Ocular Coherence Tomography Unveils Alport Syndrome: A Critical Tool in Detecting Collagen IV Nephropathies

Background: Alport Syndrome (AS) and Focal Segmental Glomerulosclerosis (FSGS) pose diagnostic challenges due to overlapping clinical, histopathological, and genetic features. AS is characterized by mutations in collagen genes (COL4A3, COL4A4, COL4A5), leading to glomerular basement membrane (GBM) abnormalities, while FSGS can be primary, autoimmune mediated, or secondary to systemic causes or to genetic mutations, including mutations in the collagen 4 genes. Optical Coherence Tomography (OCT) aids in identifying these conditions by demostrating temporal macular thinning in COL4 nephropathies. We describe two cases presenting with proteinuria that were initially diagnosed as primary FSGS and treated with long term steroid therapy. Subsequent genetic testing and OCT imaging were carried out. Methods: Genetic analysis was conducted using next-generation sequencing (NGS) with copy number variation (CNV) analysis. Mutations were confirmed through polymerase chain reaction (PCR) and Sanger sequencing. Under high-resolution spectral OCT done by ophthalmologists, the Temporal Thinning Index (TTI) was measured using the formula: TTI = {(N1 + N2) − (T1 + T2)} / (N1 + N2) × 100. Severe thinning is defined as TTI exceeding 2 standard deviations above the mean for healthy eyes. Results: Case 1: We identified a novel deletion in COL4A5 exons 8 and 9. OCT: TTI 8.21 OD and 8.36 OS, indicating severe temporal thinning, consistent with Alport Syndrome. Case 2: We detected two variants in COL4A3: a missense mutation (COL4A3:c.2452G>A; p.Gly818Arg) and a novel nonsense mutation (COL4A3:c.4722G>A; p.Trp1574*). OCT: TTI 10.5 OD and 10.8 OS, suggesting severe temporal thinning, indicative of Alport Syndrome. Conclusion: OCT assists clinicians when the diagnosis of a COL4 nephropathy is unclear. Earlier use of OCT could have established a precise diagnosis in these cases, thus avoiding unnecessary immune suppression. These findings highlight OCT's vital role in distinguishing COL4A nephropathy from primary FSGS, guiding diagnosis, management, and genetic counseling. In broader contexts, OCT can potentially assist in more accurately assessing the prevalence of COL4 nephropathies, identifying individuals for phenotype studies, and exploring potential therapeutic options.