GeneticsTier 2Medical Sciences concept

Alport syndrome - genetics and associated features

Core concept

Defective type IV collagen alpha-3/4/5 network of the glomerular basement membrane

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COL4A3/4/5 mutation

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Form	Gene	Share
X-linked	COL4A5	~65-85% - males severe, females variable (skewed X-inactivation)
Autosomal recessive	COL4A3 / COL4A4, biallelic	~15% - severe in both sexes
Autosomal dominant	COL4A3 / COL4A4, heterozygous	~5-20%; the same genotype as "thin basement membrane nephropathy"/benign familial haematuria - now regarded as mild Alport, with a real ESKD risk

There is no male-to-male transmission in X-linked disease; an affected father transmits to all daughters (obligate carriers) and no sons

The triad

Kidney - persistent glomerular haematuria from birth (dysmorphic RBC, RBC casts), episodic macroscopic haematuria with URTI, then proteinuria, hypertension, ESKD
- X-linked males: ESKD median ~25 yr with severe (truncating) mutations, ~40 yr with missense - genotype predicts age at ESKD
Ear - bilateral high-frequency sensorineural hearing loss, adolescence onward, never congenital
Eye - anterior lenticonus (pathognomonic), perimacular/dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy, recurrent corneal erosion
Leiomyomatosis (oesophageal, tracheobronchial, genital) with contiguous COL4A5-COL4A6 deletion
Diagnosis is genetic - NGS panel of COL4A3/4/5 on blood
- Biopsy: EM shows GBM thinning, splitting and basket-weave; IF shows absent alpha-5 (IV) staining in GBM and skin in X-linked males
- Skin biopsy alpha-5 staining is a quick test in X-linked disease but is normal in autosomal forms

Treat on proteinuria, not on eGFR - the earlier RAS blockade starts, the later ESKD occurs
- ACE inhibitor (ramipril) is first-line and started once microalbuminuria appears, even in normotensive children
- Add an SGLT2 inhibitor in adults with CKD and persistent albuminuria despite RAS blockade; not established in children
Transplantation works well, but ~3-5% of transplanted X-linked males develop anti-GBM disease against the alpha-3/5 chains they have never seen - early, aggressive, usually graft-lost, and a contraindication to re-grafting
Family screening - urinalysis and genetic testing of relatives; do not accept "familial benign haematuria" without genotyping
Living-related donation from a heterozygous COL4A3/4/5 relative is discouraged - they are not benign carriers
Annual audiometry, ophthalmology; hearing aids

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