Alport syndrome

Alport syndrome
File:Alport haring loss.jpg Hearing loss effect of Alport syndrome in 13-year-old boy.
Classification and external resources
Specialty
ICD-10	Q87.8
ICD-9-CM	759.89
OMIM	301050 104200 203780 300195
DiseasesDB	454
MedlinePlus	000504
eMedicine	med/110
Patient UK	Alport syndrome
MeSH	y D009394 y
GeneReviews	Collagen IV-Related Nephropathies (Alport Syndrome and Thin Basement Membrane Nephropathy)

Alport syndrome or hereditary nephritis is a genetic disorder affecting around 1 in 5,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, causing eye abnormalities including cataracts, lenticonus, kerataconus, as well as retinal flecks in the macula and mid-periphery. Visibly bloody urine and protein in the urine are common features of this condition.

The disorder was first identified in a British family by University of Edinburgh Medical School graduate Cecil A. Alport in 1927,

Causes

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, all genes involved in collagen biosynthesis. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of basement membranes in the kidney, inner ear, and eye. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, which allows blood and protein into the urine.

The abnormalities of type IV collagen in kidney basement membranes cause gradual scarring of the kidneys, eventually leading to kidney failure in many people with the disease. The thickening of the basement membrane (because of the scar tissue) gives a "basket-weave" appearance from splitting of the glomerular basement membrane, specifically the lamina densa layer. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nano-mechanical behavior of mutated molecules. Notably, these lead to a bent molecular shape with kinks in the protein at the site of the mutations.

Inheritance patterns

Alport syndrome can have different inheritance patterns depending on which specific mutation is present.

• In most people with Alport syndrome (about 85%), the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.
• Alport syndrome can also be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
• Past descriptions of an autosomal dominant form are now usually categorized as other conditions, though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published. Autosomal dominant transmission is rare and only accounts for 5% of affected patients.The clinical features of autosomal dominant Alport syndrome are similar to those of X-linked disease. However, deterioration of renal function tends to occur more slowly.

Diagnosis

At least four of the following ten criteria must be met to diagnose an individual with Alport syndrome:

• Family history of nephritis of unexplained hematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.
• Persistent hematuria without evidence of another possibly inherited nephropathy such as thin glomerular basement membrane disease, polycystic kidney disease or IgA nephropathy.
• Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy, and commonly presents before the age of 30 years.
• A mutation in COL4An (where n = 3, 4 or 5).
• Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.
• Widespread glomerular basement membrane ultrastructural abnormalities, in particular thickening, thinning and splitting.
• Eye lesions including anterior lenticonus, kerataconus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
• Gradual progression to end-stage kidney disease in the index case of at least two family members.
• Macrothrombocytopenia or granulocytic inclusions, similar to the May-Hegglin anomaly.
• Diffuse leiomyomatosis of esophagus or female genitalia, or both.

The use of eye examinations for screening has been proposed.

A review of pathogenic mutations detected in X-linked Alport syndrome patients in 2011, recommended COL4A5 analysis in any patient meeting at least two clinical diagnostic criteria. Analysis of COL4A3 and COL4A4 should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.

Clinical utility gene card for: Alport syndrome.

Immunohistochemistry

Immunohistochemical (IHC) evidence of the X-linked form Alport syndrome may be obtained from biopsies of either the skin or the renal glomerulus. In this processes, antibodies are used to detect the presence or absence of the alpha3, alpha4, and alpha5 chains of collagen type 4.

All three of these alpha chains are present in the glomerular basement membrane of normal individuals. In individuals expressing the X-linked form of Alport's syndrome, however, the presence of the dysfunctional alpha5 chain causes the assembly of the entire collagen 4 complex to fail, and none of these three chains will be detectable in either the glomerular or the renal tubular basement membrane.

Of these three alpha chains, only alpha5 is normally expressed in the skin, so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.

Treatment

As there is no known cure for the condition, treatments are symptomatic. Patients are advised on how to manage the complications of kidney failure and the spilling of protein in the urine that develops is often treated with ACE inhibitors.

Once kidney failure has developed, patients are given dialysis or can benefit from a kidney transplant, although this can cause problems. The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.

Gene therapy as a possible treatment option has been discussed.

Disease databases

ARUP COL4A5 gene variant database

LOVD Alport gene variant databases (COL4A5, COL4A3, COL4A4)

References

This article incorporates public domain text from The U.S. National Library of Medicine

See also

• Samoyed hereditary glomerulopathy, a disease shown to be a model for Alport syndrome.
• Fechtner Syndrome

External links

• Laboratory for Molecular Diagnostics, Center for Nephrology and Metabolic Disorders, Dr Mato Nagel
• Alport Syndrome Foundation
• Alport Foundation of Australia
• Alport Syndrome Support for Canadians
• GeneReview/NIH/UW entry on Alport syndrome
• Alport Syndrome Treatments and Outcomes Registry
• UK Alport syndrome testing, Molecular Genetics, Guy's Hospital