An 8-year-old boy presents with gross hematuria, mild proteinuria, and bilateral flank pain. His maternal uncle has chronic kidney disease on dialysis. Audiometry shows bilateral sensorineural hearing loss. Renal biopsy electron microscopy shows thinning, splitting, and lamellation of the glomerular basement membrane (GBM). The mode of inheritance and causative gene is most likely:
- A Autosomal recessive; NPHS1 (nephrin)
- B X-linked dominant; COL4A5 (type IV collagen alpha-5 chain) ✓
- C Autosomal dominant; COL4A3 (type IV collagen alpha-3 chain)
- D Mitochondrial; tRNA Leu mutation
Explanation
Alport syndrome is caused by mutations in genes encoding type IV collagen chains (COL4A3, COL4A4, COL4A5). The X-linked dominant form (COL4A5 mutation) is most common (80% of cases), presenting in males with hematuria, progressive CKD, and bilateral high-frequency sensorineural hearing loss. Electron microscopy of the GBM shows characteristic thinning, splitting, lamellation, and basket-weave pattern of the GBM. Females with the X-linked form are usually carriers with microscopic hematuria but can develop CKD. The autosomal recessive form (COL4A3 or COL4A4) causes severe disease in males and females equally. NPHS1 causes Finnish-type congenital nephrotic syndrome.
Reference: Ghai Essential Pediatrics, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.