| Alport syndrome |
|
Hearing loss effect of Alport syndrome in 13-year-old boy.
|
| Classification and external resources |
| 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 |
- Collagen IV-Related Nephropathies (Alport Syndrome and Thin Basement Membrane Nephropathy)
|
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]
Contents
- 1 Causes
- 2 Inheritance patterns
- 3 Diagnosis
- 4 Treatment
- 5 Disease databases
- 6 References
- 7 See also
- 8 References
- 9 External links
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.[6]
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 dominant pattern,[7] 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,[8] though some uses of the term in reference to the COL4A3 and COL4A4 loci have been published.[9][10] 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.[11]
Diagnosis
At least four of the following ten criteria must be met to diagnose an individual with Alport syndrome:[12]
- 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.[13]
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.[14]
Clinical utility gene card for: Alport syndrome.[15]
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.[16]
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.[16]
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.[17]
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.[18]
Gene therapy as a possible treatment option has been discussed.[19]
Disease databases
ARUP COL4A5 gene variant database
LOVD Alport gene variant databases (COL4A5, COL4A3, COL4A4)
References
- ^ Diseases of the Kidney: Alport Syndrome
- ^ "Alport syndrome" at Dorland's Medical Dictionary
- ^ 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.
- ^ Alport, AC (19 March 1927). "Hereditary familial congenital haemorrhagic nephritis". BMJ 1 (3454): 504–506. doi:10.1136/bmj.1.3454.504.
- ^ synd/337 at Who Named It?
- ^ 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.
- ^ The more frequent presentation of Alport Syndrome appear from mutations in the COL4A5 gene, which are inherited in an X-linked dominant form; see Jais JP et al. X-Linked Alport Syndrome: Natural History and Genotype-Phenotype Correlations in Girls and Women Belonging to 195 Families: A “European Community Alport Syndrome Concerted Action” Study J Am Soc Nephrol. 2003 Oct;14(10):2603-10. Accessed 27 May 2012.
- ^ "OMIM - ALPORT SYNDROME, AUTOSOMAL DOMINANT". Retrieved 2008-11-24.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Alport Syndrome~treatment at eMedicine
- ^ http://www.edren.org/pages/edreninfo/alport-syndrome.php
- ^ 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
- Samoyed hereditary glomerulopathy, a disease shown to be a model for Alport syndrome.[1]
- Fechtner Syndrome
References
- ^ 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
- 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
|
Genetic disorder, extracellular: scleroprotein disease (excluding laminin and keratin)
|
|
| Collagen disease |
| COL1: |
- Osteogenesis imperfecta
- Ehlers–Danlos syndrome, types 1, 2, 7
|
|
| COL2: |
- Hypochondrogenesis
- Achondrogenesis type 2
- Stickler syndrome
- Marshall syndrome
- Spondyloepiphyseal dysplasia congenita
- Spondyloepimetaphyseal dysplasia, Strudwick type
- Kniest dysplasia (see also C2/11)
|
|
| COL3: |
- Ehlers–Danlos syndrome, types 3 & 4
|
|
| COL4: |
|
|
| COL5: |
- Ehlers–Danlos syndrome, types 1 & 2
|
|
| COL6: |
- Bethlem myopathy
- Ullrich congenital muscular dystrophy
|
|
| COL7: |
- Epidermolysis bullosa dystrophica
- Recessive dystrophic epidermolysis bullosa
- Bart syndrome
- Transient bullous dermolysis of the newborn
|
|
| COL8: |
|
|
| COL9: |
- Multiple epiphyseal dysplasia 2, 3, 6
|
|
| COL10: |
- Schmid metaphyseal chondrodysplasia
|
|
| COL11: |
- Weissenbacher–Zweymüller syndrome
- Otospondylomegaepiphyseal dysplasia (see also C2/11)
|
|
| COL17: |
|
|
|
| Laminin |
- Junctional epidermolysis bullosa
- Laryngoonychocutaneous syndrome
|
|
| Other |
- Congenital stromal corneal dystrophy
- Raine syndrome
- Urbach–Wiethe disease
- TECTA
|
|
|
see also fibrous proteins
|
Index of cells
|
|
| Description |
- Structure
- Organelles
- peroxisome
- cytoskeleton
- centrosome
- epithelia
- cilia
- mitochondria
- Membranes
- Membrane transport
- ion channels
- vesicular transport
- solute carrier
- ABC transporters
- ATPase
- oxidoreduction-driven
|
|
| Disease |
- Structural
- peroxisome
- cytoskeleton
- cilia
- mitochondria
- nucleus
- scleroprotein
- Membrane
- channelopathy
- solute carrier
- ATPase
- ABC transporters
- other
- extracellular ligands
- cell surface receptors
- intracellular signalling
- Vesicular transport
- Pore-forming toxins
|
|
|
|
Congenital malformations and deformations of urinary system (Q60–Q64, 753)
|
|
| Abdominal |
| Kidney |
- Renal agenesis/Potter sequence, Papillorenal syndrome
- cystic
- Polycystic kidney disease
- Meckel syndrome
- Multicystic dysplastic kidney
- Medullary sponge kidney
- Horseshoe kidney
- Renal ectopia
- Nephronophthisis
- Dent's disease
- Alport syndrome
|
|
| Ureter |
- Ectopic ureter
- Megaureter
- Duplicated ureter
|
|
|
| Pelvic |
| Bladder |
|
|
| Urethra |
- Epispadias
- Hypospadias
- Posterior urethral valves
|
|
|
| Vestigial |
|
|
|
Index of the urinary system
|
|
| Description |
- Anatomy
- Physiology
- Development
- Cells
|
|
| Disease |
- Electrolyte and acid-base
- Congenital
- Neoplasms and cancer
- Other
- Symptoms and signs
- Urine tests
- Blood tests
|
|
| Treatment |
- Procedures
- Drugs
- Intravenous fluids
|
|
|
|
Sex linkage: X-linked disorders
|
|
|
X-linked recessive
|
|
| Immune |
- Chronic granulomatous disease (CYBB)
- Wiskott–Aldrich syndrome
- X-linked severe combined immunodeficiency
- X-linked agammaglobulinemia
- Hyper-IgM syndrome type 1
- IPEX
- X-linked lymphoproliferative disease
- Properdin deficiency
|
|
| Hematologic |
- Haemophilia A
- Haemophilia B
- X-linked sideroblastic anemia
|
|
| Endocrine |
- Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
- KAL1 Kallmann syndrome
- X-linked adrenal hypoplasia congenita
|
|
| Metabolic |
- Amino acid: Ornithine transcarbamylase deficiency
- Oculocerebrorenal syndrome
- Dyslipidemia: Adrenoleukodystrophy
- Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
- Pyruvate dehydrogenase deficiency
- Danon disease/glycogen storage disease Type IIb
- Lipid storage disorder: Fabry's disease
- Mucopolysaccharidosis: Hunter syndrome
- Purine-pyrimidine metabolism: Lesch–Nyhan syndrome
- Mineral: Menkes disease/Occipital horn syndrome
|
|
| Nervous system |
- X-linked mental retardation: Coffin–Lowry syndrome
- MASA syndrome
- X-linked alpha thalassemia mental retardation syndrome
- Siderius X-linked mental retardation syndrome
- Eye disorders: Color blindness (red and green, but not blue)
- Ocular albinism (1)
- Norrie disease
- Choroideremia
- Other: Charcot–Marie–Tooth disease (CMTX2-3)
- Pelizaeus–Merzbacher disease
- SMAX2
|
|
| Skin and related tissue |
- Dyskeratosis congenita
- Hypohidrotic ectodermal dysplasia (EDA)
- X-linked ichthyosis
- X-linked endothelial corneal dystrophy
|
|
| Neuromuscular |
- Becker's muscular dystrophy/Duchenne
- Centronuclear myopathy (MTM1)
- Conradi–Hünermann syndrome
- Emery–Dreifuss muscular dystrophy 1
|
|
| Urologic |
- Alport syndrome
- Dent's disease
- X-linked nephrogenic diabetes insipidus
|
|
| Bone/tooth |
- AMELX Amelogenesis imperfecta
|
|
| No primary system |
- Barth syndrome
- McLeod syndrome
- Smith–Fineman–Myers syndrome
- Simpson–Golabi–Behmel syndrome
- Mohr–Tranebjærg syndrome
- Nasodigitoacoustic syndrome
|
|
|
|
X-linked dominant
|
|
- X-linked hypophosphatemia
- Focal dermal hypoplasia
- Fragile X syndrome
- Aicardi syndrome
- Incontinentia pigmenti
- Rett syndrome
- CHILD syndrome
- Lujan–Fryns syndrome
- Orofaciodigital syndrome 1
- Craniofrontonasal dysplasia
|
|
|