Alport syndrome

Alport syndrome

Other Names: Alport syndrome, X-linked; Hemorrhagic familial nephritis; Hemorrhagic hereditary nephritis; Congenital hereditary hematuria

Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities. Most affected individuals experience progressive loss of kidney function, usually resulting in end-stage kidney disease. People with Alport syndrome also frequently develop sensorineural hearing loss in late childhood or early adolescence. The eye abnormalities characteristic of this condition seldom lead to vision loss.

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Epidemiology

Alport syndrome occurs in approximately 1 in 50,000 newborns.

Cause

Mutations in the COL4A3, COL4A4, and COL4A5 genes cause Alport syndrome. These genes each provide instructions for making one component of a protein called type IV collagen. This protein plays an important role in the kidneys, specifically in structures called glomeruli. Glomeruli are clusters of specialized blood vessels that remove water and waste products from blood and create urine. Mutations in these genes result in abnormalities of the type IV collagen in glomeruli, which prevents the kidneys from properly filtering the blood and allows blood and protein to pass into the urine. Gradual scarring of the kidneys occurs, eventually leading to kidney failure in many people with Alport syndrome.

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Type IV collagen is also an important component of inner ear structures, particularly the organ of Corti, that transform sound waves into nerve impulses for the brain. Alterations in type IV collagen often result in abnormal inner ear function, which can lead to hearing loss. In the eye, this protein is important for maintaining the shape of the lens and the normal color of the retina. Mutations that disrupt type IV collagen can result in misshapen lenses and an abnormally colored retina.

Inheritance

Alport syndrome can have different inheritance patterns. About 80 percent of cases are caused by mutations in the COL4A5 gene and are inherited in an X-linked pattern. This gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the COL4A5 gene in each cell is sufficient to cause kidney failure and other severe symptoms of the disorder. In females (who have two X chromosomes), a mutation in one copy of the COL4A5 gene usually only results in hematuria, but some women experience more severe symptoms. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In approximately 15 percent of cases, Alport syndrome results from mutations in both copies of the COL4A3 or COL4A4 gene and is inherited in an autosomal recessive pattern. The parents of an individual with the autosomal recessive form of this condition each have one copy of the mutated gene and are called carriers. Some carriers are unaffected and others develop a less severe condition called thin basement membrane nephropathy, which is characterized by hematuria.

Alport syndrome has autosomal dominant inheritance in about 5 percent of cases. People with this form of Alport syndrome have one mutation in either the COL4A3 or COL4A4 gene in each cell. It remains unclear why some individuals with one mutation in the COL4A3 or COL4A4 gene have autosomal dominant Alport syndrome and others have thin basement membrane nephropathy.

Signs and symptoms

Alport syndrome is characterized by kidney disease, hearing loss, and eye abnormalities. Symptoms typically begin in childhood, and the first sign of the condition is usually the presence of blood in the urine (hematuria). Other symptoms of kidney disease can include having protein in the urine (proteinuria). Over time, an affected person may experience swelling (edema), bone weakening, and joint pain (osteodystrophy). Without treatment, affected individuals will experience end-stage renal disease. Alport syndrome also causes sensorineural hearing loss, or hearing loss that is due to the inner ear or the nerves not working properly. Hearing loss typically develops during late childhood or early adolescence, and most affected individuals become deaf by age 40. Alport syndrome is also characterized by specific eye changes. Most commonly, affected individuals have an eye finding called anterior lenticonus, which causes the lens to become cone-shaped. Other affected individuals may have abnormal coloration of the retina (dot-and-fleck retinopathy), which can sometimes lead to vision loss. Some individuals may experience maculopathy, or damage to the part of the eye (macula) that allows for central vision.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Diffuse glomerular basement membrane lamellation
• Thin glomerular basement membrane

30%-79% of people have these symptoms

• Hypertension
• Mesangial hypercellularity
• Proteinuria(High urine protein levels)

5%-29% of people have these symptoms

• Abnormal corneal endothelium morphology
• Anterior lenticonus
• Focal segmental glomerulosclerosis
• Glomerular C3 deposition
• IgA deposition in the glomerulus
• Microscopic hematuria(Small amount of blood in urine)
• Nephritis(Kidney inflammation)
• Nephrotic syndrome
• Recurrent corneal erosions(Recurrent breakdown of clear protective layer of eye)
• Renal glomerular foam cells
• Renal tubular atrophy
• Retinal flecks
• Sensorineural hearing impairment
• Stage 5 chronic kidney disease
• Thickening of glomerular capillary wall
• Thickening of the glomerular basement membrane
• Tubulointerstitial fibrosis

Diagnosis

Alport syndrome is suspected based on a family history or clinical signs of the condition. A doctor may order a kidney biopsy to look for signs of the condition such as abnormalities of the cells of the glomeruli. A kidney biopsy can also allow to test specifically for type IV collagen protein, as this protein would be absent in a person with Alport syndrome.

Doctors may also order a test to measure the amount of blood and protein in the urine. An ophthalmologic exam may be used to look for signs characteristic of the condition such as anterior ]]lenticonus]]. When Alport syndrome is suspected, genetic testing can be used to confirm the diagnosis and determine the pattern of inheritance. This can provide information about the chance that other family members are affected.

Treatment

Although there is no one specific treatment for Alport syndrome, the goals of treatment include monitoring and controlling progression of the disease and treating the symptoms. Strict control of blood pressure is very important in order to keep the kidneys as healthy as possible.

Research suggests that ACE inhibitors, angiotensins, and statins can help reduce proteinuria and the progression of kidney disease. However, treatment of chronic kidney failure often becomes necessary. This can include dietary modifications and fluid restriction. Ultimately, chronic kidney failure progresses to end-stage kidney disease, requiring dialysis or transplantation. Kidney transplantation in people with Alport syndrome is usually successful, but some studies have reported that about 10% of transplanted patients develop inflammation of the kidneys (nephritis).

Treatment for other aspects of the condition are addressed as needed. For instance, surgical repairs of the eye manifestations may be recommended. Loss of hearing is likely to be permanent, but affected individuals can be assisted with hearing aids. Counseling and education to increase coping skills can be helpful. Learning new skills such as lip reading or sign language may be of some benefit. Young men with Alport syndrome should use hearing protection in noisy environments. Genetic counseling may be recommended to explain the inherited pattern of the disorder.

Prognosis

Studies of the life expectancy of patients with Alport syndrome are rare, but one 2012 study of 456 male patients from across Europe who received a kidney transplant found that they had somewhat increased life expectancy compared to matched controls (the controls were "randomly selected from the same age, year, and modality categories").

NIH genetic and rare disease info

• NIH info on Alport syndrome

Alport syndrome is a rare disease.

Alport syndrome Resources
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