BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (−6.6 g/m2 (−11.0 to −2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration number:NCT00925301; Pre-results.

Plants can alter biotic and abiotic soil characteristics in ways that feedback to change the performance of that same plant species relative to co-occurring plants. Most evidence for this plant-soil feedback comes from greenhouse studies of potted plants, and consequently, little is known about the importance of feedback in relation to other biological processes known to structure plant communities, such as plant-plant competition. In a field experiment with three C4 grasses, negative feedback was expressed through reduced survival and shoot biomass when seedlings were planted within existing clumps of conspecifics compared with clumps of heterospecifics. However, the combined effects of feedback and competition were species-specific. Only Andropogon gerardii exhibited feedback when competition with the clumps was allowed. For Sorghastrum nutans, strong interspecific competition eliminated the feedback expressed in the absence of competition, and Schizachyrium scoparium showed no feedback at all. That arbuscular mycorrhizal (AM) fungi may play a role in the feedback was indicated by higher AM root colonization with conspecific plant neighbours. We suggest that feedback and competition should not be viewed as entirely separate processes and that their importance in structuring plant communities cannot be judged in isolation from each other.

Fabry disease is caused by mutations in the gene (GLA) that encodes α-galactosidase A (α-Gal A). The iminosugar AT1001 (GR181413A, migalastat hydrochloride, 1-deoxygalactonojirimycin) is a pharmacological chaperone that selectively binds and stabilizes α-Gal A, increasing total cellular levels and activity for some mutant forms (defined as “responsive”). In this study, we developed a cell-based assay in cultured HEK-293 cells to identify mutant forms of α-Gal A that are responsive to AT1001. Concentration-dependent increases in α-Gal A activity in response to AT1001 were shown for 49 (60%) of 81 mutant forms. The responses of α-Gal A mutant forms were generally consistent with the responses observed in male Fabry patient-derived lymphoblasts. Importantly, the HEK-293 cell responses of 19 α-Gal A mutant forms to a clinically achievable concentration of AT1001 (10 µM) were generally consistent with observed increases in α-Gal A activity in peripheral blood mononuclear cells from male Fabry patients orally administered AT1001 during Phase 2 clinical studies. This indicates that the cell-based responses can identify mutant forms of α-Gal A that are likely to respond to AT1001 in vivo. Thus, the HEK-293 cell-based assay may be a useful aid in the identification of Fabry patients with AT1001-responsive mutant forms. Hum Mutat 32:1–13, 2011. © 2011 Wiley-Liss, Inc.

Feedback between plants and arbuscular mycorrhizal (AM) fungi can affect species diversity in plant and fungal communities. Feedback depends on (1) some specificity between plants and fungi and (2) fungi exhibiting specificity either improving (positive feedback) or decreasing (negative feedback) host performance relative to other fungi. Associations between AM fungi and plant species in a serpentine grassland dominated by Andropogon gerardii, Schizachyrium scoparium, Sorghastrum nutans, and Sporobolus heterolepis were examined, and their performance consequences were evaluated. Specificity was determined from AM fungal spore abundance under plants in the field and from trap cultures established by inoculating greenhouse plants with field‐collected roots containing fungal material. Seven AM fungal species were unevenly distributed among plant species, with differences in total spore numbers and evenness. In the field, Gigaspora gigantea exhibited specificity to Sporobolus compared to Andropogon and Sorghastrum, and Glomus microcarpum exhibited specificity to Schizachyrium compared to Andropogon and Sporobolus. In trap cultures, Glomus etunicatum exhibited specificity to Andropogon compared to Sorghastrum, and an unidentified species of Glomus exhibited specificity to Sorghastrum compared to Sporobolus. The AM fungal community associated with Smilax rotundifolia, a grassland invader, was not qualitatively different from those of grasses. In the greenhouse, plant and fungal performance was examined as a function of three host plant species (excluding Sporobolus), four AM fungal species, and the same three plant species on which the fungi had been collected in the field. Fungal species affected host plant biomass and fungal performance, measured by AM root length and percentage of colonization. Compared to other fungal species, Gigaspora gigantea increased plant biomass and had a higher percentage of colonization and AM root length on both Andropogon and Schizachyrium. Glomus etunicatum, which exhibits specificity on Andropogon, depressed growth of Andropogon relative to other fungi, implicating negative feedback. Schizachyrium had reduced biomass when inoculated with Glomus microcarpum, its specific fungus. Additionally, fungi originating on a conspecific host depressed plant growth compared to fungi collected from other host species, an effect strongest for Andropogon. Percentage of AM colonization on Andropogon was also greater for fungi originating on Andropogon. The latter two effects serve as another example of negative plant–fungal feedback and could represent intraspecific fungal variation within this community. Corresponding Editor: S. H. Faeth