Question
A 21-year-old male is referred to the renal clinic for long-standing asymptomatic haematuria detected since early childhood. Over the years, he has developed gradual decline in hearing and now complains of reduced exercise tolerance. His mother is well, but one of her brothers developed kidney failure in his third decade. Urine examination shows proteinuria. Electron microscopy of a renal biopsy demonstrates irregular thickening and splitting of the glomerular basement membrane.
Which pattern of inheritance most plausibly explains this condition?
A. Autosomal recessive
B. Autosomal dominant
C. X-linked dominant
D. Mitochondrial
E. Y-linked
Answer
C. X-linked dominant
Detailed discussion for MRCP
This clinical picture is classic for Alport syndrome, a hereditary disorder of type IV collagen that primarily affects the kidneys, inner ear, and eyes. The glomerular basement membrane (GBM) is rich in type IV collagen, particularly the α3, α4, and α5 chains. Mutations in the genes encoding these chains lead to structurally abnormal GBM, which progressively deteriorates with time.
The most common genetic abnormality involves the COL4A5 gene on the X chromosome, resulting in X-linked dominant inheritance. Because males have only one X chromosome, they express the disease fully and typically present earlier with more severe manifestations, including progression to end-stage kidney disease in early adulthood. Females, having two X chromosomes, are usually carriers and often have milder disease due to lyonisation, although some may still develop significant renal disease.
Key renal features include persistent microscopic haematuria (often the earliest sign), progressive proteinuria, and eventual renal failure. The characteristic electron microscopy finding is splitting and lamellation of the lamina densa, producing the classic “basket-weave” appearance. Light microscopy may initially be normal, making electron microscopy crucial for diagnosis.
Extra-renal features are important exam clues. Bilateral sensorineural hearing loss is common and usually affects high frequencies. Ocular manifestations include anterior lenticonus (pathognomonic), perimacular flecks, and, less commonly, retinitis pigmentosa.
Autosomal recessive Alport syndrome accounts for about 10–15% of cases and is due to COL4A3 or COL4A4 mutations. These patients can resemble affected males with X-linked disease but usually lack the typical X-linked pedigree. Autosomal dominant disease is rare and generally milder. A high-yield MRCP point is that patients with Alport syndrome who receive a renal transplant may develop anti-GBM nephritis post-transplant, as their immune system recognises normal type IV collagen in the graft as foreign, producing a Goodpasture-like picture.
Cheat sheet
- Cause: mutation in type IV collagen genes
- Commonest gene: COL4A5 (X chromosome)
- Inheritance: X-linked dominant (~85%)
- Renal features: microscopic haematuria → proteinuria → renal failure
- EM finding: splitting/lamellation of lamina densa (“basket weave”)
- Hearing: bilateral sensorineural deafness
- Eye signs: anterior lenticonus, retinal flecks
- Males: severe, early ESRD
- Females: carriers, milder disease
- Post-transplant risk: anti-GBM nephritis
Flash cards
Q1: What structural protein is defective in Alport syndrome?
A: Type IV collagen.
Explanation: Type IV collagen forms the scaffold of the GBM; defects weaken the filtration barrier.
Q2: Which gene is most commonly mutated in Alport syndrome?
A: COL4A5.
Explanation: COL4A5 mutations cause the X-linked dominant form.
Q3: What is the earliest renal manifestation?
A: Persistent microscopic haematuria.
Explanation: It often appears in childhood before proteinuria.
Q4: Why are males more severely affected?
A: They have only one X chromosome.
Explanation: No normal allele is available to compensate.
Q5: What hearing abnormality is typical?
A: Bilateral sensorineural hearing loss.
Explanation: Due to basement membrane defects in the cochlea.
Q6: Which ocular feature is pathognomonic?
A: Anterior lenticonus.
Explanation: Lens protrusion into the anterior chamber is highly suggestive.
Q7: What EM finding is characteristic?
A: Basket-weave appearance of the GBM.
Explanation: Caused by splitting of the lamina densa.
Q8: What inheritance accounts for ~10–15% of cases?
A: Autosomal recessive.
Explanation: Usually due to COL4A3 or COL4A4 mutations.
Q9: Which inheritance pattern is rare in Alport syndrome?
A: Autosomal dominant.
Explanation: Produces a milder phenotype.
Q10: What complication can occur after renal transplantation?
A: Anti-GBM nephritis.
Explanation: Recipient forms antibodies against normal type IV collagen.
Q11: Which chromosome carries COL4A5?
A: X chromosome.
Explanation: Explains maternal transmission to affected males.
Q12: What urine finding suggests progression?
A: Increasing proteinuria.
Explanation: Indicates worsening GBM damage.
Q13: Why is light microscopy often normal early?
A: Structural defects are ultrastructural.
Explanation: EM is required for diagnosis.
Q14: What family history pattern supports X-linked disease?
A: Affected maternal male relatives.
Explanation: Transmission occurs through carrier females.
Q15: What retinal finding may be seen?
A: Perimacular flecks.
Explanation: Reflects basement membrane abnormalities.
Q16: What is lyonisation?
A: Random X chromosome inactivation.
Explanation: Explains variable severity in females.
Q17: What is the usual age of renal failure in affected males?
A: Second to third decade.
Explanation: Progressive GBM damage accelerates renal loss.
Q18: What lab abnormality often precedes renal failure?
A: Persistent haematuria.
Explanation: It is the earliest marker.
Q19: Which collagen chains are involved?
A: α3, α4, and α5 chains.
Explanation: These are essential for GBM integrity.
Q20: What is the main diagnostic approach today?
A: Molecular genetic testing.
Explanation: Confirms diagnosis and inheritance pattern.
MCQs to test yourself
- The most common inheritance pattern in Alport syndrome is:
A. Autosomal recessive
B. X-linked dominant
C. Y-linked
D. Mitochondrial
E. Autosomal dominant
Answer: B – accounts for ~85% of cases. - The characteristic EM finding in Alport syndrome is:
A. Subepithelial humps
B. Diffuse GBM thinning only
C. Basket-weave GBM splitting
D. Mesangial expansion
E. Crescents
Answer: C – due to lamina densa splitting. - Which collagen type is affected?
A. Type I
B. Type II
C. Type III
D. Type IV
E. Type V
Answer: D – major GBM component. - Which clinical feature is most specific?
A. Microscopic haematuria
B. Proteinuria
C. Anterior lenticonus
D. Hypertension
E. Oedema
Answer: C – pathognomonic ocular sign. - In X-linked Alport syndrome, females usually:
A. Are unaffected
B. Have severe early renal failure
C. Die in childhood
D. Are carriers with milder disease
E. Have normal kidneys always
Answer: D – due to lyonisation. - Which of the following is false regarding Alport syndrome?
A. It can cause sensorineural deafness
B. It may present in childhood
C. It commonly shows basket-weave GBM
D. It is always autosomal recessive
E. It can progress to ESRD
Answer: D – most cases are X-linked. - Which gene is mutated in X-linked disease?
A. COL1A1
B. COL2A1
C. COL3A1
D. COL4A5
E. COL5A1
Answer: D – located on the X chromosome. - A post-transplant complication unique to Alport syndrome is:
A. Acute rejection
B. Recurrent IgA nephropathy
C. Anti-GBM disease
D. Amyloidosis
E. FSGS recurrence
Answer: C – due to antibodies against normal GBM collagen. - Which hearing loss is typical?
A. Conductive
B. Mixed
C. Sensorineural
D. Central
E. Noise-induced only
Answer: C – bilateral sensorineural. - Which inheritance would show affected males only with father-to-son transmission?
A. Autosomal dominant
B. Autosomal recessive
C. X-linked dominant
D. Mitochondrial
E. Y-linked
Answer: E – not seen in Alport syndrome. - Which of the following is false?
A. Renal biopsy may be normal on light microscopy early
B. EM is diagnostic
C. Hearing loss precedes haematuria
D. Proteinuria suggests progression
E. Renal failure may occur in young adults
Answer: C – haematuria usually appears first. - Autosomal recessive Alport syndrome accounts for approximately:
A. <1%
B. 1–5%
C. 10–15%
D. 30–40%
E. >50%
Answer: C – minority of cases. - Which ocular abnormality involves lens protrusion?
A. Cataract
B. Glaucoma
C. Lenticonus
D. Retinal detachment
E. Uveitis
Answer: C – anterior lenticonus. - The “basket-weave” appearance results from:
A. Immune complex deposition
B. GBM thinning
C. Splitting of lamina densa
D. Podocyte effacement
E. Mesangial hypercellularity
Answer: C – hallmark EM feature. - Which family history best fits X-linked disease?
A. Affected father and son
B. Affected mother and all children
C. Affected maternal uncle and nephew
D. Only sisters affected
E. Only females affected
Answer: C – transmission through carrier females. - Which of the following is false?
A. Males progress faster than females
B. Females can be asymptomatic
C. Disease affects type IV collagen
D. It is caused by immune complex deposition
E. Sensorineural deafness is common
Answer: D – pathology is structural, not immune complex. - Which test is increasingly first-line for diagnosis?
A. Ultrasound
B. Light microscopy
C. Serology
D. Genetic testing
E. IV pyelogram
Answer: D – confirms mutation and inheritance. - Which collagen chains are involved?
A. α1 and α2 only
B. α3, α4, α5
C. α6 only
D. β chains
E. Elastin
Answer: B – essential for GBM strength. - Which presentation is typical in childhood?
A. Nephrotic syndrome
B. Gross haematuria after infections only
C. Persistent microscopic haematuria
D. Acute kidney injury
E. Renal colic
Answer: C – earliest sign. - Which of the following best explains post-transplant anti-GBM disease?
A. Drug toxicity
B. Recurrence of original mutation
C. Antibodies against normal donor collagen
D. Viral infection
E. Ischaemia-reperfusion injury
Answer: C – immune response to normal type IV collagen.
Summary for quick exam revision
Alport syndrome is a hereditary disorder caused by mutations in type IV collagen, most commonly due to X-linked dominant inheritance involving the COL4A5 gene. It typically presents in childhood with persistent microscopic haematuria and progresses to proteinuria and renal failure, particularly in males who are more severely affected. Females are usually carriers with milder disease due to lyonisation. Extra-renal features include bilateral sensorineural hearing loss and characteristic ocular abnormalities such as anterior lenticonus. The hallmark diagnostic finding on electron microscopy is splitting and lamellation of the lamina densa of the glomerular basement membrane, producing a basket-weave appearance. Autosomal recessive forms account for a minority of cases, while autosomal dominant disease is rare. Genetic testing is now central to diagnosis and counselling. A high-yield exam point is the risk of anti-GBM nephritis after renal transplantation due to antibodies formed against normal donor type IV collagen.