Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

Abstract

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

Pharmacological Interventions in the Management of Alport Syndrome: A Systematic Review

“…In our review, both Boeckhaus et al and Gross et al investigated ramipril, a widely-used ACE inhibitor, demonstrating a potential role in decelerating disease progression, although the benefits were not statistically significant in Gross et al's study [10,11]. The use of RAAS inhibitors like ramipril, based on their antiproteinuric and nephroprotective effects, has been previously recommended as a standard of care for patients with Alport syndrome [13][14][15]. However, these two studies reinforce the need for more robust evidence concerning its clinical efficacy in both adult and pediatric populations.…”

Genetic Kidney Diseases (GKDs) Modeling Using Genome Editing Technologies

“…Individuals with pathogenic mutations in any of these genes can present with a wide phenotypic variability, ranging from isolated hematuria to renal failure, depending, among others, on the affected gene and if only one or the two copies of the gene are altered [39]. X-linked disease accounts for 70-75% of Alport patients [40][41][42].…”

Good maternal and fetal outcomes of three consecutive pregnancies in a Mediterranean woman with Alport syndrome: a case report

“…2 Obstetrics and Gynecology Department, Jordan University of Science and Technology (Retired), Irbid, Jordan. 3 Internal Medicine Department, Jordan University of Science and Technology, Irbid, Jordan. 4 Obstetrics and Gynecology Department at King Abdulla University Hospital.…”

“…AS is caused by mutations in any type IV collagen genes COL4A3, COL4A4 (2q36.3 both), and COL4A5 (Xq22.3). While there are three different genetic forms of Alport syndrome (X-linked, autosomal recessive, and autosomal dominant), it has been suggested that, in females, it is either X-linked in 85% of cases or autosomal recessive in the remaining 15% [1][2][3].…”