By Clifford E. Kashtan, MD

Alport syndrome is an inherited disease of the kidney, inner ear (cochlea) and eye caused by genetic mutations that affect the type IV collagen family of proteins. Type IV collagen is a major part of important tissue structures known as basement membranes. Abnormal basement membranes in the kidney, cochlea and eye are responsible for the clinical features of Alport syndrome.

Type IV collagen is a family of six proteins, or chains, known as alpha-1 through alpha-6 chains. Alport syndrome is caused by mutations that affect the alpha-3, alpha-4 or alpha-5 type IV collagen chains.

Three Genetic Types of Alport Syndrome X-linked Alport syndrome is the most common form, accounting for at least 80 percent of people with the disease. X-linked Alport syndrome results from mutations in the gene that produces the alpha-5 chain of type IV collagen, which is located on the X chromosome. Males have only one X chromosome, so boys with mutations in the alpha-5 chain are severely affected and always develop kidney failure sometime in their lives, because they do not have a normal copy of the gene to buffer the effect of the mutant gene. Girls, who have two X chromosomes, have two copies of the alpha-5 chain gene. In girls with X-linked Alport syndrome, one copy of the alpha-5 chain gene carries a mutation, but the other copy is normal. The normal copy of the gene counters the effect of the mutation, so that girls with X-linked Alport syndrome usually have milder symptoms than boys. However, girls with X-linked Alport syndrome may also develop kidney failure.

Because men pass their X chromosomes to their daughters but not to their sons, a man with X-linked Alport syndrome will pass the disease to all of his daughters but his sons cannot inherit the disease. As for a woman with X-linked Alport syndrome, every time she is pregnant there is a 50:50 chance she will pass the X chromosome carrying the mutant alpha-5 chain gene (and the disease) to the baby, whether the baby is a girl or a boy.

At least 15 percent of people with Alport syndrome have the autosomal recessive form of the disease. The genes that make the alpha-3 and alpha-4 type IV collagen chains are located on chromosome 2. Everyone has two copies of chromosome 2, so everyone has two copies of the alpha-3 and alpha-4 chain genes. Autosomal recessive Alport syndrome results when a person has mutations in both copies of the alpha-3 chain gene or the alpha-4 chain gene. Unlike X-linked Alport syndrome, the autosomal recessive type affects girls just as severely as boys.

A person with autosomal recessive Alport syndrome can only pass one of their mutant copies of the alpha-3 or alpha-4 chain gene to a child. Therefore, the risk of passing this type of disease to children is almost zero. However, each child of a person with autosomal recessive Alport syndrome carries one mutant copy of the affected gene.  

At least five percent of people with Alport syndrome have the autosomal dominant form of the disease. These people have one mutant copy of the alpha-3 or alpha-4 chain gene. Most of these people will have blood in their urine, without any other symptoms of kidney disease such as protein in the urine or high blood pressure. People carrying a mutation in one copy of the alpha-3 or alpha-4 chain gene, who have blood in the urine without any other symptoms of kidney disease and no family history of kidney failure, are said to have Thin Basement Membrane Nephropathy. On occasion, a person with a mutation in one copy of the alpha-3 or alpha-4 chain gene has protein in the urine and other symptoms of kidney disease in addition to blood in the urine. These people are said to have autosomal dominant Alport syndrome.

Every time a person with a mutation in one copy of the alpha-3 or alpha-4 chain gene has a child, there is a 50:50 chance that the child will inherit the mutant copy of the gene.

Clinical Features of Alport Syndrome

People with Alport syndrome always have kidney involvement. Many people with the disease also have deafness and abnormalities of the eyes, because the type IV collagen proteins are important to the normal structure and function of the cochlea and the eye.

The hallmark of Alport syndrome is blood in the urine (hematuria). In boys with X-linked Alport syndrome, hematuria first appears in early childhood and their urine always tests positive for blood. More than 90 percent of girls with X-linked Alport syndrome have hematuria, but it may be intermittent. Some girls who carry a mutation in the alpha-5 chain gene do not have blood in their urine.

All boys and girls with autosomal recessive Alport syndrome have hematuria. Most people who carry a mutation in one copy of the alpha-3 or alpha-4 chain genes have hematuria, but some do not.

The hematuria of Alport syndrome is usually microscopic, meaning it can only be detected with a microscope or a urine dipstick. Sometimes children with Alport Syndrome have brown, pink or red urine (gross hematuria) for several days, associated with a cold or the flu. This gross hematuria eventually stops on its own. It can be frightening, but it is not harmful.

As boys with Alport syndrome get older, they begin to show additional signs of kidney disease, such as protein in the urine (proteinuria) and high blood pressure. These symptoms are often present by the time the boys are teenagers. Girls with Alport syndrome usually do not have protein in the urine and high blood pressure until much later in life, but occasionally these symptoms appear in childhood or adolescence.

Deafness is an important feature of Alport syndrome. At least 80 percent of boys with the disease develop deafness at some point in their lives, often by adolescence. Fortunately, hearing aids are usually very effective in boys with deafness caused by Alport syndrome. Girls with the disease may also develop deafness, but less frequently than boys, and usually later in life. 

At least 15 percent of men with Alport syndrome have an abnormality in the shape of the lens called anterior lenticonus, which may cause problems with vision and lead to cataract formation. Some people with Alport syndrome have abnormal pigmentation of the retina, but this does not result in any abnormalities of vision. Recurrent corneal erosion is another eye problem that can occur in people with Alport syndrome.

Prognosis of Alport Syndrome

Alport syndrome causes progressive damage to the kidneys through the gradual replacement of normal kidney structures (glomeruli and tubules) by scar tissue. This process is known as fibrosis. All boys with X-linked Alport syndrome eventually develop kidney failure. Dialysis or transplantation often becomes necessary by adolescence or early adulthood, but kidney failure may be de- layed until 40 to 50 years of age in some men with Alport syndrome. Most girls with X-linked Alport syndrome do not develop kidney failure. However, as women with Alport syndrome age, the risk of kidney failure increases. 

Usually by their teens or young adult years, all boys and girls with autosomal recessive Alport syndrome develop kidney failure. People with autosomal dominant Alport syndrome are usually well into middle age before kidney failure develops.

Diagnosis of Alport Syndrome

The diagnosis of Alport syndrome is based on careful evaluation of the patient’s clinical features, family history and results of tissue biopsies. Alport syndrome produces unique changes in the walls of the blood vessels of the glomeruli that can be detected by electron microscopy of kidney biopsy material. Kidney biopsies can also test for the presence or absence of the type IV collagen alpha-3, alpha-4 and alpha-5 chains. This information is often very helpful in confirming a suspected diagnosis of Alport syndrome. Skin biopsy can be used to diagnose X-linked Alport syndrome. The type IV collagen alpha-5 chain is normally present in the skin. In most males with X-linked Alport syndrome, the alpha-5 chain is completely missing from the skin.

In some people with hematuria, it is difficult to determine whether they have Alport syndrome or Thin Basement Membrane Nephropathy, even after a kidney biopsy, because these conditions can have a very similar appearance, especially in children. In these cases, the true diagnosis may not become clear until years later.

It is possible to diagnosis Alport syndrome by examining the alpha-3, alpha-4 and alpha-5 chain genes. However, this kind of testing is not yet commercially available in the United States.

Treatment of Alport Syndrome:

Good News and Bad

First, the bad news. There is no treatment that has been proven to prevent the development of kidney failure in people with Alport syndrome. It is very important for people with Alport syndrome to be examined regularly by a nephrologist, so that effects of the kidney disease, such as hypertension, can be identified early and treated. Many nephrologists will consider using a type of antihypertensive agent that interferes with the production or action of angio- tensin, because these medications can slow the progression of other types of kidney disease and have a low occurrence of major side effects. Regular hearing evaluation is important after about 8-years-of-age.

Kidney transplantation has a very high success rate in people with Alport syndrome and is the best treatment when end-stage renal failure is approaching. Because Alport syndrome is a familial condition, related kidney donors must be carefully evaluated for the disease. Under most circumstances, a carrier of a mutation in one of the type IV collagen chain genes should not be a kidney donor.

The good news is that we have very good animal models of Alport syndrome in mice and dogs. These models are being used in studies of the mechanisms of kidney injury in Alport syndrome and to test potential therapies. There is reason to hope that this research will eventually identify ways to delay or even prevent kidney failure in people with Alport syndrome.

Clifford E. Kashtan, MD, is a Professor of Pediatrics in the Division of Pediatric Nephrology at the University of Minnesota. Dr. Kashtan has a long-standing research interest in Alport syndrome, focusing on the use of animal models to understand the disease and develop effective treatments.

This article originally appeared in the July 2004 issue of aakpRENALIFE, Vol. 20, No. 1.

Back