Symptoms and Causes
Signs and Symptoms
Symptoms vary from person to person depending on sex, age, and how Alport syndrome was inherited.
Kidneys
• Microscopic hematuria: red blood cells in the urine that can only be seen under a microscope. This is usually the earliest and most common sign, often present from childhood.
• Visible blood in the urine: red, pink, or cola-colored urine, often during a cold, the flu, or after exercise
• Proteinuria: abnormal amounts of protein in the urine, which tends to increase over time
• High blood pressure (hypertension)
• Swelling (edema) around the eyes and in the legs, ankles, and feet
• As kidney function declines: fatigue, poor appetite, nausea, and changes in how often you urinate
Ears
• Sensorineural hearing loss affecting both ears, usually beginning with high-pitched sounds
• X-linked: common in males, often starting in late childhood or the early teenage years; females may develop hearing loss later in life
• Autosomal recessive: both boys and girls typically develop hearing loss during childhood
• Autosomal dominant: hearing loss is less common and, when present, usually occurs later in life
• Hearing loss usually appears before kidney failure. Regular hearing checks allow early support with hearing aids.
Eyes
These eye changes occur mainly in X-linked and autosomal recessive Alport syndrome:
• Anterior lenticonus: an abnormal, cone-shaped bulging of the lens that can cause gradually worsening vision and may lead to cataracts
• Recurrent corneal erosion: damage to the outer layer of the cornea (the clear front surface of the eye), which can cause:
• Pain
• Itching or a gritty feeling
• Redness
• Blurred vision
• Sensitivity to light
• Dot-and-fleck retinopathy: small yellow-white spots on the retina that usually do not affect vision but can help confirm the diagnosis
• Macular hole: thinning of, or a break in, the macula (the part of the retina responsible for sharp central vision), which can cause blurred or distorted central vision
Causes: Genetics
Alport syndrome is caused by pathogenic variants (mutations) in the COL4A3, COL4A4, or COL4A5 genes. These genes provide instructions for making type IV collagen, which is essential to the structure of the basement membranes (thin supporting layers) in the kidney's glomeruli, the inner ear (cochlea), and the eye. When this collagen is abnormal, these membranes gradually break down, leading to the kidney, hearing, and eye problems seen in Alport syndrome.
X-linked Alport syndrome
X-linked inheritance (COL4A5) is the most commonly diagnosed form.
• In males: Because males have only one X chromosome, nearly all males with X-linked Alport syndrome develop proteinuria and progressive loss of kidney function. About 50% need dialysis or a kidney transplant by age 30, and about 90% reach kidney failure before age 40.
• In females: Disease severity varies much more widely, from microscopic hematuria alone to kidney failure. About 12% of females reach kidney failure by age 40, about 30% by age 60, and about 40% by age 80. Because females have two X chromosomes and one is randomly switched off in each cell, some cells use the altered gene and others use the working copy. How severe the disease becomes depends partly on that balance. Women with X-linked Alport syndrome need ongoing monitoring and should not be considered "just carriers."
Autosomal recessive Alport syndrome
In this form, a person inherits an altered copy of COL4A3 or COL4A4 from each parent. Males and females are affected equally, and the course is often similar to that of males with X-linked disease, including kidney failure in early adulthood and childhood-onset hearing loss. The parents each carry one
altered copy. Many have only microscopic hematuria, but some develop proteinuria and declining kidney function over time, so they also benefit from regular kidney monitoring.
Autosomal dominant Alport syndrome
In this form, a single altered copy of COL4A3 or COL4A4 is enough to cause disease, and each child of an affected parent has a 50% chance of inheriting it. The course is usually milder and more variable. Kidney failure, if it occurs, typically develops in middle age or later, and hearing and eye problems are less common. Once thought to be rare, this form now appears considerably more common than previously recognized thanks to expanded genetic testing. Many people once diagnosed with "thin basement membrane nephropathy" are now understood to have autosomal dominant Alport syndrome.