Alport Syndrome Pathophysiology

First described in the early 20th century, Alport syndrome (AS), also known as hereditary nephritis, is a rare genetic disorder. Mutations in genes encoding type IV collagen give rise to primary basement membrane disruption and are implicated in AS.

It is the second commonest inherited cause of renal failure and is characterized by sensorineural (hearing) and ocular (visual) abnormalities in addition to progressive kidney dysfunction. Approximately 1 in 50,000 newborns may be affected by the condition and it accounts for up to 2.3 percent of newly diagnosed end-stage renal disease (ESRD) cases. Young men are most commonly affected, but cases involving women and older people are not unusual.

Hematuria (i.e., blood in the urine) is the clinical hallmark of the disease. Affected infants may have hematuria with normal renal and hearing functions. However, abnormalities begin to develop as the child grows older and progressively become more severe in adolescence and early adulthood.

Kidney failure may ensue by the third decade of life. There is no full loss of hearing and devices may be used to aid the patient. Likewise, eye changes may occur with rarely any dramatic effects to vision.

Genetics

AS may be inherited in three ways. The first and most common, approximately 90% of cases, is inherited in an X-linked fashion and is called X-linked Alport Syndrome (XL-AS). Because men have only one X chromosome, they are much more severely affected in comparison to women who have two X chromosomes. Unlike XL-AS, the second mode of inheritance, autosomal recessive Alport syndrome (AR-AS) shows similarities in terms of disease severity between affected males and females. Lastly, there is an autosomal dominant Alport syndrome (AD-AS), which shows equal disease severity between both sexes.
 

About half of all affected XL-AS males will develop renal failure by their mid twenties, which increases to about 9 in every 10 men by the fourth decade of life and nearly all of them by the age of 60. On the other hand, XL-AS females may not develop any renal pathology at all, but if they do, it is typically much later on in their lifetime.

The chances of developing renal insufficiency increases as an XL-AS female grows older. In contrast to XL-AS, both males and females with AR-AS develop renal failure in their adolescent or early adulthood years. Men and women affected with AD-AS tend to have a slower onset of kidney failure, which typically occurs well into their adult years.

Mutations

The mutations in genes COL-4A3, 4A4 and 4A5, which are usually responsible for encoding the protein called collagen type IV, cause AS. This protein is crucial to the glomeruli, which are important structures required for the filtration of blood in the kidneys. Mutations in the genes responsible for collagen type IV leads to glomerular basement membrane abnormalities and ultimately prevents proper filtration and results in gradual scaring, dysfunction and failure of the kidneys.

Collagen type IV is also found in the components of the inner ear structures, which are critical for the transformation of sound waves into neural impulses. Hence, abnormalities here result in hearing loss. In addition to the ear, collagen type IV is also found in the eye and is responsible for the maintenance of the lens shape and the color of the retina.

COL4A5 mutations are found in XL-AS patients. COL4A3 or COL4A4 mutations in both copies of either gene are found in AR-AS patients, while mutations in only one copy of either gene are found in AD-AS patients. Being a genetic disorder, there is no cure for AS. Treatment is entirely symptomatic and drugs may be used to delay the onset of renal failure, which ultimately may require a kidney transplant.