A Case Study of Fabry Nephropathy and Its Progression: The First Reported Case in Malaysia


 IntroductionFabry disease (FD) is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, causing common and serious kidney complications. We report the first case of Fabry disease detected in Malaysia. Clinical ScenarioA 35-year-old man had an incidental finding of proteinuria during routine health screening. His symptoms included frothy urine and intermittent lower limb swelling. Renal biopsy showed features of Fabry’s disease which was confirmed with genetic testing. He had classical hemizygous Fabry disease of c.610 C>T with Fabry nephropathy, cardiomyopathy, and cornea verticillata. He was then started on be Enzyme Replacement Therapy (ERT) with agalsidase till date. ConclusionProteinuria is the predominant factor in Fabry nephropathy predicting renal disease progression rate. Early Fabry Disease diagnosis could prevent kidney disease progression through the timely initiation of treatment which will help enhance the quality of life of the patient, as the disease progresses.


Background
Fabry Disease (FD) an X-linked lysosomal storage genetic disorder, is caused by de ciency of the αgalactosidase A enzyme (α-Gal A). (1) As a result of the defects in this enzyme, there will be an intralysosomal accumulation of glycospingolids, particularly globotriosylceramide (GL-3) in different cells, plasma and urine leading to renal, cardiac, and cerebral dysfunction and early death. (2,3).
The initial proteinuria in the 20s and 30s is among the features of Fabry nephropathy. Among others, there are also features of glomerular sclerosis, tubular atrophy, and interstitial brosis. Fabry nephropathy patients may have progressive kidney failure comparable to diabetic nephropathy.(4) Furthermore, Fabry nephropathy is also associated with cardiovascular morbidity and mortality in FD patients. (5) It is estimated that the incidence ranges from 1:40000 to 1:60000 males. (3) The alpha-galactosidase A gene is located on the long arm of chromosome X. Due to its X-linked inheritance, the disease is completely expressed in hemizygous males(3) resulting in the classic form of disease.

Case Presentation
A 35 year old gentleman, who was a non-smoker and teetotaller, complained of intermittent lower limb swelling and frothy urine since 2009. He was normotensive and euglycemic with no known family history of kidney disease. Physical examinations were unremarkable.
Further investigations showed a urine protein dipstick was 2+ with absence of red blood cell or cast under microscopy. His renal pro le was normal [initial serum creatinine 63 umol/l, estimated glomerular ltration rate (eGFR) 118 mL/min/1.73m 2 with the CKD-Epi formula)]. 24-hour urine protein was 1.19 g/L with no kidney structural abnormalities being detected by ultrasonography (Right and left kidney sizes measuring11.3cm and 12.0 cm, respectively). The serum albumin was 39 g/dl with normal total cholesterol level. He was seronegative for syphilis, human immunode ciency virus (HIV), Hepatitis B and C. Autoimmune screening was negative.
During follow-up, his proteinuria worsened with 24-hour urine protein rising to 2.8 g/L 4 years later. He remained normotensive and euglycemic with no evidence of retinopathy. In view of persistent unexplained proteinuria, renal biopsy ( Figure 1) was performed which showed prominent podocytes with expanded abundant cytoplasm that appears pale with ne vacuolation forming lacy appearance. There were also moderate intimal thickening of artery and small foci of tubular atrophy surrounded by interstitial brosis seen under microscopy. The immuno uorescence staining for (Ig) G, Ig A, Ig M, (C)3 and C1q were negative. Hence, FD was highly suspected from the overall ndings.
Blood sample for Lysosomal Enzymes Assay Test was subsequently sent. Plasma Alpha-galactosidase A (AGAL) Zero nmol/ml/hour (normal reference 2-10). A Genetic study (GLA gene variant Analysis) was conducted based on polymerase chain reaction (PCR) ampli cation and sequencing methods, con rming the fact that our patient was hemizygous for pathogenic p.Trp204Arg variant (c.610T>C) in the GLA gene, consistent with a nal diagnosis of Fabry disease.
Serial system-based physical and ancillary investigations were performed to assess the end-organ involvement of FD. Cornea verticillate were noted in both eyes via slit-lamp examination. Transthoracic echocardiogram showed moderate concentric left ventricular hypertrophy (LVH) with LV ejection fraction above 55%. The other organ systems, including neurology, cutaneous, ears, gastrointestinal tract, cerebrovascular and psychology were unremarkable. Hence, a nal diagnosis of FD with renal, ocular, and cardiovascular was made.
He was then commenced on ERT -intravenous Fabrazyme 35 mg two weekly for rst two doses, followed by the maintenance regimen 70 mg (1mg/kg) every 2 weeks ve years after the FD diagnosis was made and almost a decade after his initial presentation. He was also started on low dose Perindopril (a type of angiotensin-converting enzyme ACE inhibitor) for his proteinuria. He remained on these treatments with normal blood pressure to date (approximately two years post ERT commencement). The serial investigation was shown in Table 1. He has 2 younger brothers and 1 younger sister. Enzyme and genetic studies were performed for the siblings using Dry Blood Spot with capillary blood. His younger sister was detected to have FD through the screening with heterozygous mutation of p.Trp204Arg. His mother was also found to have similar mutation.
He has 5 children: 1 son and 4 daughters. His son was tested but was found to be healthy. However, 4 of his daughters were detected to have heterozygous mutation for p.Trp204Arg. This is illustrated in the Figure 2.

Discussion
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. 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. 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 signi cantly 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 con rmed. 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 insu ciency (GFR < 45 ml/min/1.73 m 2 ) 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 bene ts include, for example, decrease in neuropathic pain, improvement of gastrointestinal symptoms, and reduction of left ventricular mass.(4)

Conclusion
To conclude, Fabry Disease is a rare disease with wide spectrum of clinical manifestations which makes the diagnosing even more di cult for clinicians. Thus, in cases where no apparent causes can be found, high index of suspicion is the key. Proteinuria is the predominant factor in Fabry nephropathy predicting renal disease progression rate. Therefore, an early Fabry Disease diagnosis could prevent kidney disease progression through the timely initiation of treatment which will help enhance the quality of life of the patient, as the disease progresses.

Learning points
Fabry Disease is a rare disease with wide spectrum of clinical manifestations