Autosomal dominant Alport syndrome (ADAS) is one of three forms of Alport syndrome. As in the other two types —  X-linked Alport syndrome (XLAS) and autosomal recessive Alport syndrome (ARAS) — patients with ADAS experience kidney problems and hearing loss, but unlike the two other forms, they do not develop eye abnormalities.

ADAS is thought to account for 5 percent of all Alport syndrome cases. Advances in diagnosis through genetic testing suggest, however, that it might be more common than previously thought.

The inheritance pattern of ADAS

In each individual, the genetic information is packed in 23 chromosome pairs (46 chromosomes in total). The sex chromosomes, X and Y, determine the gender of a person: women have two X chromosomes and men have one X and one Y chromosome. The remaining 44 chromosomes are known as the autosomes. Men and women have an equal number of autosomes and genes that are located on autosomes are present in two copies.

ADAS is caused by mutations in the COL4A3, or COL4A4, which are both located on autosomes. It is sufficient that one of the two copies of either gene is mutated for a person to develop ADAS. These kinds of mutations are called autosomal dominant. They are distinguished from autosomal recessive mutations, where two copies of the disease-causing mutation are necessary for the disease to develop. Patients with ARAS have mutations either in both copies of the COL4A3 or the COL4A4 gene.

If one parent has ADAS, a 50 percent risk exists of the disease being passed to a child.

Clinical characteristics

Eye abnormalities do not usually occur in ADAS. Hearing loss occurs but is relatively infrequent. A study that analyzed data from 25 ADAS patients reported hearing loss in 19 percent of patients. Another study that analyzed data from 38 ADAS patients reported hearing loss in 13.3 percent of patients. In XLAS, the most common form of Alport syndrome, 90 percent of male patients are deaf before age 40.

Proteinuria, or the presence of protein in the urine, a measure of kidney function, is also less common in ADAS compared to XLAS. The two aforementioned studies reported proteinuria in 9 percent and 50 percent of patients, respectively. In contrast, 95 percent of males with XLAS develop proteinuria.

Hematuria (blood in the urine) is another common symptom of ADAS and a measure of kidney function. Almost all patients in the above studies had microhematuria (urinary blood that is only visible under a microscope), and 22 percent and 5.4 percent of ADAS patients had macrohematuria (urinary blood that can be seen), respectively. Macrohematuria occurs in 62 percent of males with XLAS.

The progression of kidney disease is much slower in ADAS than in XLAS. In ADAS patients, kidney failure usually occurs after age 40, whereas 70 percent of males with XLAS have end-stage kidney disease by age 30, and 90 percent by age 40.

Additional information

Mutations in one copy of the COL4A3 or COL4A4 gene can also cause a condition called thin basement membrane nephropathy (TBMN). Individuals with TBMN have hematuria and proteinuria but normal kidney function.

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