Fabry disease is caused by mutations in the gene encoding the lysosomal enzyme α-galactosidase A [1]. This results in reduced or absent α-galactosidase A activity and intra-lysosomal accumulation of neutral glycosphingolipids, mainly Gb3 (a substrate of α-galactosidase A), in many cells including renal epithelial cells, endothelial cells, vascular smooth muscle cells, cardiac myocytes and neurons of the autonomic nervous system. As Gb3 is easily accessible in both plasma and urine and seems to be directly involved in the renal pathology of Fabry disease, it may be a potential diagnostic assay for patients presenting with the classical disease phenotype [2]. However, its exact utility in the diagnosis and prognosis of Fabry remains contentious [3].
Interestingly, the genetic sequence analysis in this case revealed a hemizygous mutation for a G to C transversion at nucleotide 1067 (c.1067 G > C) in exon 7 of the α-galactosidase A (GLA) gene. This variant is predicted to result in the substitution of arginine with proline at amino acid residue 356 (p. Arg356Pro). Although not previously described in the literature, two mutations have been reported in Fabry patients that cause substitution of the same Arg356 residue (p. Arg356Trp and p. Arg356Gln) [4, 5]. Both mutations produce small amounts of residual enzyme (as in this case), but still at levels that would cause disease. Therefore, in the context of all the other clinical findings, this variant is considered to be pathogenic.
Estimates of the incidence of Fabry disease vary markedly and although rare, it is likely to be more common than originally thought. A newborn screening study in Italy of more than 37,000 consecutive male neonates demonstrated an incidence of α-galactosidase A deficiency of 1 in 3100 [6]. In patients with end-stage renal disease on haemodialysis, studies have reported a prevalence from anywhere between 0.33% up to 1.2% [7, 8]. One potential reason that the condition is under-recognised is that from the total number of cases of Fabry patients diagnosed, nearly half of them (46%) come from family screening [9]. This clearly demonstrates how difficult it is to find new cases / families and emphasising that when a new index of Fabry is diagnosed, screening the family is an important way of diagnosing previously undetected disease.
In general, hemizygous males are more severely affected than heterozygous females. In males, life expectancy is reduced by an average of 20 years [10] and in females by 15 years [11] with both being affected from an early age [12]. Death usually occurs due to renal, cardiovascular or cerebrovascular complications [1, 10, 11], with renal dysfunction being the main cause of death in men prior to the advent of renal failure requiring dialysis or transplantation [9].
Fabry nephropathy is characterised by variable levels of disease severity but with an overall rate of progression of chronic kidney disease (CKD) very similar to diabetic nephropathy, with evidence suggesting that all patients living into their 50s with classical Fabry disease will develop end-stage renal failure [9]. Accordingly, in addition to the aggressive treatment of hypertension, renoprotective measures should be introduced as soon as hyperfiltration and/or microalbuminuria are detected. Two enzyme replacement therapies (ERTs) have been shown to be effective in halting the progression of renal manifestations in patients with mild or moderate Fabry nephropathy and in slowing the progression of CKD in patients with advanced disease. Significant proteinuria and marked glomerulosclerosis (as with this patient) are the best predictors of progression of Fabry nephropathy despite ERT [13]. Consequently, ERT and nephroprotective measures should be started as soon as possible in male patients with the disease [14].
Given the importance of early initiation of treatment, timely and accurate diagnosis of Fabry disease is key. With this patient, as there were no clues to the presence of Fabry disease in the presentation, family history or clinical findings, making the correct diagnosis unknowingly rested on the interpretation of the needle biopsy. In general, this is not usually difficult however in this case which presented with advanced renal impairment; all 22 of the glomeruli obtained for light microscopy were globally sclerosed. Consequently the diagnosis rested completely on tissue collected and processed for EM. A semi-thin (0.5 μm) resin embedded survey section was stained with Toluidine blue to check for the presence of glomeruli before ultra thin sectioning for transmission EM. These steps showed the characteristic osmiophilic inclusions and Zebra bodies respectively (see Figure 2). A second histopathologist and member of the European Network of Fabry Pathologists confirmed these findings. A recent survey suggests that only half of institutions routinely collect tissue from native biopsies specifically for EM [15], confounded by an inadequate sampling rate. This case highlights the importance of EM in the evaluation of renal biopsies, underlining previous advice that this should be standard practice [16]. Indeed, in a review of laboratory practice in renal pathology, the evaluation of renal biopsy specimens without electron microscopy was regarded as negligent [17].
