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.

Keywords: Fabry-s disease; alpha galactosidase A; natural disease course; natural history; phenotype.

Figure 1.

Event-free survival (any event) stratified for sex and phenotype. Shaded areas represent the 95% CIs; + indicates censoring (i.e., first visit).

Figure 2.

Robust linear regression of eGFR. Shaded areas represent the 95% CIs for the fitted curves. Black dots represent patients with classical FD, and gray triangles represent patients with nonclassical FD.

Figure 3.

Log–linear regression curve of the LVM measured by echocardiography corrected for height (meters^2.7). Shaded areas represent the 95% CIs for the fitted curves. The dashed horizontal lines represent the upper reference limits (men: 48 g/m^2.7; women: 44 g/m^2.7). Black dots represent patients with classical FD, and gray triangles represent patients with nonclassical FD.

Figure 4.

Log–linear regression curve of the LVM measured by cardiac MRI corrected for body surface area (BSA). Shaded areas represent the 95% CIs for the fitted curves. The solid black lines represent the adjusted (not including the papillary muscles) upper reference limits for men (83 g/m²), and the dashed black lines represent the upper reference limits for women (71 g/m²). Black dots represent patients with classical FD, and gray triangles represent patients with nonclassical FD.

Figure 5.

Boxplot of lysoGb3 stratified for sex and phenotype. The horizontal line inside the box from the 25th to 75th percentile depicts the median, the whiskers extend to the most extreme data point that is no more than 1.5 times the interquartile range. Outliers are indicated by squares. ***P<0.001.