Identification of a novel GLA mutation (Y88C) in a Korean family with Fabry nephropathy: a case report

Abstract

Background: Fabry disease is a rare X-linked lysosomal storage disorder caused by α-galactosidase A deficiency. With the advancement of molecular diagnostic tools, more disease-causing mutations in α-galactosidase A (GLA) have been identified in Fabry disease. We found a novel mutation in a Korean family with predominant renal manifestations of the disease.

Case presentation: A 24-year-old man who wanted to donate a kidney to his 28-year-old brother with end-stage renal disease of unknown cause was evaluated. The 24-year-old man underwent percutaneous renal biopsy because of an accidentally found proteinuria. Electron microscopy of his renal biopsy showed numerous electron-dense multi-lamellar inclusions in the epithelial cytoplasm, typical for Fabry disease. Clinical and laboratory evaluation including the assessment of GLA enzyme activity and direct DNA sequencing in four members of the family were performed. Renal biopsy findings in the two affected male patients were described. Re-evaluation of a renal biopsy specimen of his 28-year-old brother obtained when he was diagnosed with renal failure revealed a very focal area of suspicious multilamellated structures in the Bowman's space. DNA sequencing on the young man, his brother, and his mother revealed a novel GLA gene mutation, c.263A > G (p.Tyr88Cys). The three all showed decreased α-galactosidase A activity.

Conclusion: A novel GLA mutation, c.263A > G (p.Tyr88Cys), was found in a Korean family with predominant renal manifestations of Fabry disease.

Keywords: Dialysis; Fabry disease; Kidney biopsy; Proteinuria; α-galactosidase A.

Fig. 1

The family pedigree. The shaded squares indicate affected men (patients 1 and 2). The circle with a dot indicates heterozygous woman (patient 3). ESRD, end-stage renal disease; y, years

Fig. 2

Light and electron microscopic findings of renal biopsies from patients 1 and 2. a On microscopic examination of patient 1, there are some vague vacuolizations of podocytes (black arrowhead), although he showed normal renal function and proteinuria (H&E stain, ×400). b Multilamellated myelin figures (white arrowhead), so-called zebra bodies—which are typical findings in Fabry disease—are found in patient 1’s podocytes on electron microscopy. c Similar vacuolated epithelial cells (black arrowhead) are found in the relatively preserved glomerulus of patient 2, whereas most glomeruli are damaged by sclerosis (H&E stain, ×400). d A focal area showing a tiny, dark–stained, round multilamellar inclusion (white arrowhead) on the electron microscopy result for patient 2

Fig. 3

Electropherogram of exon 2 of α-galactosidase A in this family with Fabry nephropathy. The analysis shows a mutation of A > G at nucleotide 263, resulting in an amino acid substitution p.Tyr88Cys