Alport syndrome is a genetic disease that prevents the body from correctly producing a protein called type IV collagen. The disease primarily affects the functioning of the kidneys and the structure of the eye and inner ear, all of which require type IV collagen. Alport syndrome can be inherited in three different ways, X-linked, autosomal recessive, and autosomal dominant.

X-linked Alport syndrome

Most cases of Alport syndrome, between 80 and 85 percent, result from genetic mutations in the COL4A5 gene, which is located on the X chromosome, and so are inherited in an X-linked pattern.

X-linked Alport syndrome typically causes significantly more severe symptoms in males than females. Men only have one X chromosome, so if they inherit an X-chromosome carrying the faulty COL4A5 gene from their mother, they will develop Alport syndrome. Women have two X chromosomes, so if one inherited X chromosomes  carries a defective COL4A5 gene, the other is usually able to compensate, producing enough type IV collagen to prevent severe symptoms.

Autosomal recessive Alport syndrome

Alport syndrome can also be caused by mutations in the COL4A3 or COL4A4 genes, which are located on non-sex chromosomes. In about 15 percent of cases, a child inherits two faulty copies of either gene (one from the mother and one from the father) and develops the disease. This is known as an autosomal recessive pattern of inheritance.

Parents of patients with this form of Alport syndrome must each have a genetic defect in the same gene, either COL4A3 or COL4A4, making them disease carriers. Typically, carriers will not experience any symptoms, although some may develop thin basement membrane nephropathy, whose main symptom is the presence of blood in the urine (known as hematuria). This disease is not associated with kidney failure or hearing loss.

If both parents are carriers, each child — whether male or female — has a 25 percent risk of developing Alport syndrome.

Autosomal dominant Alport syndrome

In fewer than 5 percent of all cases, Alport syndrome is inherited in an autosomal dominant pattern, where a single copy of a faulty COL4A3 or COL4A4 gene is sufficient to cause the disease.

The exact biology of autosomal dominant Alport syndrome is still not fully understood, but as with autosomal recessive Alport syndrome, both males and females have an equal risk of inheriting the disease, but from either parent. Unlike autosomal recessive inheritance, one parent will also be an Alport syndrome patient and a child’s risk of acquiring a defective gene from that parent is 50 percent.

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