Background/Aims: Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy. Methods: One out of 108 male hemodialysis patients screened for FD presented low α-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy. Results: Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively. Conclusion: The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non-invasive markers are required for early detection of Fabry nephropathy.
Background Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease. Therefore, studies involving large samples are scarce, making registries powerful tools to evaluate cases. We present herein the first analysis of the Brazilian aHUS Registry (BRaHUS). Methods Analysis of clinical, laboratory, genetic and treatment data from patients inserted in the BRaHUS, from 2017 to 2020, as an initiative of the Rare Diseases Committee of the Brazilian Society of Nephrology. Results Cohort of 75 patients (40 adults and 35 pediatric). There was a predominance of females (56%), median age at diagnosis of 20.7 years, and a positive family history in 8% of cases. Renal involvement was observed in all cases and 37% had Low C3 levels. In the <2 years of age-group, males were predominant. Children presented lower levels of hemoglobin (p = 0.01) and platelets (p = 0.003), and higher levels of LDH (p = 0.004) than adults. Genetic analysis performed in 44% of patients revealed pathogenic variants in 66.6% of them, mainly in CFH and the CFHR1-3 deletion. Plasmapheresis was performed more often in adults (p = 0.005) and 97.3% of patients were treated with eculizumab and its earlier administration was associated with dialysis-free after 3 months (p = 0.08). Conclusions The cohort of BRaHUS was predominantly composed of female young adults, with renal involvement in all cases. Pediatric patients had lower hemoglobin and platelet levels and higher LDH levels than adults, and the most common genetic variants were identified in CFH and the CFHR1-3 deletion with no preference of age, a peculiar pattern of Brazilian patients.
Background and Aims Fabry disease (FD) is a rare X-linked lysosomal storage disease that can affect multiple organs, including the kidneys. The main objective of this study was to evaluate the effectiveness of a combination of α-GAL enzyme activity and plasma levels of lyso-GL3 for screening FD in women with chronic kidney disease (CKD). Method Women with CKD, stages 3 to 5, in regular nephrological follow-up were selected from renal centers in all regions of Brazil. Exclusion criteria: under 18 years old and known diagnosis of CKD. Patients underwent biochemical analysis of α-GAL enzyme activity and plasma levels of lyso-GL3. GLA gene sequencing was performed if α-GAL enzyme activity was below and/or lyso-GL3 levels were above the reference range. Sensitivity and specificity analyzes were performed to evaluate the performance of the combined biochemical approach for the diagnosis of FD. Results From October 2020 to December 2022 1,647 collections were carried out. Low α-GAL activity was found in 44 (2.6%) of the cases and increased lyso-GL3 was found in 101 (6.1%) of the cases. The mean age was 53 [42 – 64] years. All cases of low α-GAL and/or increased lyso-GL3 were submitted to genetic analysis, and 6 positive cases were found. As for genetic variants, four patients have R118C, one A143T and other with T430G, all considered variants of uncertain significance (VUS). The sensitivity and specificity of α-GAL reduction for the detection of FD was 83.3% and 97.6%, respectively. As for the increase in lyso-GL3, the values were 16.6% and 93.9%, respectively. There were no cases that presented a concomitant increase in lyso-GL3 and a reduction in enzymatic activity. Conclusion Preliminary results suggest that the combination of α-GAL enzymatic activity with lyso-GL3 measurement may be a good alternative for screening FD in women with CKD. A thorough medical evaluation is required to determine the pathogenicity of variants in these patients.
Background and Aims Fabry Disease (FD) is a multisystemic disorder that affects the function of major organs, such as the kidneys, the heart and the central nervous system, reducing the quality of life and leading ultimately to premature death. Early diagnosis and timely treatment are the cornerstones to change the natural history of this disorder. Method To evaluate clinical, laboratory and renal histological profiles of FD patients with a classic pathogenic variant (p.G35V), identified by targeted screening in hemodialysis patients followed by family screening, who were under enzyme replacement therapy (ERT), algalsidase-beta (0.1 mg/kg/e.o.w), for at least 48 months. Kidney biopsy was performed at baseline. Glomerular filtration rate, estimated according to the CKD-Epi equation, 24h-urinary protein and albumin were measured annually. Cardiac manifestations were evaluated by eletrocardiogram, transthoracic echocardiography (TTE) or magnetic resonance imaging (cMRI) at baseline and at the end of the study. cMRI was not performed in the index patient, due to CKD 5D, and in a pregnant female patient. Results Nine patients (age: 33.8±12.3 years) were followed-up for 80.67±5.43 months. Their main clinical manifestations were hypohidrosis (67%) gastrointestinal symptoms (56%), cornea verticilata and acroparesthesia (100%). Angiokeratomas were present only in males (100%). Five (56%) and 3 (33%) patients presented CKD G1 and G2, respectively. Only the index case presented CKD G5D. Short PR interval was observed in 44.4%. LVH was detected by TTE in 2 patients (index case and a 46-years old female); whereas based on cMRI no patient had LVH and one female had myocardial fibrosis. Patients received ERT for 70.22±12.92 months, together with adequate adjunctive therapy. eGFR and proteinuria / albuminuria remained stable during the follow-up in both sexes. Female patients presented a mean reduction of LV mass index of 9.73g/m2 (CI95%: -26.9 - 6.8). Patients who started ERT older than 30 years tended to have a higher interventricular septal thickness at the end of the follow-up (8.4 ± 2.2 vs 10.0 ± 2.7 mm; P = .08). Concerning the kidney biopsy findings, patients with higher proteinuria presented more global glomeruli sclerosis; and mild interstitial fibrosis (5%) could be detected even among young patients with normal albuminuria and eGFR. There was a significant correlation between baseline global glomeruli sclerosis and albuminuria at baseline (r=0.9; P = .01) and at the end of the follow-up (r=0.87; P = .01); and between baseline interstitial fibrosis and proteinuria at the end of the follow-up (r=0.80; P = .03). Conclusion Females with a pathogenic variant (p.G35V) for FD may develop cardiac and renal injury. FD-related renal histological changes and chronic tissue damage may be present before clinical and laboratory signs of renal dysfunction. Persistence of proteinuria during ERT might be related to the presence of interstitial fibrosis. Treatment with ERT may stabilize renal and cardiac involvement in FD. Regular monitoring and adequate pathogenetic and adjunctive treatment should be offered to FD patients of both sexes. Kidney biopsy is an important tool to evaluate pre-clinical renal involvement. Timely treatment may potentially change the natural history of the disease.
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