Alport syndrome is an X-linked recessive hereditary nephritis due to type IV collage defect in the GBM often accompanied by haematuria, sensorineural deafness and eye abnormalities, with the most common renal imaging finding being bilateral renal cortical thinning and increased echogenicity.
Description
Alport syndrome is a genetic disorder affecting the basement membranes of the kidneys, ears, and eyes, leading to end-stage renal disease (ESRD), sensorineural hearing loss, and ocular abnormalities. The condition is mainly due to mutations in the COL4A5 gene on the X chromosome, which encodes the type IV collagen alpha-5 chain, a crucial component of basement membranes.
Pathogenesis
The COL4A5 mutations lead to abnormalities in the synthesis or assembly of the type IV collagen network, disrupting the structural integrity of the glomerular basement membrane (GBM). This causes the GBM to become progressively thickened and irregular, leading to glomerular filtration barrier damage and haematuria. Subsequent progressive fibrosis results in renal failure. Similarly, defects in basement membranes in the cochlea and eyes result in sensorineural deafness and various ocular abnormalities.
Subtypes
Alport syndrome is classified based on its pattern of inheritance:
- X-linked Alport syndrome (most common, accounts for approximately 85% of cases)
- Autosomal recessive Alport syndrome
- Autosomal dominant Alport syndrome
Epidemiology, Risk Factors & Associations
- Occurs in all ethnic groups and regions (prevalence: 1 in 5,000-10,000 individuals)
- Males with X-linked Alport syndrome are most severely affected
Clinical Features
- Haematuria (earliest sign)
- Proteinuria
- Progressive renal dysfunction leading to ESRD
- Sensorineural hearing loss (typically starting during late childhood or adolescence)
- Ocular abnormalities (anterior lenticonus, corneal opacities)
Complications
- ESRD, typically by young adulthood in males with the X-linked form
- High-frequency sensorineural hearing loss
- Vision problems due to ocular abnormalities
Pathological Features
Histopathology
- Macroscopic: Kidneys may be normal or reduced in size in late disease stages
- Microscopic: Irregular thickening and thinning of GBM, “basket weave” appearance of the GBM on electron microscopy
Serology
- Genotyping to identify mutations in COL4A5 or other relevant genes
Biochemistry
- Increased creatinine and urea levels as kidney function declines
Radiological Features
General Features
- Kidneys may initially appear normal or show mild enlargement on imaging
- In the later stages, bilateral renal cortical thinning and increased echogenicity
- In some cases, bilateral small kidneys
US
- B-mode: Increased renal cortical echogenicity
- Colour: Not typically applied in this context
Diagnosis
- The diagnosis is made based on clinical features, renal biopsy findings, and genetic testing
- Urinalysis typically shows persistent haematuria
Differential Diagnosis
- Other causes of chronic kidney disease and haematuria, such as IgA nephropathy, thin basement membrane disease, and post-streptococcal glomerulonephritis
Prognosis
- Most males with X-linked Alport syndrome develop ESRD by age 40
- The prognosis is typically better for females and for individuals with the autosomal forms of the disease
Management
- Management typically involves a nephrologist and may include ACE inhibitors to slow disease progression, hearing aids for sensorineural deafness, and renal transplantation for ESRD
- Genetic counselling is recommended for affected individuals and their families