What is Alport Syndrome?
Alport syndrome is a genetic illness that affects the functioning of the kidneys, eyes, and ears. It affects the collagen type IV in the body, which prevents these organs from functioning naturally. Also, it damages the glomeruli in the kidneys, which prevents the filtering of wastes from the blood. If not treated in time, the disease may cause damage to the kidneys at the subsequent stages. In medical terms, this stage is called ESRD (End Stage Renal Disease).
Those who are affected with Alport syndrome experience issues with hearing either in the final stage of their childhood or the beginning of their teenage. The disease also negatively impacts their power of visibility by altering the size of their eye lens or by causing myopia or cataract. Individuals may also develop flecks in their eyes. However, they do not cause complete blindness. Compared to females, the illness affects more males, due to which they (men) develop severe complications. But it is frequent only in one out of 5,000-10,000 individuals.
History of Alport Syndrome
It is named after British doctor A. Cecil Alport, who in 1927 described three generations of a family in which multiple individuals exhibited progressive kidney disease and hearing loss. Dr. Alport also observed that blood in the urine (hematuria) was the most common symptom and that males were affected more severely than females. After Dr. Alport’s observations, many more families were described and the disease was named Alport syndrome in 1961.
Types and causes
It is primarily a genetic disorder caused by mutations in genes that encode for type IV collagen, a crucial component of basement membranes in various tissues, including the kidney, inner ear, and eye. The primary genes associated with Alport syndrome are COL4A3, COL4A4, and COL4A5. These genes provide instructions for making different chains of type IV collagen. Mutations in these genes can result in the defective production and assembly of type IV collagen, leading to the characteristic abnormalities seen in Alport syndrome.
The inheritance pattern can vary, and there are three main forms:
- X-Linked Alport Syndrome (XLAS): This form is the most common and is caused by mutations in the COL4A5 gene, which is located on the X chromosome. XLAS primarily affects males, who have only one X chromosome, but females can also be carriers or affected if they have one abnormal X chromosome.
- Autosomal Recessive Alport Syndrome (ARAS): ARAS is caused by mutations in both copies of either the COL4A3 or COL4A4 gene, which are located on autosomal chromosomes (non-sex chromosomes). Both males and females can be affected by ARAS.
- Autosomal Dominant Alport Syndrome (ADAS): ADAS results from mutations in one copy of either the COL4A3 or COL4A4 gene. It tends to be milder than XLAS or ARAS, and individuals with ADAS often have a slower disease progression. Both males and females can be affected by ADAS.
In all forms, the underlying cause is genetic mutations affecting the production and structure of type IV collagen, leading to the characteristic kidney, ear, and eye problems associated with the condition. Genetic testing can be used to identify the specific genetic mutations responsible for Alport syndrome in an individual.
It has an incidence of approximately 1 in 50,000 newborns, with a higher likelihood of symptomatic cases in males compared to females. In the United States, it is estimated that 30,000 to 60,000 individuals are affected by this disorder. In the US, the overall prevalence of end-stage renal disease (ESRD) is around 3% in children and 0.2% in adults. It specifically contributes to about 2.2% of ESRD cases in children and 0.2% in adults in the United States. In Europe, it accounts for 0.6% of ESRD cases.
The common X-linked variant of Alport syndrome, which leads to ESRD, predominantly affects males. However, the X-linked form of the condition also affects nearly as many females, although they often go undiagnosed. Nonetheless, around 15% to 30% of affected women eventually experience renal failure by the age of 60, along with hearing loss in middle age. It is a significant contributor to chronic kidney disease (CKD), resulting in ESRD primarily in adolescents and young adults. It is responsible for 1.5% to 3.0% of children undergoing renal replacement therapies in both Europe and the US.
Pathophysiology of Alport Syndrome
It is characterized by impaired production and deposition of collagen 4 α345 network in the basement membranes of the glomerulus, cochlea (inner ear), and eye. Autosomal recessive Alport syndrome (ARAS) results from mutations in both alleles of COL4A3 and COL4A4, while autosomal dominant Alport syndrome (ADAS) is caused by heterozygous mutations. Next-generation sequencing (NGS) has shown that ADAS accounts for a greater number of cases and progresses more slowly to end-stage renal disease (ESRD) with fewer extra-renal manifestations compared to X-linked Alport syndrome (XLAS). In Alport syndrome, the glomerular basement membrane (GBM) is more susceptible to proteolytic injury, leading to the activation of adhesion kinase in podocytes, endothelin receptors, glomerular inflammation, tubulointerstitial fibrosis, and ESRD. The primary pathology varies between XLAS and ARAS/ADAS, with XLAS affecting the noncollagenous (NC1) C-terminal of the alpha-5 chain, while ARAS and ADAS affect the alpha-3 or alpha-4 chains.
During kidney development, alpha-1 and alpha-2 chains predominate in the GBM, but with maturation, alpha-3, alpha-4, and alpha-5 chains become dominant through isotype switching. Abnormalities in any of these chains, as seen in Alport syndrome, disrupt the collagen network formation, leading to improper incorporation of other collagen chains. XLAS is characterized by developmental arrest in the isoform switching of type IV collagen, retaining the fetal distribution of alpha-1 and alpha-2 isoforms while lacking alpha-3, alpha-4, and alpha-5 isoforms. This abnormal retention of alpha-1 and alpha-2 isoforms makes the GBM susceptible to proteolytic enzymes, causing basement membrane damage.
Additionally, patients with this syndrome who develop anti-GBM nephritis have circulating antibodies targeting specific collagen chains, which differ in XLAS and ARAS patients and can affect transplanted kidneys but not native ones. Posttransplant anti-GBM nephritis in Alport syndrome presents with rapidly progressive glomerulonephritis but does not involve lung hemorrhage, as observed in de novo anti-GBM nephritis. Treatment options for posttransplant anti-GBM nephritis include plasmapheresis, cyclophosphamide (often unsuccessful), and in some cases, intravenous immunoglobulins along with plasmapheresis.
Symptoms of Alport Syndrome
Below is a list of symptoms associated with Alport Syndrome. Not all will be present, and some symptoms will only show up as the disease progresses. But in all cases, the kidneys will be affected. You should make a list of any symptoms you suspect and provide them to your physician. These, along with the test results, will help to confirm the diagnosis, and provide for a more effective treatment plan.
Some of the symptoms may include:
- Hematuria (blood in urine)
- Abnormal urine color
- Proteinuria (large amounts of protein “spilling” into the urine)
- Edema (swelling in parts of the body, most noticeable around the eyes, hands and feet, and abdomen)
- Foamy urine
- Low blood albumin levels
- Decreased or loss of vision (more common in males)
- Flank pain
- Loss of hearing (more common in males)
- High cholesterol in some cases
- High blood pressure in some cases
- Tendency to form blood clots if spilling large amounts of protein
- Kidney failure in only some cases as the disease progresses
Risk factors of Alport Syndrome
The primary risk factor is having a family history of the condition, as it is a genetic disorder. The risk factors associated include:
- Family History: If someone in your family has Alport syndrome, you might be at risk because it’s a genetic condition that can be passed down.
- Gender: If you’re a male, you could be more severely affected by Alport syndrome if you inherit the gene mutation. Females can also be affected but often less severely.
- Genetic Mutations: The specific changes in certain genes (COL4A3, COL4A4, COL4A5) can determine how Alport syndrome affects you.
- Advanced Paternal Age: Older fathers may have a slightly higher chance of passing on new gene mutations that cause Alport syndrome to their children.
- Consanguinity: If close relatives in your family have children together (like cousins marrying), it can increase the risk of having children with Alport syndrome, especially if both carry the gene mutations.
Remember, Alport syndrome is not very common, but if you have concerns or a family history of the condition, talking to a doctor or genetic counselor can help you understand your risk and make informed decisions. Early diagnosis and care are important for managing the condition.
Complications of Alport Syndrome
It affects multiple organ systems. It can lead to the following complications:
- End-stage renal disease (ESRD)
- Hearing loss
- Visual defects
- Leiomyomatosis (smooth muscle overgrowth in the respiratory and gastrointestinal tract)
- Aneurysms of the thoracic and abdominal aorta
- Mental retardation
Diagnosis and test
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.
How to treat Alport Syndrome?
The treatment for Alport syndrome primarily focuses on managing its symptoms and complications, particularly kidney-related issues. The specific treatment approach can vary depending on the severity of the condition and the individual’s needs. Here are some common treatments and management strategies for Alport syndrome:
Blood Pressure Control
High blood pressure (hypertension) is a common complication of Alport syndrome. Controlling blood pressure through lifestyle modifications (such as dietary changes and exercise) and medication is essential to protect the kidneys and slow down the progression of kidney damage.
Alport syndrome often leads to proteinuria (the presence of excess protein in the urine). Medications called angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are commonly prescribed to reduce proteinuria and protect the kidneys from further damage.
Monitoring Kidney Function
Regular monitoring of kidney function is crucial. This includes blood tests to assess kidney function and urine tests to check for proteinuria. Monitoring helps detect any decline in kidney function early, allowing for timely interventions.
A kidney-friendly diet, often low in salt and protein, may be recommended to reduce the workload on the kidneys and manage blood pressure.
Hearing Aids and Cochlear Implants
For individuals with hearing impairment due to Alport syndrome, hearing aids or cochlear implants may be recommended to improve hearing.
Regular eye exams can help identify and manage eye-related complications of Alport syndrome, such as cataracts or retinal abnormalities.
In advanced stages of kidney disease (end-stage renal disease or ESRD), a kidney transplant may be necessary to replace the damaged kidneys. Transplants can significantly improve the quality of life and survival for individuals with ESRD.
Genetic counselling can be valuable for individuals with Alport syndrome and their families. It helps in understanding the genetic inheritance pattern and making informed decisions about family planning.
Some individuals with Alport syndrome may choose to participate in clinical trials to access experimental treatments and contribute to the advancement of Alport syndrome research.
It’s important for individuals with Alport syndrome to work closely with healthcare providers, including nephrologists (kidney specialists), audiologists (hearing specialists), and ophthalmologists (eye specialists), to develop a personalized treatment plan that addresses their specific needs and helps manage the condition effectively.
Medications to slow the progression of damage to the kidneys
If you develop signs that suggest your kidneys are being damaged, your physician may recommend that you start medications that slow the progression of kidney damage. These include:
- Lisinopril (Prinivil)
- Enalapril (Vasotec)
- Ramipril (Altace)
- Losartan (Cozaar)
Further medications and lifestyle changes
If kidney damage occurs to the point that you begin experiencing high blood pressure or swelling of the body, likely due to imbalanced minerals in the blood, your physician can recommend various medications and lifestyle changes to relieve the symptoms. These include:
- Diuretics: Such as furosemide (Lasix), which will increase the amount of urine you make
- Diet: Limiting the salt, potassium and phosphate you eat
- Sodium bicarbonate (Neut): Used to maintain a balance of acid and base levels
- Calcium or vitamin D: To help maintain healthy bones
Prevention of Alport Syndrome
You can’t prevent Alport syndrome, but being aware of your family history can help you detect it early. Awareness can also help prevent you from passing it on to your biological child.
- Diagnosing Alport syndrome early and starting therapy with ACE inhibitors/ARBs and SGLT-2 inhibitors is the best way to delay kidney failure.
- If a provider diagnoses blood in your pee, it’s a good idea to get additional testing for Alport syndrome, especially if you have any hearing issues or decreased kidney function.
- If you have a family history of hematuria, a provider should test your pee for blood and order blood tests to check your kidney function.