Alport syndrome, COL4A4-related

What is Alport syndrome, COL4A4-related?

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 Alport syndrome, COL4A4-related, is caused by harmful genetic changes in the COL4A4 gene. Alport syndrome can be inherited in an X-linked or autosomal-recessive manner. Alport syndrome, COL4A4-related, is inherited in an autosomal-recessive manner.

The presentation of Alport syndrome is variable in severity. Some individuals have a milder disease course, while others develop more severe symptoms. Males and females with Alport syndrome, COL4A4-related, have similar disease severity. Although the data are somewhat limited, recent studies have shown that some individuals with Alport syndrome may have a harmful genetic change in COL4A4 and another gene (suggesting digenic inheritance).

The first symptom of Alport syndrome is typically blood in the urine (hematuria) from kidney disease, which usually presents during childhood. This is usually not detectable by the naked eye, but it 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. This kidney failure is associated with various symptoms, including high blood pressure, fatigue, poor appetite, swelling of legs and feet, and frequent urination. Medications may delay the progression of kidney failure, but typically, a kidney transplant and/or dialysis will eventually be necessary.

Alport syndrome 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

Approximately two-thirds of all carriers of a harmful change in COL4A4 will have small amounts of blood in their urine (hematuria). Some carriers may develop other symptoms of Alport syndrome over their lifetime, including high blood pressure, protein in the urine, or poor kidney function. Carriers should not be kidney donors because this could increase their chance of developing kidney disease. Carriers of harmful genetic changes in COL4A4 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 Alport syndrome, COL4A4-related?

All forms of Alport syndrome are estimated to occur in approximately 1 in 50,000 live births. The two genes associated with the recessive form of Alport syndrome, COL4A3 and COL4A4, are responsible for about 20% of all cases. Alport syndrome occurs at a similar frequency amongst all ethnicities. Alport syndrome, COL4A4-related, is more common in certain populations, such as individuals of Ashkenazi Jewish descent.

How is Alport syndrome, COL4A4-related, treated?

Currently, there is no cure for Alport syndrome. 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 eventually develop. 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 Alport syndrome.

What is the prognosis for an individual with Alport syndrome, COL4A4-related?

While the prognosis of Alport syndrome 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. In addition, hearing loss typically develops in most individuals by 40 years of age. Often, the eye complications do not cause any severe visual abnormalities, although cataract surgery and/or corrective lenses may be required.