.
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Fluorescein angiography once every 6 months for 3 years
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Presence of specific findings commonly associated with Fabry's disease using neuroretinal examination
Time Frame: every 6 months, for up to 3 years
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every 6 months, for up to 3 years
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Capillary perfusion abnormalities in optic nerve and retina
Time Frame: every 6 months, for up to 3 years
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every 6 months, for up to 3 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Deborah M Grzybowski, PhD, Ohio State University
Publications and helpful links
General Publications
- Caggana M, Ashley GA, Desnick RJ, Eng CM. Fabry disease: molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at Xq22.1. Am J Med Genet. 1997 Aug 22;71(3):329-35.
- Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007 Apr;30(2):184-92. doi: 10.1007/s10545-007-0521-2. Epub 2007 Mar 8.
- Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP; Fabry Registry. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008 Feb;93(2):112-28. doi: 10.1016/j.ymgme.2007.09.013. Epub 2007 Nov 26.
- Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M, Desnick RJ. Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. J Comput Assist Tomogr. 2004 Mar-Apr;28(2):158-68. doi: 10.1097/00004728-200403000-00002.
- Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006 Sep;8(9):539-48. doi: 10.1097/01.gim.0000237866.70357.c6.
- Svarstad E, Bostad L, Kaarboe O, Houge G, Tondel C, Lyngdal PT, Iversen BM. Focal and segmental glomerular sclerosis (FSGS) in a man and a woman with Fabry's disease. Clin Nephrol. 2005 May;63(5):394-401. doi: 10.5414/cnp63394.
- Tondel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008 May;51(5):767-76. doi: 10.1053/j.ajkd.2007.12.032. Epub 2008 Mar 20. Erratum In: Am J Kidney Dis. 2009 Mar;53(3):567.
- Tondel C, Bostad L, Laegreid LM, Houge G, Svarstad E. Prominence of glomerular and vascular changes in renal biopsies in children and adolescents with Fabry disease and microalbuminuria. Clin Ther. 2008;30 Suppl B:S42. doi: 10.1016/s0149-2918(08)80036-7. No abstract available.
- Tondel C, Laegreid LM, Hirth A, Houge G, Mansson JE, Sovik O. [Intravenous enzyme substitution therapy in children with Fabry's disease]. Tidsskr Nor Laegeforen. 2003 Dec 4;123(23):3388-90. Norwegian.
- Strujic BJ, Jeren T. Fabry disease--a diagnostic and therapeutic problem. Ren Fail. 2005;27(6):783-6. doi: 10.1080/08860220500244856.
- Gilbert-Barness E. Review: Metabolic cardiomyopathy and conduction system defects in children. Ann Clin Lab Sci. 2004 Winter;34(1):15-34.
- Kampmann C, Wiethoff CM, Perrot A, Beck M, Dietz R, Osterziel KJ. The heart in Anderson Fabry disease. Z Kardiol. 2002 Oct;91(10):786-95. doi: 10.1007/s00392-002-0848-5.
- Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Bruhl K, Gal A, Bunge S, Beck M. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis. 2001 Dec;24(7):715-24. doi: 10.1023/a:1012993305223.
- Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996 Jul;40(1):8-17. doi: 10.1002/ana.410400105.
- Mehta A, Ginsberg L; FOS Investigators. Natural history of the cerebrovascular complications of Fabry disease. Acta Paediatr Suppl. 2005 Mar;94(447):24-7; discussion 9-10. doi: 10.1111/j.1651-2227.2005.tb02106.x.
- Michels H, Mengel E. Lysosomal storage diseases as differential diagnoses to rheumatic disorders. Curr Opin Rheumatol. 2008 Jan;20(1):76-81. doi: 10.1097/BOR.0b013e3282f169fe.
- Knowles SR, Weber EA, Berbrayer CS. Allergic reaction to fluorescein dye: successful one-day desensitization. Can J Ophthalmol. 2007 Apr;42(2):329-30.
- Cook SC, Ferketich AK, Raman SV. Myocardial ischemia in asymptomatic adults with repaired aortic coarctation. Int J Cardiol. 2009 Mar 20;133(1):95-101. doi: 10.1016/j.ijcard.2007.12.015. Epub 2008 Feb 11.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Metabolic Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Metabolism, Inborn Errors
- Lysosomal Storage Diseases
- Lipid Metabolism Disorders
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Sphingolipidoses
- Lysosomal Storage Diseases, Nervous System
- Cerebral Small Vessel Diseases
- Lipidoses
- Lipid Metabolism, Inborn Errors
- Fabry Disease
Other Study ID Numbers
- 2009H0137
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