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Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease.
Cerebrovasc Dis. 2014; 38(6):448-56.CD

Abstract

BACKGROUND

The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown.

METHODS

The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up.

RESULTS

MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n=25 on ERT, n=16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n=11, 39-68 years) showed an increase in the number of WMLs (p=0.005). A greater proportion of younger patients (≤50 years) on ERT (n=18) had stable WML burden compared with younger patients in the placebo group (n=13): 44% (8 of 18) versus 31% (4 of 13), p=0.014. The number needed to treat was 8.

CONCLUSIONS

This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk.

Authors+Show Affiliations

Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase IV
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25502511

Citation

Fellgiebel, Andreas, et al. "Enzyme Replacement Therapy Stabilized White Matter Lesion Progression in Fabry Disease." Cerebrovascular Diseases (Basel, Switzerland), vol. 38, no. 6, 2014, pp. 448-56.
Fellgiebel A, Gartenschläger M, Wildberger K, et al. Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovasc Dis. 2014;38(6):448-56.
Fellgiebel, A., Gartenschläger, M., Wildberger, K., Scheurich, A., Desnick, R. J., & Sims, K. (2014). Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovascular Diseases (Basel, Switzerland), 38(6), 448-56. https://doi.org/10.1159/000369293
Fellgiebel A, et al. Enzyme Replacement Therapy Stabilized White Matter Lesion Progression in Fabry Disease. Cerebrovasc Dis. 2014;38(6):448-56. PubMed PMID: 25502511.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. AU - Fellgiebel,Andreas, AU - Gartenschläger,Martin, AU - Wildberger,Kerstin, AU - Scheurich,Armin, AU - Desnick,Robert J, AU - Sims,Katherine, Y1 - 2014/12/11/ PY - 2014/06/03/received PY - 2014/10/21/accepted PY - 2014/12/16/entrez PY - 2014/12/17/pubmed PY - 2015/9/15/medline SP - 448 EP - 56 JF - Cerebrovascular diseases (Basel, Switzerland) JO - Cerebrovasc. Dis. VL - 38 IS - 6 N2 - BACKGROUND: The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown. METHODS: The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up. RESULTS: MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n=25 on ERT, n=16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n=11, 39-68 years) showed an increase in the number of WMLs (p=0.005). A greater proportion of younger patients (≤50 years) on ERT (n=18) had stable WML burden compared with younger patients in the placebo group (n=13): 44% (8 of 18) versus 31% (4 of 13), p=0.014. The number needed to treat was 8. CONCLUSIONS: This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk. SN - 1421-9786 UR - https://www.unboundmedicine.com/medline/citation/25502511/Enzyme_replacement_therapy_stabilized_white_matter_lesion_progression_in_Fabry_disease_ L2 - https://www.karger.com?DOI=10.1159/000369293 DB - PRIME DP - Unbound Medicine ER -