Long-term enzyme replacement therapy for Fabry disease: efficacy and unmet needs in cardiac and renal outcomes

Abstract

Fabry disease is a progressive lysosomal storage disease caused by alpha-galactosidase A deficiency. This condition is characterized by progressive accumulation of glycosphingolipids with functional impairment in various organs, including the kidney, heart and cerebrovascular system. Enzyme replacement therapy (ERT) is essential because it attenuates the disease progression. The present study investigated the long-term efficacy of ERT in 19 Korean Fabry patients (11 adult males, 4 symptomatic female carriers and 4 pediatric males) who had received ERT for 8.1±2.2 years (range, 5.3-10.5 years). In the 11 adult males, the mean reduction in the estimated glomerular filtration rate (eGFR) was -3.8±4.5 ml min 1.73 m. The rate of eGFR decline was significantly lower in patients with lower proteinuria (<1 g per day) before ERT. The left ventricular mass index decreased or was stable throughout the ERT in male patients with or without left ventricular hypertrophy before ERT initiation. In female carriers and pediatric male patients, renal and cardiac functions remained stable with ERT. Arrhythmias were observed in 10 adult males and 1 female patient before ERT and persisted during ERT. One pediatric patient newly developed arrhythmia despite ERT. In conclusion, long-term ERT has beneficial effects on the renal and cardiac outcomes of Fabry patients but has limited effect in patients with irreversible organ damage. Identification of patients in the early disease stage and rapid ERT initiation might be the best strategy to improve the natural course of the disease.

Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events

“…Our findings are consistent with other published analyses showing stable or improved cardiac or renal parameters in patients receiving ERT with agalsidase alfa [3,[8][9][10][11][12]. Compared with similar analyses in the published literature [8,[13][14][15], our analysis is based on the largest dataset of clinical events in the long-term treatment of Fabry disease to date. However, the number of renal events recorded in the FOS database was still relatively small, limiting the analysis of renal events and indicating that renal function is well maintained over years of ERT.…”

Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey

“…When we evaluated the renal outcomes of those patients who received ERT for more than 5 years, the age at diagnosis, amount of proteinuria, and glomerular filtration rate before ERT were the most important factors affecting the renal outcomes. [15] …”

“…[14,15] The renal pathological findings were recorded in those patients whose renal function was significantly deteriorated. Of note, complement 3 was often deposited in certain patients with Fabry disease before the ERT, indicating the constitutional activation of the complement system at the baseline.…”

“…[14,15] However, there is no nationwide data available on the baseline clinical characteristics, molecular spectrum of the GLA gene mutations, and effects of ERT in a large cohort of patients in Korea. Thus, this study was performed to determine the baseline demographic profiles, clinical characteristics, and GLA mutation spectrum in patients with Fabry disease in Korea by using a nationwide survey.…”

Biomarkers in Lysosomal Storage Diseases

“…The GLA enzyme activity assays enable the identification of affected males relatively easily, but in the case of heterozygous females, an overlap occurs that makes the clear classification of these patients difficult. This limitation, coupled with the difficult goal of implementing ERT in FD [16,17], has led to the search for early diagnostic biomarkers that have been incorporated into the habitual study of the disease.…”