ABSTRACT
PURPOSE: Although Fabry disease is X linked and considered to affect primarily male hemizygotes, female heterozygotes may experience all the signs and symptoms of this metabolic disorder. This prospective, single-center, open-label, clinical trial was performed to evaluate the long-term response of female patients with Fabry disease to enzyme replacement therapy. METHODS: Symptomatic women (average age = 47 years) enrolled in this 4-year study were treated with agalsidase alfa (Replagal, Shire HGT, Inc.) at a dose of 0.2 mg/kg, every other week for 4 years (N = 36). Clinical and biochemical assessments were conducted at 12-month intervals. RESULTS: The Mainz Severity Score Index, a measure of total disease burden, was significantly reduced after 12 months (P < 0.01) of treatment and continuously improved over 4 years. Brief Pain Inventory "pain at its worst" score was reduced from 4.6 +/- 2.9 at baseline to 3.3 +/- 2.9 after 12 months (P = 0.001) and remained reduced through 4 years. Mean left-ventricular mass decreased from 89.4 +/- 29.3(2.7) g/m at baseline to 66.5 +/- 29.3(2.7) g/m after 12 months (P < 0.001) and remained reduced through 4 years. Average kidney function (estimated glomerular filtration rate and proteinuria) remained constant during the study. No safety issues were identified. CONCLUSIONS: Long-term agalsidase alfa is effective and was well tolerated in women with Fabry disease.
Subject(s)
Fabry Disease/drug therapy , alpha-Galactosidase/therapeutic use , Adult , Aged , Analysis of Variance , Drug Administration Schedule , Fabry Disease/genetics , Fabry Disease/pathology , Female , Glomerular Filtration Rate/drug effects , Humans , Isoenzymes/therapeutic use , Leukocytes/enzymology , Middle Aged , Mutation , Prospective Studies , Recombinant Proteins , Severity of Illness Index , Treatment Outcome , Young Adult , alpha-Galactosidase/genetics , alpha-Galactosidase/metabolismABSTRACT
Fabry disease (FD) is an X-chromosomal disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. We performed mutation screening on a cohort of 121 patients including 84 male and 37 female index cases and identified a total of 90 different mutations, 34 of which are reported for the first time here. Both point mutations (74.4%) and 'short length' rearrangements (25.6%) were found, including missense (54.4%), nonsense (14.4%), and splice site point mutations (5.6%), deletions (17.8%) or insertions/duplications (5.6%) of a few nucleotides, and complex rearrangements including larger deletions (2.2%). GLA mutations were identified in 82 (97.6%) of the 84 unrelated male patients.