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 in the COL4A5 gene. Alport syndrome caused by the COL4A5 gene is inherited in an X-linked manner because the gene is located on the X chromosome. Males have one copy of the X-chromosome, while females have two copies. Because males only have one copy of the COL4A5 gene, a harmful change in the COL4A5 gene typically causes more severe symptoms in males.

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. Males with XLAS and greater than 90% of females with XLAS will have persistent blood in the urine during childhood. This is usually not detectable by the naked eye, but may be visible during periods of 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 will develop in all males with XLAS and some females with XLAS. Medications may delay the progress of kidney failure, but most often, a kidney transplant and/or dialysis will eventually be necessary.

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

Most carrier females exhibit symptoms of Alport syndrome, but there is a wide range of severity. A few carrier females may have no symptoms. Female carriers of XLAS typically have small amounts of blood in their urine. Some females are also affected by varying degrees of hearing loss, which tends to occur later in life. By late adulthood, up to 40% of female carriers experience kidney failure. Female 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. Approximately 10-15% of males with X-linked Alport syndrome do not inherit a mutation from a carrier mother (de novo mutation).

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. However, kidney failure will develop eventually in all males with XLAS and some females. 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 required 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.