X-linked Alport syndrome

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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 and X-linked Alport syndrome is caused by harmful genetic changes (mutations) in the COL4A5 gene. Alport syndrome can be inherited in an X-linked or autosomal recessive manner, depending on what gene causes the disease. 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 and the COL4A5 gene, while females have two copies. Because of this, men with a mutation in COL4A5 are affected by Alport syndrome, while most female carriers still have one working copy of the gene. Carrier females may be asymptomatic or may exhibit symptoms that are typically less severe than males.

The presentation of X-linked Alport syndrome (XLAS) is variable in severity; some individuals have a milder disease course, while others develop more severe disease with complications. Although the data is somewhat limited, recent studies have shown that some individuals with XLAS may have a harmful change in the COL4A5 gene as well as a harmful change in a different gene (digenic inheritance).

The first sign of disease is often blood in the urine (hematuria) 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 a variety of 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, either a kidney transplant and/or dialysis is necessary.

XLAS is also associated with varying degrees of progressive hearing loss and eye abnormalities. The onset and severity of hearing loss is variable, but it is not uncommon for some degree of hearing loss to develop by adolescence. Eye abnormalities including in the outer protective layer of the eye (cornea), the transparent tissue behind the iris (lens), and the light-sensitive tissue in the back of the eye (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.

Carrier Females

Most female carriers of XLAS will have blood in the urine that is not detectable by the naked eye. Some females are also affected by varying degrees of hearing loss, but this tends to occur later in life. By late adulthood, up to 40% of female carriers experience kidney failure.

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 85% 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 in some females. Because the onset of kidney failure is variable, transplantation or dialysis may be required as early as the teenage years, but most often is necessary by adulthood. Hearing aids may be required to treat hearing loss. Additionally, ophthalmologic intervention, such as cataract surgery, may be required for some 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, the vast majority of affected individuals develop kidney failure by 40 years of age. Renal transplantation and/or dialysis are typically successful as patients are approaching 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. Many times, the eye complications associated with XLAS do not cause any severe visual abnormalities, although cataract surgery and/or corrective lenses may be required.