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Ophthalmic Findings During 10-year Enzyme Substitution of Danish Fabry Patients.

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ClinicalTrials.gov Identifier: NCT01997489
Recruitment Status : Completed
First Posted : November 28, 2013
Last Update Posted : October 28, 2014
Sponsor:
Information provided by (Responsible Party):
Ulla Feldt-Rasmussen, Rigshospitalet, Denmark

Brief Summary:

Fabry disease is a recessively inherited disorder due to systemic storage of abnormal metabolites (ceramide trihexocide, in particular) caused by lack of the lysosomal enzyme α-galactosidase. Though X-linked, in patient series there are often equal numbers of males (hemizygotes ) and females (heterozygotes, probably caused by a mutation in one allele and an inactivation on the other allele in the X chromosomes), and many clinical features are shared.

Abnormal storage in endothelial and smooth muscle cells explains morbidity, including a shortened life expectancy. This is due to age dependent ischaemic manifestations that affect heart, kidney and brain. Angiofibroma is an early cutaneous manifestation, and painful acro-paresthesias express juvenile neuropathy.

Cornea verticillata is an almost obligate ophthalmic finding. The brown-yellow Bowman membrane related corneal deposits and teleangiectatic conjunctival vessels are early ophthalmic slit-lamp markers of the disorder; further there can be subtle lens opacities. Fundus vessel tortuosity is observed in many patients, in particular of the retinal venules, but best corrected visual acuity (BCVA) is usually normal.

After the introduction of enzyme substitution therapy in 2001, ophthalmic examinations were scheduled as regular part of the general evaluation of the Fabry patients at Rigshospitalet, Denmark. A 10-year ophthalmic state of arts was part of oral presentations at a Copenhagen conference in December 2011. In contrast to the common occurrence of systemic vascular sequels, only one patient in the series had suffered severe visual loss; this was unilateral and occurred years before institution of the enzyme therapy. In 2013, however, another young male presented a similar retinal event. Sporadic cases of visual loss are reported in the literature, but in larger Fabry series ocular vascular catastrophes appear the exception to the rule.

Following the introduction of enzyme substitution, we found it of interest to present our nationwide Danish experience. We focused on retinal vessel morphology and the relation to systemic morbidity.


Condition or disease Intervention/treatment Phase
Fabry Disease Drug: Enzyme replacement Phase 4

Detailed Description:

Fabry disease is a recessively inherited disorder due to systemic storage of abnormal metabolites (ceramide trihexocide, in particular) caused by lack of the lysosomal enzyme α-galactosidase. Though X-linked, in patient series there are often equal numbers of males (hemizygotes ) and females (heterozygotes, probably caused by a mutation in one allele and an inactivation on the other allele in the X chromosomes), and many clinical features are shared (Cox 2005).

Abnormal storage in endothelial and smooth muscle cells explains morbidity, including a shortened life expectancy (Frost & Tanaka 1966; Desnick et al. 1976; deVeber et al.1992; Hughes & Mehta 2005; Nguyen et al. 2005; Sodi et al. 2007). This is due to age dependent ischaemic manifestations that affect heart, kidney and brain. Angiofibroma is an early cutaneous manifestation, and painful acro-paresthesias express juvenile neuropathy (Cox 2005; Cleary et al. 2005).

Cornea verticillata is an almost obligate ophthalmic finding. The brown-yellow Bowman membrane related corneal deposits and teleangiectatic conjunctival vessels are early ophthalmic slit-lamp markers of the disorder; further there can be subtle lens opacities. Fundus vessel tortuosity is observed in many patients, in particular of the retinal venules, but best corrected visual acuity (BCVA) is usually normal (Ballantyne & Michaelson 1970; Lou et al. 1970; Sher et al. 1979; Utsumi et al. 2009).

After the introduction of enzyme substitution therapy in 2001, ophthalmic examinations were scheduled as regular part of the general evaluation of the Fabry patients at Rigshospitalet, Denmark. A 10-year ophthalmic state of arts was part of oral presentations at a Copenhagen conference in December 2011. In contrast to the common occurrence of systemic vascular sequels, only one patient in the series had suffered severe visual loss; this was unilateral and occurred years before institution of the enzyme therapy (Andersen et al. 1994). In 2013, however, another young male presented a similar retinal event. Sporadic cases of visual loss are reported in the literature (Sher et al. 1978,1979; Tuupurainen et al. 1981; Sakkuraba et al. 1986; Utsumi et al. 2009), but in larger Fabry series ocular vascular catastrophes appear the exception to the rule (Orssaud et al. 2003; Hughes & Mehta 2005; Nguyen et al. 2005; Sodi et al. 2007; Utsumi et al. 2009)).

Following the introduction of enzyme substitution, we found it of interest to present our nationwide Danish experience. We focused on retinal vessel morphology and the relation to systemic morbidity.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ophthalmic Findings During 10-year Enzyme Substitution of Danish Fabry Patients
Study Start Date : September 2001
Actual Primary Completion Date : September 2013
Actual Study Completion Date : October 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Fabry patients during treatment
39 patients with Fabry disease having had baseline examinations of the eyes were assessed also at follow-up 10 years after enzyme replacement therapy
Drug: Enzyme replacement
Observational study of current treatment and with no comparative groups
Other Names:
  • Replagal
  • Fabrazyme




Primary Outcome Measures :
  1. cornea vercillitata [ Time Frame: change from baseline to 10 years ]
    Eye examination of 39 Fabry patients before starting therapy with enzyme replacement and after 10 years



Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All Danish patients with Fabry disease before starting therapy

Exclusion Criteria:

  • Missing values for eye examination at baseline or follow-up

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): NCT01997489


Locations
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Denmark
Ulla Feldt-Rasmussen
Copenhagen, Capital region, Denmark, DK-2100
National University Hospital, Department of Medical Endocrinology
Copenhagen, Denmark, DK-2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Investigators
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Principal Investigator: Ulla Feldt-Rasmussen, MD, DMSc Rigshospitalet, Denmark

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Responsible Party: Ulla Feldt-Rasmussen, Professor, chief physician, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01997489     History of Changes
Other Study ID Numbers: Fabry-Eyes-13
RH-F-2013 ( Other Identifier: Rigshospitalet )
First Posted: November 28, 2013    Key Record Dates
Last Update Posted: October 28, 2014
Last Verified: October 2014
Keywords provided by Ulla Feldt-Rasmussen, Rigshospitalet, Denmark:
Eye
Fabry
vessels
Additional relevant MeSH terms:
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Fabry Disease
Sphingolipidoses
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
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders