Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression.

Andrea Frustaci,Giuseppe Donato,Enza Vernucci,Cristina Chimenti,Behzad Najafian,Matteo Antonio Russo,Luigi Sansone,Manuel Belli,Romina Verardo

doi:10.3390/jcm11051344

Abstract

Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression.

Highlights

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that is caused by deleterious mutations in the GLA gene encoding the lysosomal hydrolase, alpha-galactosidase A (α-Gal A) [1,2]
Before and after enzyme replacement therapy (ERT), as evaluated by morphometry, there are no significant differences in the glycolipid bodies content
The protein analysis showed that mannose-6-phosphate receptor expression in normal intestinal tissue was 1.6-fold increased compared with normal myocardium (38,376 ± 1788 vs. 23,117 ± 2230, respectively, p < 0.01)

Summary

Introduction

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that is caused by deleterious mutations in the GLA gene encoding the lysosomal hydrolase, alpha-galactosidase A (α-Gal A) [1,2]. Gastrointestinal symptoms, including abdominal pain, diarrhea/constipation and intestinal malabsorption, have been reported in 19 to 70% of patient with Fabry disease in the literature [10–12]. These symptoms are linked to accumulation of GL-3 in intestinal epithelial cells, other stromal cells vessels and ganglion cells (Meissner’s and Auerbach’s plexus). Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression

Methods

Results

Conclusion