Genetic mutations in the genes that produce type IV collagen, a protein vital to the structure and function of these organs, are responsible for Alport syndrome, a rare genetic disorder that affects the kidneys, ears, and eyes. Alport syndrome causes progressive kidney damage, hearing loss, and eye problems that can cause blindness.
Alport syndrome is inherited in three different ways:
A mutation of the COL4A5 gene on the X chromosome causes Alport syndrome. It is most common in males and those assigned as males at birth (AMAB). Females with one mutated copy of this gene will have mild symptoms or none at all if they inherit one copy from their father.
A mutation in the COL4A3 or COL4A4 gene on chromosome 2 or 15 causes this autosomal dominant form of Alport syndrome, which affects both males and females equally.
The autosomal recessive pattern of Alport syndrome affects mostly females and people who were assigned female at birth. It is caused by mutations in the COL4A3 or COL4A4 genes on either chromosome 2 or 15. The severity of symptoms depends on which gene pair is mutated.
The main symptoms of Alport syndrome are related to kidney disease, hearing loss, and eye problems.
The kidneys are responsible for filtering waste and excess fluid from the blood and producing urine. By abnormal type IV collagen, the glomeruli, tiny filters in the kidneys known as glomerular basement membranes (GBMs), are damaged in people with Alport syndrome. As a result, blood or protein leaks into the urine (hematuria) and the kidney's ability to filter waste from the blood is reduced. Eventually, this leads to kidney failure (end-stage renal disease), which requires dialysis or kidney transplantation.
Additionally, type IV collagen is present in the inner ear, where it contributes to its shape and functionality. In Alport syndrome patients with X-linked inheritance or autosomal dominant inheritance with mutations in both copies of the COL4A3 or COL4A4 genes, they may develop sensorineural hearing loss before puberty. Hearing loss caused by sensorineural damage occurs when both the inner ear and the nerve carrying sound signals to the brain are damaged.
A type IV collagen also keeps the lens capsule and retina of the eye in shape and color. Alport syndrome patients whose COL4A3 or COL4A4 genes are mutated and have X-linked inheritance or autosomal dominant inheritance may develop eye problems, such as:
Lenticonus: This is a condition where the lens capsule becomes abnormally thin and bulges outwards like an eggshell.
Retinal abnormalities: These include white flecks scattered around the retina called dot-and-fleck retinopathy; abnormal blood vessels called drusen; abnormal growths called epiretinal membrane; and abnormal pigmentation called macular edema.
Cataracts: These are cloudy areas in front of the lens that block the passage of light and impair vision.
Some people with Alport syndrome may also have other eye problems such as glaucoma, nystagmus, or strabismus.
The diagnosis of Alport syndrome is based on the following criteria:
Family history: A doctor may ask about the medical history of the person and their relatives, especially those who have kidney disease, hearing loss, or eye problems.
Urinalysis: A urine test may show the presence of blood or protein in the urine, which indicates kidney damage.
Kidney biopsy: A small sample of kidney tissue may be taken and examined under a microscope to look for signs of abnormal type IV collagen in the GBMs.
Genetic testing: A blood test may identify the specific gene mutation that causes Alport syndrome. This can help confirm the diagnosis and determine the inheritance pattern.
Hearing test: A hearing test may measure the person’s ability to hear different sounds and frequencies. This can help detect sensorineural hearing loss.
Eye exam: An eye exam may check the person’s vision and look for any abnormalities in the lens capsule, retina, or other parts of the eye.
Alport syndrome has no cure, but treatment can slow down kidney disease progression, manage hearing loss and eye problems, and prevent complications.
Alport syndrome kidney disease is treated mainly by controlling blood pressure and proteinuria (excess protein in the urine). ACE inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers can be used to accomplish this. As well as relaxing blood vessels and reducing pressure on the kidneys, these drugs can protect the kidneys from further damage by lowering the amount of protein leaking into the urine.
The following medications can be prescribed for kidney disease: diuretics (to reduce fluid retention and swelling), statins (to lower cholesterol and prevent cardiovascular complications), and erythropoietin (to treat anemia caused by low red blood cell production).
When kidney disease progresses to kidney failure, which means that the kidneys are no longer able to function properly, the patient may need dialysis or a kidney transplant. A dialysis procedure is one that filters the blood and removes waste and excess fluid. The procedure of kidney transplant involves replacing a damaged kidney with a healthy one.
The treatment for hearing loss caused by Alport syndrome depends on the severity and type of hearing loss. Some options include:
Hearing aids: These are devices that amplify sound and help the person hear better. They can be worn behind the ear, in the ear, or in the ear canal.
Cochlear implants: These are devices that bypass the damaged inner ear and stimulate the auditory nerve directly. They consist of an external part that captures sound and a surgically implanted part that delivers electrical signals to the brain.
Bone-anchored hearing systems: These are devices that use a titanium screw implanted in the skull to transmit sound vibrations to the inner ear. They can be used for people who have conductive hearing loss (caused by problems in the outer or middle ear) or mixed hearing loss (caused by problems in both the inner and outer or middle ear).
The treatment for eye problems caused by Alport syndrome depends on the type and severity of the problem. Some options include:
Glasses or contact lenses: These can correct refractive errors such as nearsightedness, farsightedness, or astigmatism, and improve vision.
Surgery: This can be done to remove cataracts, repair retinal detachment, or correct strabismus. Surgery may also be needed to treat glaucoma or epiretinal membrane.
Medications: These can be used to lower eye pressure, reduce inflammation, or prevent infection. Medications may be given as eye drops, pills, or injections.
People who have a family history of Alport syndrome can take steps to reduce their risk of passing it on to their children by taking the following steps:
In genetic counseling, people with or at risk of genetic disorders receive information and guidance. A genetic counselor can help people understand the inheritance pattern, the chances of having a child with Alport syndrome, and the testing options available.
Prenatal testing: This test can detect genetic abnormalities in the fetus before birth. It can be performed with either chorionic villus sampling (CVS) or amniocentesis. A CVS test identifies the gene mutation causing Alport syndrome by taking a small sample of tissue from the placenta, while an amniocentesis test identifies the gene mutation from the amniotic sac.
An embryo can be screened for genetic disorders prior to being implanted in the uterus with preimplantation genetic diagnosis (PGD). This can be accomplished by in vitro fertilization (IVF), which involves fertilizing an egg with sperm. Only the healthy embryos can be transferred to the uterus after testing for the gene mutation that causes Alport syndrome.
The Alport syndrome is a rare genetic disorder that affects the eyes, ears, and kidneys. It is caused by mutations in genes that produce type IV collagen, a protein essential for the structure and function of these organs. Alport syndrome is characterized by progressive kidney damage, hearing loss, and eye problems that can cause blindness. Family history, urinalysis, kidney biopsy, genetic testing, hearing tests, and eye exams are used to diagnose Alport syndrome. It is intended to slow down the progression of kidney disease, treat hearing loss and eye problems, and prevent complications in Alport syndrome. Although Alport syndrome cannot be prevented, people who have a family history of the condition can take steps to reduce the risk of passing it on to their children. Genetic counseling, prenatal testing, and preimplantation genetic diagnosis are some of these steps.
