Alport Syndrome

Alport Syndrome 

Overview

Alport syndrome is a genetic condition in which your kidneys don’t produce normal type IV collagen proteins.

Type IV collagen consists of three individual collagen chains (alpha chains) that twist together like rope. The chains are alpha 3, alpha 4 and alpha 5. If your body doesn’t produce one of these chains, the other two can’t combine. This results in the most severe Alport syndrome symptoms.

If your body produces all of the chains but doesn’t make one correctly, sometimes the chains can’t combine and other times the chains combine but don’t function properly. Alport syndrome symptoms may be milder in these instances.

Type IV collagen is an important protein in the filtration membranes in your kidneys (glomerular basement membranes or GBM).

The GBM is part of a three-layer structure that filters your blood to remove toxins and other contents that your body doesn’t need to make urine (pee). The GBM also make sure that contents like blood cells and proteins remain in your blood instead of entering your pee.

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

Type IV collagen is also present in your ears and eyes. So if you have Alport syndrome, it can cause problems with your vision and hearing as well as kidneys

Type of Alport syndrome.

Alport syndrome has three genetic types. They include:

X-linked Alport syndrome (XLAS)

XLAS relates to your X chromosome. Your X chromosome is one of your two sex chromosomes (X and Y). It’s where the gene that produces your alpha 5 chain (COL4A5) resides.

Males have one X chromosome and one Y chromosome. Females have two X chromosomes. Males only have the abnormal X chromosome, so they’re more likely to have more severe symptoms. Females have one abnormal X chromosome and one normal X chromosome, so their symptoms are usually milder.

Males pass their Y chromosome to their male children. Therefore, they can’t pass XLAS to them. However, males pass their X chromosome to all of their female children. As a result, all of their female children will have Alport syndrome.

Females pass one of their X chromosomes on to their child of either sex. Therefore, they have a 50% chance of passing XLAS to any of their children.

XLAS is the most common type of Alport syndrome. It accounts for about 60% to 80% of all cases of Alport syndrome.

Autosomal recessive Alport syndrome (ARAS).

“Autosomal” refers to the 23 pairs of autosomal genes. Autosomal recessive is a pattern of inheritance. If a parent has an autosomal recessive trait, they won’t show any symptoms. In order to pass it on to their children, both parents must carry the trait. However, because they don’t have any symptoms, they often don’t even know they have it. Both parents need to pass an altered gene to their child for the child to inherit the genetic condition or trait in an autosomal recessive pattern. One-quarter of the children will get an autosomal recessive trait if both parents have it. Only changes that occur in the DNA of the sperm or egg can pass on to children from parents.

In Alport syndrome, the genes that encode the alpha 3 (COL4A3) and alpha 4 (COL4A4) proteins reside on chromosome 2.

“Recessive” refers to a disease that needs mutations on both genes in a pair to develop.

In ARAS, there’s a mutation on both genes on chromosome 2, which encodes the alpha 3 or alpha 4 proteins. ARAS doesn’t depend on a person's sex, so the inheritance and severity of ARAS is the same in everyone.

If you have ARAS, there’s a 50% chance of passing one of the abnormal genes to any of your biological children. This usually doesn’t result in Alport syndrome. There’s a 25% chance of passing on both abnormal genes to your biological children. If this occurs, your child will have ARAS.

ARAS accounts for about 15% of all cases of Alport syndrome.

Autosomal dominant Alport syndrome (ADAS)

“Dominant” refers to a disease that requires a mutation on only one of the genes in a pair to develop a disease. In ADAS, there’s a mutation on one of the genes in chromosome 2 that encodes the COL4A3 or COL4A4 proteins.

ADAS doesn’t depend on sex, so the inheritance and severity of ARAS is the same in everyone.

If you have ADAS, there’s a 50% chance of passing the abnormal gene on to your biological children, in which case ADAS will develop.

ADAS accounts for 25% to 35% of all cases of Alport syndrome.

Symptoms

Alport syndrome symptoms may vary according to which type you have. The main symptoms include:

Blood in your pee that you can’t see (microscopic hematuria).

Protein in your pee (proteinuria).

Chronic kidney disease or kidney failure.

Hearing loss.

Problems with your eyes.

The first sign of Alport syndrome is microscopic hematuria. Microscopic hematuria occurs because your abnormal GBMs leak red blood cells into your pee. You can’t see the blood cells with your naked eye — you can only see it under a microscope. Males who have XLAS and anyone who has ARAS will have microscopic hematuria at birth. Most females who have XLAS will develop microscopic hematuria over time. Not everyone with ADAS will develop microscopic hematuria.

As your kidney function starts to decline, chronic kidney disease (CKD) develops. Most people don’t have CKD symptoms until they reach kidney failure.

Kidney failure symptoms include:

Swelling (edema), especially around your hands or ankles.

Extreme tiredness (fatigue).

Nausea and vomiting.

Muscle cramps.

Hearing loss is more common in males who have XLAS and people with ARAS. However, it can occur in anyone with Alport syndrome. Hearing loss is usually gradual. Many people don’t realize they have hearing loss until it becomes more severe. Most people have a harder time hearing higher-pitched sounds, though some people may eventually not be able to hear any sounds. You may eventually need hearing aids. In severe cases, total hearing loss (deafness) occurs.

You may develop a wide range of problems with your eyes. Some people are more likely to scratch the surface of their eyes (corneal abrasion), which can take a long time to heal. Corneal abrasions may cause your eyes to water and hurt, but it usually doesn’t lead to vision loss. Some people also develop problems with the clear part of their eye that helps focus their vision (the lens), which can eventually lead to cataracts.

If you have Alport syndrome and develop problems with your hearing or vision, talk to a healthcare provider right away.

Causes

If you have Alport syndrome, the glomerular basement membranes don’t filter properly, so blood and protein leak into your pee. However, it also isn’t as supportive for the cells that line both sides of it. As a result, the cells become irritated and inflamed. Podocytes are the cells that produce the GBMs, and they try to put more type IV collagen into the GBMs when the surrounding cells become inflamed. When this happens, the GBMs become thicker and disorganized. This causes protein to leak into your pee (proteinuria).

Over time, as more protein leaks into your pee and as your GBMs become thicker, scar tissue may develop (fibrosis). As a result, your kidneys’ ability to clean your blood starts to decline (chronic kidney disease). As more scar tissue develops, your kidney function gets worse until your kidneys eventually stop working (kidney failure).

Diagnosis

If you have microscopic hematuria or chronic kidney disease, a healthcare provider may raise Alport syndrome as a concern. If you have a biological family history of Alport syndrome, screenings can help diagnose it. If no one in your family has Alport syndrome, a provider can diagnose you based on your history and additional testing.

A healthcare provider will examine your symptoms and ask about your biological family history. A variety of tests can also help a provider diagnose Alport syndrome. These tests include:

Urinalysis. A urinalysis (urine test) examines the visual, chemical and microscopic aspects of your pee. This test can help a healthcare provider identify blood or protein in your pee.

Creatinine clearance test or cystatin C blood tests. These tests measure the waste product creatinine and the protein cystatin C levels in your blood. The tests reflect how well your kidneys filter blood.

Estimated glomerular filtration rate (eGFR). The eGFR is a value that a provider calculates from creatinine or cystatin C. It estimates how well your kidneys clean your blood.

Kidney biopsy. A healthcare provider will remove several tiny pieces of your kidney tissue to examine under a microscope at a lab. The samples can show different patterns that affect your kidney. In Alport syndrome, the abnormal GBMs appear thin, but they may include thickened areas. If Alport syndrome is more severe, the filtering units and supporting structure may show scarring.

Genetic testing. A genetic test can identify mutations in your collagen genes. You may have to go to a special genetic medicine clinic to get genetic testing. A provider will either conduct blood tests or saliva (spit) tests with a mouth swab.

Hearing test. A healthcare provider may order a hearing test (audiogram) if they suspect Alport syndrome. Providers should order a hearing test for anyone who has Alport syndrome. You should get tests every few years to determine if hearing loss develops or worsens.

Eye exam. An eye care specialist who specializes in diagnosing and treating eye conditions should perform an eye exam. They’ll test your vision and look at the surface of your eye (cornea), your lens and the back of your eye (retina) to see if Alport syndrome is affecting these areas. They may also conduct an optical coherence tomography (OCT) imaging test.

Treatment

There isn’t a cure for Alport syndrome. Researchers are working on gene therapies that fix the abnormal genes, but are not yet successful. If they can develop a successful gene therapy, it won’t be available for many years. However, treatments are available now that slow down kidney decline and delay kidney failure.

A provider may prescribe the following:

Angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors lower your blood pressure, decrease protein in your pee and help protect your kidneys. Males who have XLAS or anyone with ARAS should start taking ACE inhibitors after diagnosis. Females who have XLAS or ADAS should start ACE inhibitors after protein starts to appear in your pee or even at the time of diagnosis.

Angiotensin II receptor blockers (ARBs). ARBs are similar to ACE inhibitors and have the same benefits.

Sodium-glucose transported type 2 (SGLT-2) inhibitors. SGLT-2s help decrease your risk of kidney failure if you have CKD or Alport syndrome. Your healthcare provider may add these to your ACE inhibitor or ARB. The Food and Drug Administration (FDA) hasn’t approved all SGLT-2 inhibitors to help treat CKD. Your provider also won’t prescribe them if your glomerular filtration rate is too low.

Sodium-controlled diet. Limiting the amount of salt and sodium in your diet helps lower your blood pressure and can help maintain kidney and heart health.

Type of Doctor Department : A nephrologist