#2834 When Fabry was not the one to blame

Abstract Background and Aims Fabry Disease (FD) and Alport syndrome (AS) are genetic kidney diseases that account for 0.2 to 1% of patients with end-stage renal disease (ESRD), respectively. AS is caused by pathogenic variants in COL4A3, COL4A4, and COL4A5 genes, including autosomal, X-linked, or digenic inheritance. It encompasses a spectrum of nephropathy, from microscopic hematuria to progressive renal disease and ESRD. FD is an X-linked disorder caused by the hereditary deficiency of the enzyme α-galactosidase A (α-Gal A), potentially causing disease in the kidneys, heart, and peripheral and central nervous systems. Diagnosing these entities can be challenging and usually integrates family history, kidney biopsy and genetic testing. Method We present a case of X-linked AS in a patient with familial microscopic hematuria and a previous family diagnosis of FD. Results A 30-year-old male patient was referred to the nephrology department at the age of 18 for microhematuria and proteinuria 1 g/24 hours. He had family history of microhematuria in his 14-year-old brother, 13-year-old sister, and two male paternal first-degree cousins of 19 and 30 years old. His kidney biopsy showed mesangial hypercellularity, podocyte cytoplasm vacuolization, and interstitial foamy macrophages on light microscopy (LM), immunofluorescence exhibited IgM(+)/IgA(−)/IgG(−)/C3c(+)/C1q(−) and electron microscopy (EM) revealed diffuse podocyte foot process effacement and mesangial and glomerular basement membrane (GBM) sclerosis, without myeloid bodies. Genetic analysis was negative for COL4 gene variants but revealed a hemizygous GLA variant c.427G>A; p.(Ala143Thr). He had no skin lesions, acral paresthesias or pain, gastrointestinal distress, or heat intolerance. His electrocardiogram, echocardiography, brain magnetic resonance, and ophthalmologic and ear/nose/throat evaluations were unremarkable. α-Gal A leukocyte and plasma activity were below the normal range but above 30 percent of the mean normal, and plasma lysoGb3 and urinary Gb3 were normal. Targeted genetic testing evidenced the same variant in both siblings, his mother, his paternal male cousins, and in one of their sisters, who later developed hematuria, and their mother. None had clinical features or enzymatic study compatible with FD, except for limb paresthesia in one cousin. The patient's brother eventually developed proteinuria of 1 g/g and underwent a KB at 18 years old, with similar histologic features on LM and EM. Over the years, the patient's kidney function remained unaltered, and proteinuria ranged from 0.9 to 2.2 g/g on a renin-angiotensin-aldosterone system inhibitor. Due to worsening proteinuria and an uncertain etiology, he underwent a second kidney biopsy after eight years. LM showed focal mesangial hypercellularity, and EM revealed irregular GBM with variable thick and thin segments, without myeloid bodies. Repeated genetic testing showed a probable pathogenic variant in COL4A5 gene c.3791G>T p.(Gly1264Val). A diagnosis of X-linked AS was thus established. The same variant has already been identified in his brother and cousin. Conclusion We present a case of familial hematuria associated with a pathogenic variant in COL4A5 and a variant of uncertain significance in GLA. To this date, we could not establish how two variants in the X chromosome were inherited in patients whose familiar connection is through their fathers. Their respective mothers have hematuria and are from the same region in northern Portugal, so we hypothesized that they could be related. The absence of FD clinical and biochemical phenotypes in this family supports previous observations of the non-pathogenicity of this GLA variant and reflects the challenges surrounding the interpretation of genetic variants in clinical practice. Surrogate biomarkers and tissue biopsy provided insight into its clinical relevance and prevented unnecessary treatment. Finally, a re-take genetic testing almost ten years apart led to the identification of a previously unknown COL4A5 variant, highlighting the importance of re-evaluating genetic testing in cases of uncertain etiology and clinical suspicion of a genetic disease.