Alport Syndrome
Nephrology
Illness script · Nephrology
Alport Syndrome
Hereditary nephritis caused by type IV collagen gene mutations (COL4A3/A4/A5) disrupting the glomerular basement membrane, cochlea, and lens.
This illness script for Alport Syndrome covers predisposing factors, classic presentation, mechanism, workup, management, and the clinical pivots that separate it from look-alikes—written for USMLE Step 1 and clerkship reasoning.
01
Predisposing factors
- X-linked (COL4A5) most common (~80%); males severely affected, females variably
- Autosomal recessive (COL4A3/A4): both sexes equally affected, earlier ESRD
- Autosomal dominant form: milder phenotype
- Family history of hematuria, renal failure, or early deafness
- Presents in childhood; ESRD by 20s–30s in affected males if X-linked
02
Presentation
- Persistent microscopic hematuria: earliest, universal finding (often identified in childhood)
- Episodic gross hematuria after URI (similar to IgA, but no IgA deposits)
- Sensorineural hearing loss: bilateral, high-frequency (develops in adolescence)
- Anterior lenticonus: pathognomonic ocular finding (oil-droplet reflex on fundoscopy)
- Progressive proteinuria and HTN as disease advances
- ESRD in untreated males by 2nd–3rd decade (X-linked)
03
Pathophysiology
- Mutations in COL4A3, COL4A4, or COL4A5 genes encoding type IV collagen α-chains
- Type IV collagen is critical structural component of GBM, cochlear basement membrane, and lens capsule
- Defective collagen → GBM thinning early → progressive lamellation, splitting, and glomerulosclerosis
- Loss of filtration barrier integrity causes hematuria, then proteinuria, then ESRD
04
Diagnostics
- Urinalysis: dysmorphic RBCs and RBC casts on microscopy
- Renal biopsy EM (gold standard): GBM thinning early → irregular thickening with lamellation/splitting ('basket-weave')
- Immunofluorescence: absent or interrupted α3/α4/α5 type IV collagen staining (distinguishes from TBMN)
- Genetic testing (COL4A3/A4/A5): increasingly first-line, avoids biopsy in classic presentations
- Audiometry: bilateral high-frequency sensorineural hearing loss
05
Management
- ACE inhibitors (first-line): slow proteinuria progression and delay ESRD onset
- ARBs if ACE inhibitor intolerant; aggressive BP control
- Renal transplant for ESRD — curative but ~3–5% risk of post-transplant anti-GBM nephritis (new antigen exposure)
- Genetic counseling for family members; screen with urinalysis
- Annual ophthalmology, audiology, and nephrology follow-up
06
Clinical pivots
How to separate this script from the look-alikes that show up on exams and on the wards.
Thin Basement Membrane Nephropathy (Benign Familial Hematuria)
EM shows only diffuse GBM thinning without lamellation; no hearing loss, ocular findings, or progression to ESRD.
IgA Nephropathy
Mesangial IgA deposits on immunofluorescence; no sensorineural hearing loss or anterior lenticonus; no family history of ESRD.
Anti-GBM Disease (Goodpasture Syndrome)
Linear IgG deposits on IF and circulating anti-GBM antibodies; acute onset in adults; no hereditary pattern or ocular findings.
Post-infectious Glomerulonephritis
Hematuria follows streptococcal infection with low complement; granular ('starry sky') IF; self-limited course without hearing loss.
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Educational use only. This illness script is a study framework, not medical advice. Confirm decisions with current guidelines and your clinical supervisors.