Alport Syndrome

What is Alport Syndrome?

Alport syndrome is a name given to a range of inherited conditions that primarily affect the kidney’s basement membrane, but often also involve the hearing part of the ear (cochlea) and the eye. The condition is also known as hereditary nephritis and is due to mutations or genetic errors in the genes that produce parts of a protein known as type 4 collagen, which is crucial for kidney functioning.

This important protein is mainly located in the kidneys, eyes, and cochlea. The syndrome can be passed down in three manners: X-linked (where the affected gene is located on the X chromosome), autosomal recessive (where two copies of the affected gene must be passed on, one from each parent) and autosomal dominant (where the presence of the affected gene from just one parent can cause the syndrome).

This syndrome was first defined in 1927 by British physician A. Cecil Alport as a combination of inherited kidney inflammation and hearing loss. At the time, it was seen that blood in urine was the most frequent symptom and that males were more affected than females. In 1961, the syndrome was named Alport syndrome after several family members with the condition were observed.

Traditionally, Alport syndrome is marked by kidney failure, hearing loss, and eye abnormalities. As the disease progresses, patients may experience protein in their urine, high blood pressure, decreasing kidney function, and eventually complete kidney failure, also known as end-stage renal disease.

What Causes Alport Syndrome?

Alport syndrome, in most cases around 80%, is caused by changes, or mutations, in a specific gene called COL4A5. These gene changes are generally passed down from parents to children through what’s called an X-linked pattern. There are also other patterns of inheritance, where it’s passed down as an autosomal recessive or dominant pattern because of changes in other genes, COL4A3 or COL4A4. About 80% of males with Alport syndrome, inherited through the X-linked pattern, tend to develop some sort of hearing loss by the time they become teenagers.

Alport syndrome happens due to mutations in the genes that control specific parts of a protein called type IV collagen. There are three genetic types of Alport syndrome, each caused by different gene mutations:

– XLAS: This type, which accounts for 85% of Alport Syndrome cases, is caused by mutations in the COL4A5 gene.

– ARAS: This type is caused by mutations in the COL4A3 or COL4A4 gene and it’s responsible for about 10-15% of cases.

– ADAS: This rare type is also caused by mutations in the COL4A3 or COL4A4 gene.

More than 300 different mutations in the COL4A5 gene have been found in families with XLAS. Most of these mutations are small, including changes in where DNA is spliced together, shifts in the genetic code, and deletions of fewer than ten base pairs (the building blocks of DNA).

About one-fifth of the mutations found are larger deletions in the COL4A5 gene. Certain deletions involving both the COL4A5 and COL4A6 genes can lead to a combination of XLAS and abnormal growths in the esophagus, female genital tract, and airway system.

Lastly, for patients with Alport syndrome, there have been only six mutations found in the COL4A3 gene and twelve in the COL4A4 gene. These mutations include shifts in the genetic code, changes in how DNA is cut and spliced together, deletions of genetic material, and substitutions of specific amino acids, which are the building blocks of proteins.

Risk Factors and Frequency for Alport Syndrome

Alport syndrome is a condition that impacts approximately 1 in 50,000 newborns. It’s more often symptomatic in males than females, and it’s estimated that between 30,000 and 60,000 people in the United States have this disorder. The syndrome can lead to end-stage renal disease (ESRD), a severe kidney condition, which, in the United States, affects about 3% of children and 0.2% of adults.

• In the United States, Alport syndrome accounts for about 2.2% of children and 0.2% of adults with ESRD.
• In Europe, it represents 0.6% of ESRD patients.
• The X-linked type, a common variant of Alport syndrome, leads to ESRD mainly in males. But almost as many females are affected by this type too.
• Though many affected females don’t get diagnosed, between 15% and 30% of them end up with kidney failure by the age of 60, and hearing loss by middle age.
• Alport syndrome is a significant factor in chronic kidney disease (CKD), leading to ESRD in young adults and teens. This is the case for 1.5% to 3.0% of children on kidney replacement therapies in the United States and Europe.

Signs and Symptoms of Alport Syndrome

A comprehensive health and family history along with physical examination are important steps in diagnosing Alport syndrome. Laboratory testing, including urine analysis, urine microscopy, and kidney function tests, is usually conducted. Symptoms of Alport syndrome can include blood or excessive protein in urine, swelling (edema), high blood pressure, a worsening state of kidney functions, and ultimately, end-stage renal disease (ESRD). The symptoms get worse over time, leading to more severe proteinuria, high blood pressure, a decrease in the kidney’s filtering capacity (GFR), and ESRD. Symptoms of ESRD usually appear between the ages of 16 to 35. Also, people with Alport syndrome may have noticeable blood in urine after an upper respiratory tract infection.

People with Alport syndrome commonly experience bilateral (in both ears) sensorineural hearing loss during late childhood due to abnormalities in collagen in the inner ear. This hearing loss usually appears before the onset of kidney failure and typically starts with high-frequency sounds becoming less distinct.

Alport syndrome can also lead to several eye-related issues. Patients may develop a cone-shaped lens, which can interfere with normal vision and visual accuracy. Other possible eye complications include the formation of cataracts under the lens capsule, changes in retinal pigment (dot-and-fleck retinopathy), posterior polymorphous dystrophy, and corneal erosions.

Key features and symptoms of Alport syndrome can be organized by body system:

• Renal symptoms:
• Blood in urine is the most common early symptom of Alport syndrome, especially in males. 60-70% of patients may experience episodes of noticeable blood in urine, often triggered by an upper respiratory infection.
• Proteinuria (excess protein in the urine) usually develops later in the disease, particularly in males with X-linked Alport syndrome (XLAS) and both genders with autosomal recessive Alport syndrome (ARAS). The incidence and severity increase with age and extent of kidney failure.
• High blood pressure usually appears by the second decade of life.
• Swelling and nephrotic syndrome are seen in 30% to 40% of young patients with Alport syndrome, though they are not common in early childhood.
• With the onset of kidney insufficiency, chronic anemia and bone disorders can manifest.
• Hearing-related symptoms:
• Sensorineural hearing loss usually starts in late childhood or early adolescence, before the onset of kidney failure. Once it progresses, hearing aids may be needed.
• About half of male patients with XLAS have hearing impairment by the age of 25 years, and by 40 years, nearly 90% are deaf.
• Ocular symptoms:
• Anterior lenticonus, a conical protrusion of the lens, is common in Alport syndrome and can manifest as frequently needing to change prescription glasses. It’s diagnosed by an eye exam using a slit lamp.
• Dot-and-fleck retinopathy, where white and yellow dots and flecks occur around the macula (central part of the retina) is common but usually asymptomatic. It is rarely seen in childhood and tends to appear with the onset of kidney failure.
• Posterior polymorphous corneal dystrophy is a rare Alport syndrome feature that might cause gradually progressive visual impairment.
• Leiomyomatosis symptoms:
• Diffuse leiomyomatosis of the tracheobronchial tree and esophagus has been reported in some Alport syndrome patients. Symptoms include swallowing difficulties, vomiting after meals, recurrent bronchitis, chest or upper abdominal pain, shortness of breath, loud breathing, and coughing.

Testing for Alport Syndrome

If a child is continuously showing blood in their urine before they turn ten years old, this might be due to a condition called Alport syndrome which affects the filtering system in their kidneys. It’s important to catch Alport syndrome early because it can lead to more serious problems like kidney disease.

Apart from blood in the urine, patients with suspected Alport syndrome may have protein in their urine, abnormal kidney function tests, and problems with their ears and eyes. A urine test would show blood and protein and a microscopic examination of the urine is necessary to look for acanthocytes — abnormal, spiky red blood cells.

If these signs are present, a piece of kidney tissue may be needed for further analysis. This is known as a renal biopsy. Patients with possible Alport syndrome should also be sent to an ear, nose, and throat specialist for hearing checks and to an eye specialist for vision tests, due to the condition’s effect on these areas too. If the eyes are affected, they may show an unusual shape of the lens.

Genetic testing can be very helpful in confirming whether or not someone has Alport syndrome, and if it could be passed on in their family. These tests are quite straightforward, they can provide accurate results, and can even give an idea of how the disease might progress. If there is no known family history of Alport syndrome, specific genes should be tested. If the syndrome runs in the family, then the gene causing the condition in the family should be targeted.

In some cases, if the genetic test results don’t match the family’s known genetic mutation, a kidney sample may be preferred. In males with severe forms of Alport Syndrome, a key feature is the ‘splitting’ of the kidney’s filtering system. This splitting increases significantly as they get older.

For patients who don’t show the typical splitting, a more detailed examination of their kidneys’ filtering system can be conducted by staining it with special substances to highlight potential abnormalities. A skin biopsy, a less invasive procedure, can be carried out on children suspected to have the syndrome. This biopsy involves the use of a substance that reacts with a specific component of the collagen chain in their skin. This can help identify any potential abnormalities related to the disease.

Treatment Options for Alport Syndrome

Unfortunately, there’s currently no specific cure for Alport syndrome, a genetic condition that causes kidney disease and hearing loss. The aim of treatment is to slow down the disease’s progression, manage symptoms, and limit further damage to the kidneys.

One way of managing Alport syndrome involves drugs known as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). These can help control protein leakage in urine, high blood pressure, and chronic kidney disease (CKD). Depending on the severity of the condition, water pills (diuretics) can also be used. However, it’s important to note that these treatments might only delay, rather than prevent, kidney failure. As such, many people with Alport syndrome eventually need to undergo dialysis (a treatment to artificially replace some kidney functions) or a kidney transplant.

Studies suggest that ARBs could delay the worsening of CKD or end-stage renal disease (ESRD), a severe condition where the kidneys stop working. One particular study found that combining multiple types of medication – ARBs, ACE inhibitors, statins (cholesterol-lowering drugs), and non-dihydropyridine calcium channel blockers – could effectively manage various symptoms and slow down the disease’s progression.

A trial involving a drug called ramipril found that it could reduce the disease’s progression risk in children with Alport syndrome. Cyclosporine, however, wasn’t shown to be beneficial and isn’t generally recommended for people with Alport syndrome.

If the syndrome also affects the eyes causing anterior lenticonus (an eye issue causing blurred or distorted vision), a surgical procedure to remove and replace the eye’s lens can be an option. For hearing loss, hearing aids are typically very effective. Kidney transplant doesn’t affect hearing loss.

Emotional support is essential since dealing with a hereditary disease can be challenging for individuals and their families.

If kidney failure reaches a point where a transplant is necessary, there are generally no restrictions for patients with Alport syndrome. The good news is that, unlike in many other kidney diseases, the genetic abnormalities that cause Alport syndrome don’t affect the transplanted kidney. However, some patients might develop antibodies that can damage the transplanted kidney. This is rare, but when it happens, it usually occurs during the first year after the transplant. The treatment for this problem involves removing these antibodies from the patient’s blood, along with medications, but this treatment isn’t always effective.

What else can Alport Syndrome be?

When trying to diagnose Alport syndrome, doctors have to consider other health conditions that could potentially cause similar symptoms. These possibilities could include:

• Immunoglobulin A nephropathy
• Thin GBM (Glomerular Basement Membrane) disease
• Acute post-streptococcal glomerulonephritis
• Medullary cystic disease
• Multicystic renal dysplasia
• Polycystic kidney disease

One of the most major conditions that need to be ruled out when diagnosing Alport syndrome is the Thin Basement Membrane (TBM) disease. This is a medical condition that is related to Alport syndrome and appears to involve many of the same genes. However, unlike Alport syndrome, TBM disease often has fewer symptoms that affect areas outside of the kidneys, and the symptoms are generally less severe. It is also rare for TBM disease to progress to the point of causing kidney damage. Differentiating these two conditions can be difficult, especially in younger patients or females who are less likely to present other associated symptoms.

What to expect with Alport Syndrome

Alport syndrome is a disorder mainly affecting the kidneys, and it comes in different forms. In the most common form, known as the X-linked disease, about half of the male patients need dialysis or kidney replacement surgery by the age of 30. By 40, nearly 90% develop what’s known as End-stage Renal Disease (ESRD) – a severe kidney illness that requires dialysis or transplantation.

In contrast, female patients with the same X-linked form of Alport syndrome typically fare better. About 12% develop ESRD by age 40. However, research shows that females with symptoms of protein in their urine (proteinuria) and hearing loss may have more severe kidney issues.

As females grow older, the chance of developing ESRD increases. By age 60, around 30% are affected, and this rate approaches 40% by the same age. For these women, having proteinuria and hearing loss can indicate a higher risk of moving towards ESRD.

On the other hand, a different form of Alport syndrome, known as autosomal recessive, can lead to kidney failure much earlier, around age 20. In contrast again, the autosomal dominant form of the disease generally causes ESRD later in life, usually around middle age.

Possible Complications When Diagnosed with Alport Syndrome

Alport syndrome is a condition that impacts multiple parts of the body. This can cause:

• End-stage renal disease (ESRD), which means your kidneys stop working completely
• Hearing loss
• Problems with vision
• Leiomyomatosis, or an overgrowth of smooth muscle in your respiratory and digestive systems
• Aneurysms, or weakened, bulging areas, in the chest or abdomen portion of the main body artery (aorta)
• Learning disabilities

Preventing Alport Syndrome

It’s important that patients receive educational materials to help them understand the symptoms of kidney failure and how it can affect the whole body. If your child is affected by this condition, you should know the specific signs and symptoms that indicate they need to be admitted to the hospital. If someone in your family has Alport syndrome, a type of genetic kidney disease, you should consult your usual healthcare provider to ask about screenings according to local guidelines.

Individuals with Alport syndrome should consider genetic counseling before deciding to marry and have children. They can use this service to understand the genetics of the disease and their possible implications for their offspring. Additionally, there are various support groups available that can provide help for the patients and their families, making it easier for them to manage their situation.