Alport syndrome

Alport syndrome is a genetic disorder caused by mutations in genes responsible for producing type IV collagen, a key component of the basement membranes in the kidneys, inner ear, and eyes, and is characterized by progressive kidney disease, sensorineural hearing loss, and ocular abnormalities.

Alport syndrome results from mutations in the COL4A3, COL4A4, or COL4A5 genes encoding collagen IV α3, α4, and α5 chains. Most cases are inherited X-linked (80%) due to mutations in the COL4A5 gene, while mutations in COL4A3 and COL4A4 genes are inherited in autosomal recessive (15%) or dominant (5%) form. Mutations in more than one gene can occur, known as the digenic form. Abnormal synthesis of α3, α4, or α5 chains, the inability to form proper collagen IV triple helices, and podocyte damage and depletion lead to splitting, lamellation, and thinning of the GBM in kidney glomeruli, cochlea, cornea, lenses, and retina, resulting in glomerulosclerosis, sensorineural hearing loss, corenal erosions, anterior lenticonus, cataracts, and fleck retinopathy.

The prevalence of Alport syndrome is estimated at 1 per 10,000 for X-linked forms and 1 per 50,000 for autosomal recessive forms. Autosomal dominant Alport syndrome is the rarest form, accounting for only 5% of all cases.

Alport syndrome can be associated with other inherited diseases of the GBM, such as thin basement membrane disease and nail-patella syndrome. Anti-GBM disease, leiomyomatosis, and aortic aneurysms have also been reported to occure with Alport syndrome.

The clinical course of Alport syndrome varies with the type of genetic mutation and inheritance pattern. It typically presents with microhematuria, proteinuria, sensorineural hearing loss, and ocular abnormalities such as visual impairment, anterior lenticonus, and dot-fleck retinopathy. Renal failure progresses to ESRD in young adulthood. X-linked Alport syndrome has a less severe course in females compared to males, with variable kidney outcomes in females due to variable chromosome X inactivation. Autosomal dominant Alport syndrome typically shows more gradual loss of kidney function. Hearing loss and ocular abnormalities are often seen in X-linked and autosomal recessive Alport syndrome.

The prognosis of Alport syndrome depends on the inheritance pattern and sex. ESRD develops by age 40 in 90% of males with X-linked Alport syndrome and 12% of heterozygous females. Most patients with autosomal recessive Alport syndrome develop ESRD by age 30, while autosomal dominant Alport syndrome shows a slower progression of kidney failure.