Alport syndrome

Alport syndrome
Classification and external resources
ICD-10	Q87.8
ICD-9	759.89
OMIM	301050 104200 203780 300195
DiseasesDB	454
MedlinePlus	000504
eMedicine	med/110
MeSH	D009394

Alport syndrome or hereditary nephritis is a genetic disorder^[1] characterized by glomerulonephritis, endstage kidney disease, and hearing loss.^[2] Alport syndrome can also affect the eyes (lenticonus). The presence of blood in the urine (hematuria) is almost always found in this condition.

It was first identified in a British family by Dr. Cecil A. Alport in 1927,^[3][4] though William Howship Dickinson is considered by some to have made contributions to the characterization.^[5]

Causes

Alport syndrome is caused by mutations in COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes. 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, allowing 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. Progression of the disease leads to basement membrane thickening and gives a "basket-weave" appearance from splitting of the lamina densa. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules, notably leading to a bent molecular shape with kinks.^[6]

Inheritance patterns

Alport syndrome can have different inheritance patterns that are dependent on the genetic mutation.

• In most people with Alport syndrome, 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 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,^[7] though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.^[8][9]

Criteria for the clinical diagnosis

Gregory et al., 1996, gave the following 10 criteria for the diagnosis of Alport syndrome;^[10] Four of the 10 criteria must be met:

• Family history of nephritis of unexplained haematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.
• Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM 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 GBM ultrastructural abnormalities, in particular thickening, thinning and splitting.
• Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
• Gradual progression to ESRD 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.^[11]

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.^[12]

Of these three alpha chains, only alpha5 is normally expressed in the skin,^{[citation needed]} so the hallmark of X-linked Alport syndrome on a skin biopsy is the absence of alpha5 staining.^[12]

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 proteinuria that develops is often treated with ACE inhibitors, although they are not always used simply for the elevated blood pressure.^[13]

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.^[14]

Gene therapy as a possible treatment option has been discussed.^[15]

Disease database

COL4A5 gene variant database

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.^[1]

References

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