What is Alport disease?

What is Alport Syndrome?

Alport syndrome is a hereditary genetic disorder caused by mutations in genes encoding type IV collagen (COL4A3, COL4A4, or 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, 2, 3

Genetic Basis and Inheritance Patterns

Alport syndrome manifests in three distinct inheritance patterns based on the affected gene:

• X-linked Alport syndrome (XLAS) accounts for 80% of cases and results from pathogenic variants in COL4A5 3, 4
• Autosomal recessive Alport syndrome (ARAS) represents 15% of cases, caused by mutations in either COL4A3 or COL4A4 3, 4
• Autosomal dominant Alport syndrome (ADAS) is the rarest form at 5% of cases, also involving COL4A3 or COL4A4 mutations 3, 5

Recent evidence suggests that autosomal dominant inheritance may actually be more common than previously recognized 5

Pathophysiology and Structural Abnormalities

The fundamental defect involves abnormal type IV collagen in basement membranes throughout the body:

• Glomerular basement membrane (GBM) shows characteristic thinning, splitting, and lamellation on electron microscopy 1, 2
• Tubular basement membranes demonstrate lamellation (layering), a hallmark histologic feature 1
• Cochlear basement membrane abnormalities cause the characteristic high-frequency sensorineural hearing loss 1, 2

Clinical Manifestations

Renal Features

• Hematuria is present from early childhood and represents the earliest manifestation 2
• Proteinuria develops progressively over time 1
• Progressive renal insufficiency leads to end-stage renal disease, with timing dependent on genotype and inheritance pattern 6, 2
• Kidneys may appear normal or small on ultrasound depending on disease stage 1

Extrarenal Manifestations

• Sensorineural hearing loss affecting high-frequency tones develops later in the disease course, typically by middle age 1, 2, 7
• Ocular abnormalities including anterior lenticonus (lens changes) can cause vision problems 2, 8

Diagnostic Approach

Genetic testing has replaced kidney biopsy as the first-line diagnostic method, providing more precise diagnosis and revealing the inheritance pattern. 5, 4

When to Suspect Alport Syndrome

Genetic testing is indicated when clinical features suggest hereditary kidney disease 6:

• Positive family history of kidney disease or renal failure 6, 2
• Early age of onset (pediatric CKD) 6
• Hematuria with progressive proteinuria 2
• Hearing loss in a patient with kidney disease 2
• Consanguinity in the family 6

Diagnostic Methods

• Genetic testing is the gold standard, identifying specific COL4A3/4/5 mutations and determining inheritance pattern 6, 5
• Renal biopsy with electron microscopy remains definitive when genetic testing is unavailable or inconclusive 1
• Treatment may proceed without biopsy when Alport syndrome is strongly suspected based on family history, pathogenic mutations, and characteristic extrarenal manifestations 1

Critical Diagnostic Distinctions

Alport syndrome must be differentiated from conditions with similar presentations 6, 2:

Thin Basement Membrane (TBM) Disease

• Gross hematuria occurs in less than 10% of TBM patients versus episodic gross hematuria possible in Alport syndrome 6
• TBM typically has negative family history of renal failure, while Alport syndrome characteristically shows positive family history 6, 2
• TBM and early Alport syndrome may be difficult to differentiate histologically 6

IgA Nephropathy

• Episodic gross hematuria is relatively common (40-50%) in IgA nephropathy 6
• Family history of renal failure may occur in isolated IgA cases but is typical in Alport syndrome 6

Goodpasture Syndrome

• Goodpasture syndrome presents acutely over days to weeks in previously healthy adults with rapidly progressive glomerulonephritis and pulmonary hemorrhage 2
• Alport syndrome has insidious onset from birth/childhood with manifestations appearing over years 2
• Critical pitfall: Alport patients may develop anti-GBM disease after kidney transplantation, requiring maintenance immunosuppression 2

Prognosis and Gender Considerations

Women with X-linked Alport syndrome are commonly underdiagnosed but face significant risk: 15-30% develop renal failure by age 60 and often experience hearing loss by middle age. 7

• Twice as many women are affected by X-linked disease compared to men 7
• Half of their sons and daughters are also affected 7
• Women with X-linked disease should be tested at least annually for albuminuria and hypertension 7
• Autosomal recessive disease is suspected when women develop early-onset renal failure or lenticonus 7

Current Management

There is no curative treatment for Alport syndrome; management focuses on slowing disease progression using ACE inhibitors or ARBs, which can delay kidney failure by years. 5, 4

• ACE inhibitors (or ARBs if ACEi not tolerated) are the mainstay of therapy and can remarkably delay progression to end-stage renal disease 5, 4
• Women with albuminuria should receive RAAS blockade with adequate birth control due to teratogenic risks 7
• Women with autosomal recessive disease should receive RAAS blockade from time of diagnosis 7
• Regular monitoring of kidney function and blood pressure is essential 8
• Kidney transplantation may be necessary for end-stage renal disease 8

Special Considerations

• Kidney donation: Donation is contraindicated in individuals with Alport syndrome due to the positive family history of renal failure and progressive nature of the disease 6
• Genetic counseling: All women with Alport syndrome should have genetic testing to confirm diagnosis, determine inheritance pattern, and assess risk to offspring 7
• Pregnancy monitoring: Women should be monitored closely during pregnancy for development of hypertension 7
• The course and prognosis are influenced by the specific gene(s) affected and mutation type 1, 4