Alport syndrome is a genetic disorder characterized by progressive kidney disease, hearing impairment, and eye abnormalities.
Alport syndrome can be inherited in either an X-linked or autosomal recessive manner. The carrier screening looks for the autosomal recessive form only. The severity of autosomal recessive Alport syndrome varies among individuals, with some experiencing a milder course while others face more serious complications. In many cases, the initial sign of kidney disease is the presence of blood in the urine, often not visible to the naked eye but detectable during illnesses like colds or the flu. During childhood, individuals also develop proteinuria (excess protein in the urine). Kidney disease typically progresses to kidney failure by early adulthood, leading to symptoms such as high blood pressure, fatigue, poor appetite, leg and foot swelling, and frequent urination. Medications can delay kidney failure progression, but in most cases, kidney transplantation and/or dialysis becomes necessary. Autosomal recessive Alport syndrome is also associated with varying degrees of progressive hearing loss, which can onset at different times and in varying severity. Adolescence often marks the period when some degree of hearing impairment emerges. Additionally, individuals with this condition may experience eye abnormalities, most commonly affecting the lens, retina, and cornea, potentially causing light sensitivity, cataract formation, and blurred vision.
Autosomal recessive Alport syndrome is caused by pathogenic (disease-causing) variants in the COL4A3 or COL4A4 genes. Autosomal recessive inheritance means that both parents must be carriers to have a 25% chance to have a child with the condition. The risk of being a carrier is based on a person’s ancestry or ethnic background. For example, individuals of Ashkenazi Jewish descent have a 1 in 192 chance to be a carrier for COL4A3-related Alport syndrome. X-linked Alport syndrome is caused by pathogenic variants in the COL4A5 gene exhibit X-linked recessive inheritance. This means that one pathogenic variant is enough to cause the disease in both males (who have one X chromosome and one Y chromosome) and females (who have two X chromosomes) may experience symptoms depending on how many copies of the X chromosome that has the pathogenic variant are turned on in the cells.
Most female carriers of X-linked Alport syndrome will have blood in the urine that is not detectable to the naked eye. Some females are also affected by varying degrees of hearing loss, but it tends to occur later in life. By late adulthood, up to 40% of female carriers will progress to kidney failure.