Alport Syndrome: A Comprehensive Review on Genetics, Pathophysiology, Histology, Clinical and Therapeutic Perspectives

Background: Alport syndrome (AS) is a disease caused by mutations in COL4A3, COL4A4 or COL4A5, the genes that encode distinct chains of type IV collagen. The vast majority of cases present as an inherited disorder, although de novo mutations are present in around 10% of the cases.

Methods: This non-systematic review summarizes recent evidence on AS. We discuss the genetic and pathophysiology of AS, clinical manifestations, histopathology, diagnostic protocols, conventional treatment and prognostic markers of the disease. In addition, we summarize experimental findings with novel therapeutic perspectives for AS.

Results: The deficient synthesis of collagen heterotrimers throughout the organism leads to impaired basement membranes (BM) in several organs. As a result, the disease manifests in a wide range of conditions, particularly renal, ocular and auricular alterations. Moreover, leiomyomatosis and vascular abnormalities may also be present as atypical presentations. In this framework, diagnosis can be performed based on clinical evaluation, skin or renal biopsy and genetic screening, the latter being the gold standard. There are no formally approved treatments for AS, even though therapeutic options have been described to delay disease progression and increase life expectancy. Novel therapeutic targets under pre-clinical investigation included paricalcitol, sodium-glucose co-transporter- 2 inhibitors, bardoxolone methyl, anti-microRNA-21 oligonucleotides, recombinant human pentraxin-2, lysyl oxidase-like-2 blockers, hydroxypropyl-b-cyclodextrin, sodium 4-phenylbutyrate and stem cell therapy.

Conclusion: AS is still a greatly under and misdiagnosed disorder. The pathophysiology is still not fully understood and genetics of the disease also have some gaps. Up to know, there is no specific and effective treatment for AS. Further studies are necessary to establish novel and effective therapeutic protocols.