X-linked Alport syndrome

What is X-Linked Alport Syndrome?

Alport syndrome is an inherited connective tissue disorder that can cause progressive kidney disease, abnormalities affecting the eyes, and hearing loss. There are three genes associated with Alport syndrome. X-linked Alport syndrome (XLAS) is caused by harmful genetic changes (variants) in the COL4A5 gene. Alport syndrome caused by the COL4A5 gene is inherited in an X-linked manner. This means the condition is typically more severe in individuals assigned male at birth (XY). However, individuals assigned female at birth (XX) may also have symptoms of the condition.

The presentation of XLAS is variable in severity. Some individuals have a milder disease course, while others develop more severe symptoms. Although the data are somewhat limited, recent studies have shown that some individuals with Alport syndrome may have a harmful genetic change in COL4A5 and another gene (suggesting digenic inheritance).

The first sign of the disease is often blood in the urine from kidney disease and typically presents early in life. Most individuals with XLAS will have persistent blood in the urine during childhood. This usually cannot be seen by the naked eye but may be visible during illness. Individuals also develop protein in the urine (proteinuria) during childhood. Kidney disease often progresses to kidney failure by early adulthood. Kidney failure is associated with various symptoms, including high blood pressure, fatigue, poor appetite, swelling of legs and feet, and frequent urination. Kidney insufficiency and associated medical complications are commonly observed in individuals with XLAS.

XLAS is associated with varying degrees of progressive hearing loss and eye abnormalities. The onset and severity of hearing loss are variable, but it is not uncommon for some degree of hearing loss to develop by adolescence. Eye abnormalities, including those affecting the outer protective layer of the eye (the cornea), the transparent tissue behind the iris (the lens), and the light-sensitive tissue in the back of the eye (the retina), are the most common. These abnormalities may result in light sensitivity, clouding of the lens of the eye (cataracts), and blurred vision. Glasses are sometimes required to correct vision.

Additional considerations for carriers

XX individuals (who are typically assigned female at birth) are carriers of Alport syndrome. Most carriers exhibit symptoms of Alport syndrome, but there is a wide range of severity. A few carriers may have no symptoms, but most typically have small amounts of blood in their urine. Some individuals are also affected by varying degrees of hearing loss, which tends to occur later in life. By late adulthood, up to 40% of carriers experience kidney failure. Carriers of XLAS should have routine physical exams and speak with their healthcare provider about the risk of developing kidney disease. Genetic counseling is recommended.

How common is X-Linked Alport Syndrome?

Collectively, all forms of Alport syndrome are estimated to occur in approximately 1 in 50,000 live births. XLAS is the most common form, accounting for about 80% of cases of Alport syndrome. XLAS occurs at a similar frequency amongst all ethnicities. Up to 15% of individuals with X-linked Alport syndrome do not inherit a variant from a parent (de novo variant).

How is X-Linked Alport Syndrome treated?

Currently, there is no cure for XLAS. However, treatments are available to address many of the associated symptoms. Medications are used to treat high blood pressure, reduce protein in the urine, and slow the progression of kidney disease. Kidney failure will likely develop in many individuals with XLAS regardless of treatment. Because the onset of kidney failure is variable, transplantation or dialysis may be required as early as the teenage years in some individuals but is most often necessary by adulthood. Hearing aids may be needed to manage hearing loss. Additionally, ophthalmologic intervention, such as cataract surgery, may be required for some affected individuals. A multidisciplinary team of physicians, including nephrologists, audiologists, ophthalmologists, and other healthcare professionals, will need to be involved in the ongoing treatment and management of individuals with XLAS.

What is the prognosis for an individual with X-Linked Alport Syndrome?

While the prognosis of XLAS is variable, most affected individuals develop kidney failure by 40 years of age. Renal transplantation and/or dialysis are typically successful as patients approach kidney failure. Complications from kidney disease may still result in a shortened life span. Hearing loss develops in the vast majority of affected individuals by 40 years of age. Often, the eye complications associated with XLAS do not cause any severe visual abnormalities, although cataract surgery and/or corrective lenses may be required.