Revisiting Alport syndrome: Genetic background, phenotypic variability, and therapeutic approaches

Abstract

Nearly a century has passed since Cecil A. Alport first described the triad of nephritis, hearing loss, and ocular abnormalities that would later be recognized as the second most common inherited nephropathy and a significant cause of end-stage kidney disease. Pathogenic variants in COL4A3, COL4A4, and COL4A5 genes lead to compromised synthesis, assembly, and/or function of α3, α4, and α5 chains of type IV collagen (COL4). This disruption leads to an abnormal trimerization of COL4 into a stable network, impairing the integrity and function of glomerular, cochlear, and ocular basement membranes. The gold standard for Alport syndrome diagnosis is molecular genetic testing, which provides a non-invasive and highly specific approach. In settings with limited access to genetic testing, kidney biopsy with electron microscopy remains essential, revealing characteristic glomerular basement membrane abnormalities. Despite significant advancements in understanding its genetic and molecular basis, Alport syndrome remains a relentlessly progressive disorder, often culminating in end-stage kidney disease during early adulthood. While no disease-specific therapy exists, early initiation of renin-angiotensin-aldosterone system blockade is the cornerstone of AS management, delaying disease progression. Emerging therapies, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists, are being investigated for their nephroprotective potential. In addition, recent breakthroughs in therapeutic research - including gene- and cell-based treatments - hold the potential to transform disease management. Genetic factors influence treatment response, reinforcing the need for personalized therapeutic approaches. In this review, we discuss the genetic background and phenotypic correlations of Alport syndrome, the pathophysiological mechanisms driving both renal and extrarenal manifestations, and explore diagnostic approaches and emerging strategies aimed at modifying the natural course of this disease.

Keywords

Alport syndrome / Inherited nephropathy / Glomerular basement membrane / Molecular genetic testing / Nephroprotection

Funding

None.

Conflict of interest

The authors declare they have no competing interests.

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