Alport syndrome is a progressive, genetically heterogeneous inherited nephropathy caused by pathogenic variants in the genes encoding the alpha chains of type IV collagen, which is a major structural component of basement membranes.
The condition is classified into three main genetic patterns based on the affected gene and mode of inheritance:
Inheritance Pattern
Affected Gene
Frequency
Pathogenesis and Clinical Note
X-linked (XLAS)
COL4A5
~80%
Males are hemizygous and typically progress to severe disease; females are heterozygous with mosaic expression and highly variable disease severity.
Autosomal Recessive (ARAS)
COL4A3 or COL4A4
~15%
Caused by homozygous or compound heterozygous mutations; patients experience an inevitable progression to end-stage kidney disease (ESKD).
Autosomal Dominant (ADAS)
COL4A3 or COL4A4
~5–31%
Includes patients previously classified as having “thin basement membrane nephropathy”; associated with a relatively slower progression of kidney dysfunction.
Clinical Features
Renal: Persistent microscopic hematuria is the cardinal and earliest clinical feature, occurring in 100% of males with XLAS and all patients with ARAS. Episodic gross hematuria may occur, followed by progressive proteinuria that inevitably leads to ESKD.
Sensorineural Deafness: Bilateral, high-frequency sensorineural hearing loss develops in up to 90% of hemizygous males with XLAS, but importantly, it is never congenital.
Ocular: Ocular defects occur in 30–40% of XLAS patients and include anterior lenticonus (which is pathognomonic), macular flecks, and recurrent corneal erosions.
Diagnosis
Electron microscopy of the kidney biopsy is the gold standard for morphological diagnosis, classically revealing diffuse thickening, thinning, splitting, and layering (the “basket-weave” appearance) of the glomerular basement membrane (GBM).
Immunofluorescence of the kidney or skin biopsy demonstrates the absence or altered mosaic expression of the α3, α4, or α5(IV) collagen chains, which can confirm the diagnosis even before characteristic EM changes appear.
Genetic testing utilizing next-generation sequencing (NGS) provides a definitive and non-invasive diagnosis, identifying the exact pathogenic variant.
Management and Prognosis
Therapy is primarily supportive; the early initiation of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has been proven to reduce proteinuria and delay the progression to ESKD.
Kidney transplantation is the preferred renal replacement therapy; however, approximately 1–5% of XLAS males develop de novo anti-GBM nephritis in the allograft, which can lead to rapid graft loss.
