With the advent of enzyme replacement therapy, it is important that general practitioners and physicians in a range of specialties recognize the signs and symptoms of Fabry disease so that effective treatment can be given. Baseline data from FOS demonstrate that enzyme replacement therapy should not be restricted to hemizygous men, but should be considered for both heterozygous females and children.

Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P [41][42][43][44][45][46][47][48][49] ) with 100% homology to the bacterial adhesin FimH, with which they Correspondence should be addressed to R.K. (renate.kain@meduniwien.ac.at). 7 Present addresses: Interne, Hämato-Onkologie, Krankenhaus der Elisabethinen, Fadingerstrasse 1, 4010 Linz, Austria (R.Z.) and Vela Laboratories. Entwicklung und Laboranalytik Gesellschaft mit beschränkter Haftung, Brunnerstrasse 69/3, 1230 Wien, Austria (R.J.). 8 These authors contributed equally to this work. Here we establish that autoantibodies to human LAMP-2 are highly prevalent in pauci-immune FNGN and provide evidence of their pathogenicity by showing that they activate neutrophils and kill human blood microvascular endothelium in vitro and cause pauci-immune FNGN when administered to rodents. Unexpectedly, auto-antibodies to LAMP-2 in individuals with FNGN commonly recognize an epitope with considerable homology to the bacterial adhesin FimH and cross-react with it. We therefore determined whether exposure to FimH could induce antibodies to human LAMP-2 and initiate pauci-immune FNGN through molecular mimicry. The results lead us to propose a previously undescribed molecular mechanism both for the induction and development of injury in this human disease. RESULTS Autoantibodies to human LAMP-2 are common in FNGNWe established the prevalence of autoantibodies to hLAMP-2 in sera from 84 individuals with biopsy-proven active pauci-immune FNGN, either at presentation (n = 62) or during relapse (n = 22). ANCA were detectable by standard immunofluorescence assays in 80 of them (95%), and ELISA for the canonical ANCA were positive in 70 of them (83%); myeloperoxidasespecific ANCA were found in 38 people, and proteinase-3-specific ANCA were found in 39 people, including seven with antibodies to both antigens. Using a specific ELISA, we detected antibodies to human LAMP-2 in 78 of the 84 (93%) sera (Fig. 1a), and we validated the results by western blotting and indirect immunofluorescence on the O-glycosylation deficient CHO cell line ldlD cells stably expressing human LAMP-2 on their surface ( Supplementary Fig. 1a online). Notably, the human LAMP-2 ELISA was negative in all but six of the individuals when they were in remission after immunosuppressive therapy. Assays for human LA...

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.

This study confirms the high prevalence of cardiac morbidity associated with AFD. The disease burden in treated women exceeds that of untreated men, suggesting that most women selected for ERT have advanced disease. The presence of LVH is associated with higher frequency of cardiac signs and symptoms and relates independently to gender, age, and renal function.

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In this study, Port and colleagues describe hemodialysis prevalence and patient characteristics by sex, compare men-to-women mortality rate with data from the general population, and evaluate sex interactions with mortality. The results show that women's survival advantage was markedly diminished in hemodialysis patients. Please see later in the article for the Editors' Summary

These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

IntroductionFabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.MethodsA Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.ResultsFor classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m2) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.ConclusionThe recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0253-6) contains supplementary material, which is available to authorized users.