Alport syndrome

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Alport syndrome
Classification and external resources
Alport haring loss.jpg
Hearing loss effect of Alport syndrome in 13-year-old boy.
ICD-10 Q87.8
ICD-9 759.89
OMIM 301050 104200 203780 300195
DiseasesDB 454
MedlinePlus 000504
eMedicine med/110
Patient UK Alport syndrome
MeSH D009394
GeneReviews

Alport syndrome or hereditary nephritis is a genetic disorder[1] characterized by glomerulonephritis, end-stage kidney disease, and hearing loss.[2] 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,[3][4] though William Howship Dickinson is considered by some to have made contributions to the characterization.[5]

Causes[edit]

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, 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 glomerular basement membrane, specifically the lamina densa layer. Single molecule computational studies of type IV collagen molecules have shown changes in the structure and nanomechanical behavior of mutated molecules. Notably these lead to a bent molecular shape with kinks in the protein at the site of the mutations.[6]

Inheritance patterns[edit]

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

  • In most people with Alport syndrome (about 85%), the condition is inherited in an X-linked dominant 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] 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.[10]

Criteria for the clinical diagnosis[edit]

The following 10 criteria, of which 4 must be met for the diagnosis of Alport syndrome, have been given by Gregory et al. in 1996,:[11]

The use of eye examinations for screening has been proposed.[12]

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 and that COL4A3 and COL4A4 analysis should be considered if a COL4A5 mutation is not detected and primarily if autosomal inheritance is suspected.[13]

Clinical utility gene card for: Alport syndrome.[14]

Immunohistochemistry[edit]

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.[15]

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.[15]

Treatment[edit]

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.[16]

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.[17]

Gene therapy as a possible treatment option has been discussed.[18]

Disease databases[edit]

ARUP COL4A5 gene variant database

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

References[edit]

  1. ^ Diseases of the Kidney: Alport Syndrome
  2. ^ "Alport syndrome" at Dorland's Medical Dictionary
  3. ^ Lagona E, Tsartsali L, Kostaridou S, Skiathitou A, Georgaki E, Sotsiou F (April 2008). "Skin Biopsy for the diagnosis of Alport Syndrome". Hippokratia 12 (2): 116–8. PMC 2464308. PMID 18923659. 
  4. ^ Alport, AC (19 March 1927). "Hereditary familial congenital haemorrhagic nephritis". BMJ 1 (3454): 504–506. doi:10.1136/bmj.1.3454.504. 
  5. ^ synd/337 at Who Named It?
  6. ^ Srinivasan M, Uzel SGM, Gautieri A, Keten S, Buehler MJ (2009). "Alport Syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties". J. Structural Biology 168 (3): 503–510. doi:10.1016/j.jsb.2009.08.015. PMID 19729067. 
  7. ^ "OMIM - ALPORT SYNDROME, AUTOSOMAL DOMINANT". Retrieved 2008-11-24. 
  8. ^ Kharrat M, Makni S, Makni K, et al. (September 2006). "Autosomal dominant Alport's syndrome: study of a large Tunisian family". Saudi J Kidney Dis Transpl 17 (3): 320–5. PMID 16970251. 
  9. ^ Pescucci C, Mari F, Longo I, et al. (May 2004). "Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene". Kidney Int. 65 (5): 1598–603. doi:10.1111/j.1523-1755.2004.00560.x. PMID 15086897. 
  10. ^ Cheungpasitporn W; Kaewpoowat Q; Suksaranjit P; Kittanamongkolchai W; Srivali N; Ungprasert P; Rangan Y (2012). "Autosomal Dominant Alport Syndrome Presenting as Proteinuria at Marine Corps Physical Fitness Test: A Case Report and Review.". J Nephrol Therapeut S8. doi:10.4172/2161-0959.S8-001. 
  11. ^ Gregory MC, Terreros DA, Barker DF, Fain PN, Denison JC, Atkin CL (1996). "Alport syndrome--clinical phenotypes, incidence, and pathology". Contrib Nephrol 117: 1–28. PMID 8801040. 
  12. ^ Zhang KW, Colville D, Tan R, et al. (August 2008). "The use of ocular abnormalities to diagnose X-linked Alport syndrome in children". Pediatr. Nephrol. 23 (8): 1245–50. doi:10.1007/s00467-008-0759-4. PMID 18343956. 
  13. ^ Hanson H, Storey H, Pagan J, Flinter F. (2011). "The Value of Clinical Criteria in Identifying Patients with X-Linked Alport Syndrome". Clin J Am Soc Nephrol 6 (1): 198–203. doi:10.2215/CJN.00200110. PMC 3022243. PMID 20884774. 
  14. ^ Hertz JM, Thomassen M, Storey H, Flinter F (2012). "Clinical utility gene card for: Alport syndrome.". European Journal of Human Genetics 20 (6). doi:10.1038/ejhg.2011.237. PMC 3355248. PMID 22166944. 
  15. ^ a b Fausto, [ed. by] Vinay Kumar; Abul K. Abbas; Nelson (2005). Robbins and Cotran pathologic basis of disease. (7th ed.). Philadelphia: Elsevier/Saunders. p. 988. ISBN 0-7216-0187-1. 
  16. ^ Alport Syndrome~treatment at eMedicine
  17. ^ http://www.edren.org/pages/edreninfo/alport-syndrome.php
  18. ^ Tryggvason K, Heikkilä P, Pettersson E, Tibell A, Thorner P (1997). "Can Alport syndrome be treated by gene therapy?". Kidney Int. 51 (5): 1493–9. doi:10.1038/ki.1997.205. PMID 9150464. 

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

See also[edit]

References[edit]

  1. ^ Chen, Dilys; Jefferson, Barbara; Harvey, Scott J.; Zheng, Keqin; Gartley, Cathy J.; Jacobs, Robert M.; Thorner, Paul S. (October 2003). "Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis): Results from a Canine Model" (PDF). Journal of the American Society of Nephrology 14 (3): 690–698. doi:10.1097/01.ASN.0000046964.15831.16. PMID 12595505. 

External links[edit]