- Etiology/Pathophysiology
- Genetic defect in Type IV collagen, a critical structural component of basement membranes.
- Inheritance is most commonly X-linked dominant (~85%), due to a mutation in the COL4A5 gene. Autosomal recessive and dominant forms (COL4A3, COL4A4) are less common.
- Defective collagen leads to progressive thinning, splitting, and lamellation of basement membranes, particularly in the glomerulus, cochlea, and eye.
- Clinical Features
- Classic Triad: Nephritis + Sensorineural Hearing Loss + Ocular abnormalities.
- Mnemonic: “Can’t see, can’t pee, can’t hear a bee.”
- Renal:
- Presents initially as microscopic hematuria in childhood.
- Progresses to persistent hematuria, proteinuria, hypertension, and ultimately end-stage renal disease (ESRD), often in the 2nd-3rd decade of life in males.
- Auditory:
- Bilateral, high-frequency sensorineural hearing loss that develops during late childhood or adolescence.
- Ocular:
- Anterior lenticonus (cone-shaped lens) is pathognomonic.
- Other findings: Perimacular flecks (retinopathy), corneal erosions.
- Diagnostics
- Urinalysis: Hematuria (often with dysmorphic RBCs and RBC casts), progressing to significant proteinuria.
- Renal Biopsy:
- Light Microscopy: Initially normal, later shows non-specific focal segmental glomerulosclerosis (FSGS).
- Immunofluorescence: Negative for immune deposits. May show absent staining for the α5 chain of Type IV collagen in the GBM.
- Electron Microscopy (EM): Definitive diagnosis. Shows alternating thick and thin GBM with splitting and lamellation, creating a “basket-weave” appearance.
- Genetic Testing: Confirms mutation in COL4A genes.
- Treatment
- No curative therapy. Management is supportive.
- ACE inhibitors or ARBs are first-line to slow the progression of chronic kidney disease by reducing proteinuria and controlling hypertension.
- Management of ESRD requires dialysis or renal transplantation.
- Hearing aids for hearing loss.
- Differential Diagnosis
- Thin Basement Membrane Disease (Benign Familial Hematuria): Also a Type IV collagen defect. Presents with persistent microscopic hematuria but has a benign course with no progression to ESRD, hearing loss, or ocular defects. EM shows a uniformly thinned GBM.