title: Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease.
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.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fellgiebel
authors.forename: Martin
authors.initials: M
authors.lastname: Gartenschläger
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wildberger
authors.forename: Armin
authors.initials: A
authors.lastname: Scheurich
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Katherine
authors.initials: K
authors.lastname: Sims
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D018450:Disease Progression; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000627:therapeutic use*; D056784:Leukoencephalopathies / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000473:pathology*; D055815:Young Adult; D000519:alpha-Galactosidase / Q000627:therapeutic use*
chemical_list: D007527:Isoenzymes; D000519:alpha-Galactosidase; C459420:agalsidase beta