What is Alport’s syndrome?

Alport’s syndrome

It is an X-linked inherited (X linked recessive) disorder, rare and primarily affects glomerular basement membrane (GBM). 

It is caused by the mutation or deletion of the COL4A5 gene on Chromosome Xq22-24 which encode α5(IV) collagen chain of Type IV Collagen fibre (85% cases). In 15% cases, a mutation occurs in COL4A3 and COL4A4 gene of 2q35–37 (autosome) which encode α3(IV) collagen chain and α4(IV) collagen chain of Type IV Collagen fibre respectively, and inheritance is autosomal recessive.

[image from Davidsons Principles and Practice of Medicine 23 edition; Fig: 15.14; page: 404]

Clinical features of Alport’s syndrome:

Due to mutation, abnormal collagen fibres are produced and accumulated in GBM which causes progressive degeneration of it. The affected patient usually starts problems with hematuria, proteinuria and progress to ESRD in their late teens or twenties.

As the same collagen fibre present in some other sites of the body (in basement membrane) like the cochlea, beside renal symptoms, additional symptoms of Alport’s syndrome include

• Ear: Sensorineural deafness or high-frequency nerve deafness
• Eyes: Lenticonus of the anterior lens capsule (bilateral), "dot and fleck" retinopathy (macular and peri-macular retinal area) etc

Diagnosis of Alport’s syndrome:

• Clinical evaluation of eye, and hearing test
• Urine examination for hematuria and proteinuria
• Renal biopsy: GBM may be thin (in early-stage), thicken unevenly and turned into the splitting and degenerated membrane (in late-stage)
• Skin biopsy: Since α5(IV) collagen is expressed in the skin, some X-linked Alport patients can be diagnosed with a skin biopsy revealing the lack of the α5(IV) collagen chain on immunofluorescent analysis

Treatment of Alport’s syndrome:

• Control of hypertension by ACE inhibitor. It may slow the progression of the disease.
• Renal transplantation (allograft)

Complication following the renal transplantation:

Some patients with Alport’s syndrome develop anti-GBM antibodies after renal transplantation. The risk is greatest in patients with a large deletion in the gene encoding the α-3 chain of type IV collagen, in which case the Goodpasture antigen is not expressed and therefore the Goodpasture antigen in the transplanted organ is recognized as foreign. Some 5% of patients with transplants for Alport’s syndrome will develop the anti-GBM disease.

Addition:

About Type IV collagen fibre

Type-IV collagen is a type of collagen found primarily in the basal lamina. 

There are six human genes associated with it: Those are COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6 which encodes Collagen alpha-1(IV) chain, Collagen alpha-2(IV) chain, Collagen alpha-3(IV) chain, Collagen alpha-4(IV) chain, Collagen alpha-5(IV) chain, Collagen alpha-6(IV) chain respectively. These are the proteins, constituent of Collage type IV.

Source: Davidson and Harrison