Fabry nephropathy is common in Fabry’s disease. Typically, Fabry nephropathy is known and likely to start at a young age. Renal biopsies of children and adolescent who had normal eGFR and no proteinuria had exhibited glomerular sclerosis and vascular lesions;(6, 7) and glomerular GL-3 have also been detected in foetuses.(8) Our patient had a more severe form of nephropathy where his a-galactosidase levels is 0% and overt proteinuria at an early age. This is explained by Mahmud et al., where patients with a-galactosidase levels of less than 1% tends to be more severe. Those with enzyme level detectable the renal involvement is usually less severe and begins late at a mean age of 47 years.(9)
To date more than 900 mutations of agalactosidase gene have been recorded in human mutation database.(10) Most families have private mutations which may explain the variations in clinical presentation of Fabry's disease. The variant both our patient and his family have is a rare heterogenous variant of c.610T > C. To date, only 3 occurrences can be found in ClinVar with no detailed clinical information.(11)
In renal biopsy, a typical histopathological lesion is the diagnostic of Fabry Disease. Here Fabry's inclusions can be identified with PAS or Papanicolaou stain demonstrating vacuolated epithelial cells on light microscopy and Maltese cross pattern under polarized light or characteristic lamellar pattern on electron microscopy. (9) This is as shown in the renal biopsy of our patient which showed the all the typical features.
The mainstay of treatment of FD is ERT, and its initiation is recommended in classically affected males and females as soon as early clinical signs of FD occurrence.(12)
For normal population as well as for FD patients, it is a known fact that kidney function decreases with age.(2, 3) Nowak et al. found that male FD patients showed a clear decline of kidney function (eGFR) of 3.07 ml/min/1.73m2 per year over time despite being on ERT. It has also been proposed that male FD patients can pass through several CKD stages ending up with end-stage renal disease within 15 years after the initiation of ERT later in the stage. They also observed that the late initiation of ERT, does not show clear treatment-related benefit on the development of Fabry nephropathy.(13) Our patient was initiated ERT at the age after 35 which is considered late stage and already had significant proteinuria. There are no changes seen in the proteinuria over the years. He had rapid declination in renal function compared to normal population about 4.3ml/min/1.73m2 per year but slower declination compared to untreated male FD. Schiffmann et al., reported that for untreated male FD with substantial proteinuria, the rates of renal declination is 6.9 ml/min/1.73 m2 per year(14) while Branton et al reported a declination rate of 12 ml/min/1.73 m2 per year.(15)
On the other hand, recent study has found that proteinuria seems to be associated with decreased effectiveness of ERT.(16, 17) According to Nowak et al., disease progression was accelerated if ERT patients already had a more severe albuminuria at baseline, similar to this case.(13) This is supported by Wanner C et al. in which their studies showed that patients with faster progression had significantly higher proteinuria and renal function and men declined more rapidly for those with increased urinary protein levels.(18) However, studies suggest that maximal treatment effect in Fabry nephropathy can be achieved at an early stage with normal or almost normal kidney function.(19, 20) This maximal treatment also proved to provide better renal and cardiovascular outcome.(20) ACEi/ARB therapy in conjunction with ERT can reduce proteinuria and stabilize renal function in Fabry patients.(21) Similarly, in this case Perindopril was started for this reason.
In addition to that, another possibility for poor treatment response is the development of neutralizing antibody to ERT. In a study conducted by Linthrost et al., it was found that 69% of male FD developed Ig G antibodies to agalsidase alpha and beta within 6 months of treatment especially in patient who does not express residual enzyme activity, similar to our patient.(22) And it was also found that once neutralizing antibody had developed, it is irreversible and would stay positive for over 10 years.(23) However, due to restricted local resources, the Ig G antibodies development towards agalsidase beta in the patient was not able to be confirmed. Furthermore, there is no alternative treatment which is currently available for classic male FD with lack of enzyme activity.
Despite the progression of Fabry nephropathy, the treatment of ERT had not been stopped as it was not recommended to stop even in severe renal insufficiency (GFR < 45 ml/min/1.73 m2) or those on dialysis or with cognitive decline. It was however carefully considered on an individual basis.(12) As once GFR has been compromised, the goal is reduction and stabilization in the rate of CKD progresses.(24) Furthermore, ERT can reduce the occurrence of major renal, cardiac, and cerebrovascular events. Further reported extra-renal benefits include, for example, decrease in neuropathic pain, improvement of gastrointestinal symptoms, and reduction of left ventricular mass.(4)