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Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

ABSTRACT: Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P<0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P<0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype (P<0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients.

SUBMITTER: Arends M

PROVIDER: S-EPMC5407735 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

Arends Maarten M Wanner Christoph C Hughes Derralynn D Mehta Atul A Oder Daniel D Watkinson Oliver T OT Elliott Perry M PM Linthorst Gabor E GE Wijburg Frits A FA Biegstraaten Marieke M Hollak Carla E CE

Journal of the American Society of Nephrology : JASN 20161215 5

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean ...[more]

PMID: 27979989

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Project description:BACKGROUND:Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n =?103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. RESULTS:Among the patients exposed to agalsidase, 40% of men (n?=?18/45) and 8% of women (n?=?2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p?=?0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p?=?0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 ?g/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r?=?0.67, p?<?0.0001), especially IgG4 (r?=?0.75, p?=?0.0005) and IgG2 (r?=?0.72, p?=?0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p?=?0.04), which was correlated with IgG2 (r?=?0.67, p?=?0.017, n?=?12) and IgG4 levels (r?=?0.59, p?=?0.041, n?=?12). Plasma LysoGb3 levels were correlated with total IgG (r?=?0.66, p?=?0.001), IgG2 (r?=?0.72, p?=?0.004), IgG4 (r?=?0.58, p?=?0.03) and IgG1 (r?=?0.55, p?=?0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p?=?0.005). CONCLUSION:Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.

Dataset Information

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

Publications

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

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