Alport’s Syndrome

Alport’s syndrome is a rare genetic condition that affects the kidneys, ears, and eyes. It occurs when the body cannot produce normal proteins needed for healthy kidney function, which can lead to kidney failure over time.

Table of contents

• What is Alport’s syndrome?
• Causes and inheritance patterns
• Parts of the body affected
• Signs and symptoms
• How common is Alport’s syndrome?
• Diagnosis
• Treatment
• Lifestyle considerations
• Outlook

What is Alport’s syndrome?

Alport’s syndrome is a genetic condition in which the kidneys don’t produce normal type IV collagen proteins. Type IV collagen is a structural protein that acts like a foundation in several important parts of your body^[1].

This protein consists of three individual chains that twist together like rope. These chains are called alpha 3, alpha 4, and alpha 5. If your body doesn’t produce one of these chains correctly, the other chains cannot combine properly or don’t function as they should. This affects the filtering system in your kidneys, which is why people with Alport’s syndrome develop kidney problems^[1].

The syndrome was first identified in 1927 by British doctor A. Cecil Alport, who observed three generations of a family where multiple individuals had progressive kidney disease and hearing loss. Dr. Alport also noted that blood in the urine was the most common symptom and that males were affected more severely than females^[2].

Causes and inheritance patterns

Alport’s syndrome is caused by genetic mutations (changes in genes) that affect the genes responsible for making type IV collagen proteins. These genes are called COL4A3, COL4A4, and COL4A5^[4].

There are three different ways Alport’s syndrome can be inherited, which means three different patterns of how it passes from parents to children:

X-linked Alport syndrome (XLAS) is the most common type, accounting for about 60% to 80% of all cases. This type relates to the X chromosome, which is one of the two sex chromosomes (X and Y). The gene that produces the alpha 5 chain (COL4A5) is located on the X chromosome^[1].

Males have one X chromosome and one Y chromosome, while females have two X chromosomes. Because males only have one X chromosome, if it carries the mutation, they are more likely to have more severe symptoms. Females have one abnormal X chromosome and one normal X chromosome, so their symptoms are usually milder^[1].

Males cannot pass XLAS to their male children because they pass their Y chromosome to them. However, all of their female children will have Alport’s syndrome because males pass their X chromosome to all their daughters. Females have a 50% chance of passing XLAS to any of their children^[1].

Autosomal recessive Alport syndrome (ARAS) occurs when both parents carry an altered gene but don’t show any symptoms themselves. In this pattern, mutations occur in the COL4A3 or COL4A4 genes, which are located on chromosome 2. Both parents need to pass an altered gene to their child for the child to inherit the condition. If both parents carry the trait, one-quarter of their children will develop Alport’s syndrome^[1].

Autosomal dominant Alport syndrome (ADAS) occurs in about 20% to 30% of cases. People with this form have one mutation in either the COL4A3 or COL4A4 gene. In this pattern, only one parent needs to pass the altered gene for a child to potentially develop the condition^[4].

Sometimes Alport’s syndrome can occur spontaneously, which means you might be the first one in your family to have it even without a family history^[2].

Parts of the body affected

• Kidneys
• Ears (inner ear)
• Eyes (lens and retina)

Type IV collagen is an important protein in the glomerular basement membranes (GBM) of the kidneys. The GBM is part of a three-layer structure that filters your blood to remove toxins and other waste products to make urine. It also ensures that important contents like blood cells and proteins remain in your blood instead of entering your urine^[1].

When the GBM doesn’t function properly, blood or proteins can leak into your urine. Your kidneys’ ability to filter waste gets worse over time, which increases the risk of complete kidney failure^[1].

Type IV collagen is also present in the inner ear and eyes. The collagen in the inner ear, particularly in structures called the organ of Corti, helps transform sound waves into nerve signals for the brain. When this collagen is abnormal, it can impair hearing function and lead to hearing loss^[4].

In the eyes, collagen IV is important for maintaining the shape of the lens and the normal color of the retina (the light-sensitive tissue at the back of the eye). Abnormal collagen can result in misshapen lenses and an abnormally colored retina^[4].

Signs and symptoms

The primary symptom of Alport’s syndrome is blood in the urine, called hematuria. This is usually microscopic, meaning it can only be detected with a microscope or a urine test strip. Sometimes children with Alport’s syndrome have brown, pink, or red urine for several days, associated with an infection. This visible blood in the urine stops when the child recovers from the infection^[2].

Blood in urine is present from early infancy and is a universal feature of Alport’s syndrome. As the disease progresses, additional signs of kidney disease begin to appear, such as protein in the urine (proteinuria) and high blood pressure^[5].

Many people with Alport’s syndrome develop sensorineural hearing loss in late childhood or early adolescence. This type of hearing loss is caused by abnormalities of the inner ear. Early changes include reduced ability to hear high-frequency sounds. This becomes more severe over time and affects lower frequencies as well. However, hearing loss is not usually complete in Alport’s syndrome, and good communication is almost always possible with the use of hearing aids. Approximately 80% of men with X-linked Alport’s syndrome develop some hearing loss by their teenage years^[5][6].

Affected individuals may have misshapen lenses in their eyes, a condition called anterior lenticonus. They may also have abnormal coloration of the retina. Various other eye abnormalities can occur, including keratoconus (cone-shaped cornea), cataracts, and corneal erosion, as well as spots on the retina. These eye abnormalities seldom lead to vision loss^[4][5].

As kidney function declines, patients may develop swelling and flu-like symptoms. Eventually, patients can experience progressive loss of kidney function, which may require treatment with dialysis or a kidney transplant^[1][5].

A small percentage of patients with X-linked Alport’s syndrome experience leiomyomas, which are benign (not cancerous) smooth muscle tumors that can be found in the esophagus, lungs, uterus, and other female reproductive organs. The acronym ASDL is commonly used to refer to Alport syndrome with diffuse leiomyomatosis^[2].

How common is Alport’s syndrome?

Alport’s syndrome occurs in approximately 1 in 50,000 newborns. The prevalence is estimated to be less than 200,000 people in the United States, making Alport’s syndrome a rare disease. However, no reliable prevalence studies are available, and research suggests that Alport’s syndrome is often underrecognized^[2][4].

Diagnosis

Traditionally, a kidney biopsy was used to diagnose Alport’s syndrome. During a biopsy, a small sample of kidney tissue is removed and examined under a microscope. However, genetic testing now provides a more precise and less invasive means of diagnosis and reveals the underlying pattern of inheritance^[14].

Genetic testing looks for mutations in the COL4A3, COL4A4, and COL4A5 genes. This testing can confirm the diagnosis and help determine which type of Alport’s syndrome a person has^[4].

Other diagnostic tests include urine tests to check for blood and protein, blood tests to assess kidney function, and hearing and eye examinations. Regular evaluations of hearing and vision are important for people with Alport’s syndrome^[7].

A detailed family history is also valuable in diagnosing Alport’s syndrome, as the condition often runs in families^[6].

Treatment

At present, there is no FDA-approved treatment to cure Alport’s syndrome, and gene therapy is not yet available. However, treatments exist that can help slow the progression of kidney disease^[7][14].

The current goal of treatment is to help slow the progression of Alport’s syndrome so that patients can keep their own kidneys as long as possible. Blood-pressure lowering medicines are often prescribed for this reason, even if patients don’t have high blood pressure^[2][7].

ACE inhibitors (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin receptor blockers) are the main medications used. Common examples include lisinopril, ramipril, and losartan. These medications are proven to slow the spill of protein into the urine, which slows the scarring of the kidneys^[2][7].

A recent study found that ramipril decreased the risk of disease progression by almost half in children and adolescents with Alport’s syndrome, with no safety issues reported. This supports the importance of early initiation of treatment^[10][11].

Some studies suggest that combination therapy with an ACE inhibitor, an ARB, a calcium channel blocker, and a statin can help ameliorate symptoms and halt long-term progression in patients without kidney insufficiency^[11].

Additionally, while they have not been studied specifically in patients with Alport’s syndrome, SGLT2 inhibitor medications (such as Farxiga) are increasingly being used in addition to ACE inhibitors and ARBs in adult patients to help reduce the risk of kidney failure^[7].

It is very important for people with Alport’s syndrome to be examined regularly by a kidney doctor (nephrologist) so that effects of kidney disease, such as high blood pressure, can be identified early and treated. Regular evaluations of hearing and eyes are also important^[7].

If kidney failure develops, patients will need replacement therapy, which includes dialysis or a kidney transplant. Treatment may also include medications for anemia and phosphate binders^[11].

For hearing loss, hearing aids can help maintain good communication. Misshapen lenses in the eyes can be treated by replacement of the lens, similar to cataract surgery^[5].

Current research is ongoing to more fully understand the disease, identify more treatment options, and work toward a potential cure. Several human clinical trials are in progress^[2][7].

Lifestyle considerations

Many people with Alport’s syndrome speak about adopting a healthier lifestyle, particularly to prolong their kidney health. This often includes making changes to their diet and taking up sport and exercise. The specific changes people adopt depend on how they are affected by Alport’s syndrome and how much information they have been given^[16].

Having a healthy lifestyle and diet is particularly important for people with kidney disease. People with kidney disease face a lifetime of managing their condition, and some problems may be related to their kidneys, but patients with kidney disease are also more likely to develop heart disease, perhaps because of high blood pressure^[16].

Early in kidney disease, the best advice is to follow good healthy living and eating habits. There aren’t any particular restrictions at that stage, with two exceptions. First, it’s particularly important for kidney patients not to eat too much salt. When kidney function isn’t as good, the kidneys struggle to get rid of excess salt, which causes high blood pressure^[16].

Second, patients with kidney disease should avoid very high protein intake. This is not often a problem with normal diets, but it can arise with people taking protein supplements for sport. Patients with kidney disease should not take protein supplements^[16].

Maintaining a healthy lifestyle includes appropriate diet and exercise. Taking medications as prescribed is also important, as many prescriptions used by Alport’s syndrome patients can protect the kidneys and slow kidney failure^[12].

Outlook

The natural history and prognosis in patients with Alport’s syndrome is variable and is determined by genetics and environmental factors^[10].

Males with X-linked Alport’s syndrome typically experience more severe and faster progression of kidney disease compared to females. Progressive loss of kidney function can occur and may eventually lead to end-stage kidney disease (ESKD), which requires dialysis or kidney transplant^[4][6].

The use of ACE inhibitors and ARBs can delay the onset of end-stage kidney disease by years, significantly improving life expectancy. Early diagnosis and treatment are very important for slowing disease progression^[10][14].

With proper treatment and regular monitoring by healthcare professionals, many people with Alport’s syndrome can maintain good quality of life for extended periods. Following doctor’s instructions and maintaining a healthy lifestyle can help patients stay healthy longer^[12].