What is Alport Syndrome, a genetic disorder affecting kidney function, hearing, and vision, typically in males?

What is Alport Syndrome

Alport syndrome is a hereditary genetic disorder caused by mutations in genes encoding type IV collagen (COL4A3, COL4A4, and COL4A5), resulting in progressive kidney disease with characteristic hematuria and proteinuria, sensorineural hearing loss affecting high-frequency tones, and ocular abnormalities including anterior lenticonus. 1

Genetic Basis and Inheritance Patterns

The disease arises from defects in type IV collagen, a structural protein essential for basement membrane integrity in multiple organs. 2, 3

Three inheritance patterns exist:

• X-linked Alport syndrome (XLAS): Accounts for approximately 80% of cases, caused by pathogenic variants in COL4A5 on chromosome Xq22. 4, 5
• Autosomal recessive Alport syndrome (ARAS): Represents 15% of cases, caused by mutations in either COL4A3 or COL4A4 on chromosome 2q36. 4, 5
• Autosomal dominant Alport syndrome (ADAS): Rare, occurring in 5% of cases, also due to mutations in COL4A3 or COL4A4. 4

Renal Manifestations

The kidney disease follows a predictable progression:

• Hematuria is present from early childhood and represents the earliest manifestation. 1
• Proteinuria develops progressively over time as glomerular damage advances. 6, 1
• Progressive renal insufficiency leads to end-stage renal disease, with timing dependent on genotype and inheritance pattern. 1, 7

Characteristic pathologic findings include:

• Thinning or splitting of the glomerular basement membrane (GBM) on electron microscopy. 6, 8, 1
• Lamellation (layering) of both glomerular and tubular basement membranes, a hallmark histologic feature. 8, 1

Extrarenal Manifestations

Sensorineural hearing loss:

• Affects high-frequency tones specifically due to cochlear basement membrane abnormalities. 8, 1
• Typically progressive or late-onset in nature. 8

Ocular abnormalities:

• Anterior lenticonus (cone-shaped deformation of the lens) is characteristic. 1, 2
• Other vision problems may occur due to lens changes. 2

Clinical Variability and Prognosis

Disease severity varies significantly based on:

• Inheritance pattern: Autosomal recessive Alport syndrome and males with X-linked Alport syndrome typically have more severe disease, whereas autosomal dominant Alport syndrome and females with X-linked Alport syndrome show greater variability. 5
• Variant type: Protein-truncating variants often present with severe symptoms including kidney failure and extrarenal manifestations, while missense variants may display milder forms with protracted kidney involvement. 5
• Specific gene(s) affected: The course and prognosis are influenced by which collagen genes harbor mutations. 8, 1

Important caveat: Many patients with renal disease from causal variants in Alport genes may have no extrarenal manifestations, and the spectrum of renal phenotypes ranges widely. 6

Diagnostic Approach

Genetic testing is now the gold standard:

• Identifies specific COL4A3/4/5 mutations and determines inheritance pattern. 1
• Has largely replaced kidney biopsy as the primary diagnostic method. 1
• Indicated when clinical features suggest hereditary kidney disease. 1

Renal biopsy with electron microscopy:

• Remains definitive when genetic testing is unavailable or inconclusive. 1
• Shows characteristic GBM splitting and basement membrane lamellation. 8, 1

Clinical evaluation should assess:

• Family history (three to four generations) with attention to hearing status and renal disease. 6
• Visual anomalies including retinitis pigmentosa, myopia, retinal detachment, and early cataracts. 6
• Renal abnormalities including hematuria, proteinuria, and structural defects. 6
• Audiometric characteristics in affected family members. 6

Critical Diagnostic Distinctions

Alport syndrome must be differentiated from:

• Thin Basement Membrane disease: Typically has negative family history of renal failure, while Alport syndrome characteristically shows positive family history. 1
• IgA Nephropathy: Can present with similar hematuria and proteinuria. 8, 1

Special Considerations

Kidney donation is contraindicated in individuals with Alport syndrome due to the positive family history of renal failure and progressive nature of the disease. 1

Genetic counseling should be offered to families with confirmed clinical and/or genetic diagnosis, including cascade screening of relatives. 6