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Establishment of Biomarkers for Fabry Disease

This study has been completed.
ClinicalTrials.gov Identifier:
First Posted: July 20, 2010
Last Update Posted: January 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Deb Grzybowski, Ohio State University

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.

Condition Intervention
Fabry Disease Other: Fluorescein angiography

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Establishment of Biomarkers for Fabry Disease

Resource links provided by NLM:

Further study details as provided by Deb Grzybowski, Ohio State University:

Primary Outcome Measures:
  • Presence of specific findings commonly associated with Fabry's disease using neuroretinal examination [ Time Frame: every 6 months, for up to 3 years ]

Secondary Outcome Measures:
  • Capillary perfusion abnormalities in optic nerve and retina [ Time Frame: every 6 months, for up to 3 years ]

Enrollment: 4
Study Start Date: July 2010
Study Completion Date: December 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Fabry disease biomarker
Neuro-retinal fluorescein angiography (NRFA) exam will be administered once every 6 months for up to 3 years.
Other: Fluorescein angiography
Fluorescein angiography once every 6 months for 3 years

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.


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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Initially any Fabry patient, age 18 and above who has a confirmed diagnosis of Fabry disease by previously identifying plasma or leukocyte α-galactosidase A (α-gal A) deficiency, will be recruited from all participating physician practices. Those who present with evidence of angiopathy (with specific attention to the target organs: renal, cardiac, or ocular) will be recruited for the study.

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01165697

United States, Ohio
Eye and Ear Institute
Columbus, Ohio, United States, 43212
Sponsors and Collaborators
Ohio State University
Genzyme, a Sanofi Company
Principal Investigator: Deborah M Grzybowski, PhD Ohio State University
  More Information

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. 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. 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.
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. Review.
Svarstad E, Bostad L, Kaarbøe O, Houge G, Tøndel 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.
Tøndel 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.
Tøndel 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.
Tøndel C, Laegreid LM, Hirth A, Houge G, Månsson JE, Søvik O. [Intravenous enzyme substitution therapy in children with Fabry's disease]. Tidsskr Nor Laegeforen. 2003 Dec 4;123(23):3388-90. Norwegian.
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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. Review.
Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Brühl 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.
Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol. 1996 Jul;40(1):8-17.
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.
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. Review.
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.

Responsible Party: Deb Grzybowski, Research Assistant Professor, Ohio State University
ClinicalTrials.gov Identifier: NCT01165697     History of Changes
Other Study ID Numbers: 2009H0137
First Submitted: July 16, 2010
First Posted: July 20, 2010
Last Update Posted: January 13, 2017
Last Verified: January 2017

Keywords provided by Deb Grzybowski, Ohio State University:
Fabry Disease
vascular disease
storage endotheliopathy

Additional relevant MeSH terms:
Fabry Disease
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Metabolism, Inborn Errors
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders

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