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Enzyme Replacement Therapy in Fabry Disease

This study has been terminated.
(Difficulties in the patient's enrolment)
Information provided by (Responsible Party):
Mario Negri Institute for Pharmacological Research Identifier:
First received: September 6, 2005
Last updated: November 7, 2014
Last verified: November 2014

Fabry disease is an X-linked rare metabolic disease, caused by a deficient activity of the hydrolase α-Galactosidase A, and characterized by a progressive and systematic deposition of glycosphingolipids in many organs.

The disease is most severe in affected males. In the classic form (where the enzyme activity is absent) the clinical findings are represented by pain and paresthesias in the extremities, vessel ectasia (called angiokeratoma) in skin and mucous membranes, and hypohidrosis (a reduced sweating) during childhood or adolescence. Corneal and lenticular opacities may be present. Proteinuria, renal impairment,cardiac and neurological lesions develop with time, together with hypertension. When end stage renal disease occurs, dialysis or renal transplantation may be necessary. In heterozygous females a residual enzymatic activity may be demonstrated and they usually have asymptomatic or later onset disease manifestations, although rarely they could develop a disease as severe as in males.

A cardiac and a renal variant, where the heart and kidney are the only organs involved by the disease have been described too.

The recombinant human α-galactosidase A is now available for patients. Infusions of the enzyme replacement treatment have been demonstrated to be safe and effective. This study wants to evaluate the long term efficacy of enzyme replacement therapy in patients with Fabry disease and renal involvement.

Clinical period evaluations together with a genetic counselling will be offered to each patient.

Condition Intervention
Fabry Disease Other: Biochemical analyses.

Study Type: Observational
Study Design: Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Evaluation of the Long Term Efficacy of Enzyme Replacement Therapy in Fabry Disease

Resource links provided by NLM:

Further study details as provided by Mario Negri Institute for Pharmacological Research:

Biospecimen Retention:   Samples With DNA
Whole blood on EDTA. Serum. Urine samples.

Enrollment: 2
Study Start Date: December 2002
Study Completion Date: November 2014
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Patients with Fabry disease Other: Biochemical analyses.
Biochemical analyses.

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Detailed Description:

INTRODUCTION Fabry disease is an X-linked error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal hydrolase α-galactosidase A (α-gal A) in tissues and fluids of affected hemizygous males; most heterozygous females have an intermediate level of enzymatic activity. The enzymatic defect leads to a systemic deposition of glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and in the lysosomes of endothelial, perithelial, and smooth-muscle cells of blood vessels. Deposition also occurs in ganglion cells.

Clinical manifestations in classically affected hemizygotes (with absent α-gal A activity), include pain and paresthesias in the extremities, vessel ectasia (angiokeratoma) in skin and mucous membranes, and hypohidrosis during childhood or adolescence. Corneal and lenticular opacities are early findings. With increasing age, proteinuria and renal impairment lead to hypertension and uremia. Renal failure typically occurs in the third-fifth decades of life, and these patients need chronic hemodialysis and/or renal transplantation.

Atypical hemizygotes with residual α-gal A activity may be asymptomatic or have late-onset, mild disease manifestations primarily limited to the heart (the "cardiac variant"). Recently a renal variant has been identified too. Heterozygous females may have an attenuated form of the disease.The most frequent clinical finding in females is the characteristic whorl-like corneal epithelial dystrophy. They usually are asymptomatic, although rarely can be severely affected as hemizygous males.

In the kidney accumulation of glycosphingolipids appear in the sequence in endothelial and epithelial cells of the glomerulus and of Bowman's space, epithelium of the loops of Henle and in distal tubules till proximal tubules, interstitial histiocytes and fibrocytes. Lipid-laden distal tubular epithelial cells desquamate and may be detected in the urinary sediment.

Renal blood vessels may be involved progressively and extensively. An early finding is arterial fibrinoid deposits. Other histologic renal findings are severe arteriolar sclerosis, glomerular atrophy and fibrosis, pseudotubular proliferation of residual glomerular epithelium, tubular atrophy and diffuse interstitial fibrosis. Preliminary studies of enzyme replacement therapy demonstrate that periodic infusions of recombinant human α-galactosidase A are safe and effective in patients with Fabry disease.

The purpose of this study is to evaluate the long term efficacy of enzyme replacement therapy in patients with Fabry disease and renal involvement.

AIM Primary

  • To evaluate the effect of enzyme replacement therapy on the rate of decline in the glomerular filtration rate (GFR, measured by inulin clearance) in Fabry patients with renal involvement
  • To evaluate the biological activity of recombinant human galactosidase in terms of clearance of plasma Gb3 (that is directly correlated with renal endothelial glycosphingolipid clearance) Secondary

To evaluate the effect of enzyme replacement therapy on:

  • 24-hour urinary protein excretion
  • renal plasma flow (PAH renal clearance)
  • glomerular perm-selectivity (fractional dextran clearances)
  • end stage renal failure, kidney transplantation or death
  • systolic and diastolic blood pressure
  • cardiac anomalies (left ventricular hypertrophy, arrhythmias, conduction anomalies)
  • cutaneous anomalies
  • ocular anomalies DESIGN Twenty patients (males and females) with Fabry disease, and renal involvement, referred to the SMIMAF - Studio Multicentrico Italiano sulla Malattia di Anderson-Fabry - will be enrolled in the study.

Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with Fabry disease.

Inclusion Criteria:

  • age ≥ 16 years and ≤ 65 years
  • clinical diagnosis of Fabry disease, confirmed by α-galactosidase A assay and detection of mutation in α-GalA gene
  • serum creatinine ≥ 1.4 mg/dl (females) and ≥ 1.6 mg/dl (males) and/or proteinuria ≥ 0.4 g/24h
  • written informed consent

Exclusion Criteria:

  • any clinically relevant condition that may affect study participation and/or study results
  • inability to fully understand the purpose and the risks of the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00149318

Clinical Research Center for Rare Diseases
Ranica, Bergamo, Italy, 24020
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Principal Investigator: Erica Daina, MD Mario Negri Institute
  More Information

Responsible Party: Mario Negri Institute for Pharmacological Research Identifier: NCT00149318     History of Changes
Other Study ID Numbers: FABRY DISEASE
Study First Received: September 6, 2005
Last Updated: November 7, 2014

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 processed this record on July 24, 2017