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Alport syndrome, X-linked recessive(ATS)

MedGen UID:
292688
Concept ID:
C1567742
Disease or Syndrome
Synonyms: Alport Syndrome and Thin Basement Membrane Nephropathy; ATS; COL4A5 Alport Syndrome; COL4A5- Related Nephropathy; NEPHROPATHY AND DEAFNESS, X-LINKED
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
X-linked dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Alport syndrome X-linked (717768004)
 
Gene (location): COL4A5 (Xq22.3)
OMIM®: 301050
Orphanet: ORPHA88917

Disease characteristics

Alport syndrome (AS) is characterized by renal, cochlear, and ocular involvement. In the absence of treatment, renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with X-linked (XL) AS, and in all males and females with autosomal recessive (AR) AS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with autosomal dominant (AD) AS, ESRD is frequently delayed until later adulthood, SNHL is also relatively late in onset and ocular involvement is rare. Thin basement membrane nephropathy (TBMN) is characterized by persistent microscopic hematuria often first observed in childhood; progressive renal disease is relatively unusual and extrarenal abnormalities are rare. [from GeneReviews]
Authors:
Clifford E Kashtan   view full author information

Additional descriptions

From OMIM
Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by Kashtan, 1999). Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type IV collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance (104200) is rare (Kashtan, 1999). See also benign familial hematuria (BFH; 141200), a phenotypically similar, but milder disorder. Alport syndrome is also a feature of 2 contiguous gene deletion syndromes involving the COL4A5 gene: Alport syndrome and diffuse leiomyomatosis (308940) and Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME; 300194).  http://www.omim.org/entry/301050
From GHR
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).People with Alport syndrome frequently develop sensorineural hearing loss, which is caused by abnormalities of the inner ear, during late childhood or early adolescence. Affected individuals may also have misshapen lenses in the eyes (anterior lenticonus) and abnormal coloration of the light-sensitive tissue at the back of the eye (retina). These eye abnormalities seldom lead to vision loss.Significant hearing loss, eye abnormalities, and progressive kidney disease are more common in males with Alport syndrome than in affected females.  https://ghr.nlm.nih.gov/condition/alport-syndrome

Clinical features

Cataract, congenital
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Hypoparathyroidism
MedGen UID:
6985
Concept ID:
C0020626
Disease or Syndrome
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nephritis
MedGen UID:
14328
Concept ID:
C0027697
Disease or Syndrome
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
Microscopic hematuria
MedGen UID:
65997
Concept ID:
C0239937
Finding
Anterior lenticonus
MedGen UID:
473077
Concept ID:
C0344262
Congenital Abnormality
Corneal erosion
MedGen UID:
97882
Concept ID:
C0392163
Disease or Syndrome
Thickening of the glomerular basement membrane
MedGen UID:
488906
Concept ID:
C0445347
Finding
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
Diffuse glomerular basement membrane lamellation
MedGen UID:
479937
Concept ID:
C3278307
Finding
MedGen UID:
446783
Concept ID:
CN005882

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Alport syndrome, X-linked recessive in Orphanet.

Professional guidelines

PubMed

Hertz JM, Thomassen M, Storey H, Flinter F
Eur J Hum Genet 2012 Jun;20(6) Epub 2011 Dec 14 doi: 10.1038/ejhg.2011.237. PMID: 22166944Free PMC Article
ACMG.
Genet Med 2002 May-Jun;4(3):162-71. doi: 10.109700125817-200205000-00011. PMID: 12180152Free PMC Article

Recent clinical studies

Etiology

Plevová P, Gut J, Janda J
Medicina (Kaunas) 2017;53(1):1-10. Epub 2017 Jan 31 doi: 10.1016/j.medici.2017.01.002. PMID: 28236514
Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F
Clin J Am Soc Nephrol 2016 Sep 7;11(9):1713-20. Epub 2016 Jun 10 doi: 10.2215/CJN.00580116. PMID: 27287265Free PMC Article
Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K
Pediatr Nephrol 2014 Sep;29(9):1535-44. Epub 2014 Mar 15 doi: 10.1007/s00467-014-2797-4. PMID: 24633401
Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J
Pediatr Nephrol 2014 Mar;29(3):391-6. Epub 2013 Nov 2 doi: 10.1007/s00467-013-2643-0. PMID: 24178893
Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Müller GA, Gross O
Kidney Int 2012 Apr;81(8):779-83. Epub 2012 Jan 11 doi: 10.1038/ki.2011.452. PMID: 22237748

Diagnosis

Basel-Vanagaite L, Pillar N, Isakov O, Smirin-Yosef P, Lagovsky I, Orenstein N, Salmon-Divon M, Tamary H, Zaft T, Bazak L, Meyerovitch J, Pelli T, Botchan S, Farberov L, Weissglas-Volkov D, Shomron N
Gene 2017 Mar 30;606:47-52. Epub 2017 Jan 9 doi: 10.1016/j.gene.2017.01.001. PMID: 28089922
Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F
Clin J Am Soc Nephrol 2016 Sep 7;11(9):1713-20. Epub 2016 Jun 10 doi: 10.2215/CJN.00580116. PMID: 27287265Free PMC Article
Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J
Pediatr Nephrol 2014 Mar;29(3):391-6. Epub 2013 Nov 2 doi: 10.1007/s00467-013-2643-0. PMID: 24178893
Anazi S, Al-Sabban E, Alkuraya FS
Clin Genet 2014 Mar;85(3):278-81. Epub 2013 Apr 22 doi: 10.1111/cge.12156. PMID: 23551117
Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA
J Am Soc Nephrol 2013 Dec;24(12):1945-54. Epub 2013 Sep 19 doi: 10.1681/ASN.2012100985. PMID: 24052634Free PMC Article

Therapy

Uchida N, Kumagai N, Nozu K, Fu XJ, Iijima K, Kondo Y, Kure S
Tohoku J Exp Med 2016 Nov;240(3):251-257. doi: 10.1620/tjem.240.251. PMID: 27904025
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F
J Am Soc Nephrol 2013 Feb;24(3):364-75. Epub 2013 Jan 24 doi: 10.1681/ASN.2012020148. PMID: 23349312
Crovetto F, Moroni G, Zaina B, Acaia B, Ossola MW, Fedele L
Int Urol Nephrol 2013 Aug;45(4):1223-7. Epub 2012 Mar 15 doi: 10.1007/s11255-012-0154-8. PMID: 22418765
Wang XP, Fogo AB, Colon S, Giannico G, Abul-Ezz SR, Miner JH, Borza DB
J Am Soc Nephrol 2005 Dec;16(12):3563-71. Epub 2005 Oct 19 doi: 10.1681/ASN.2005060670. PMID: 16236801

Prognosis

Basel-Vanagaite L, Pillar N, Isakov O, Smirin-Yosef P, Lagovsky I, Orenstein N, Salmon-Divon M, Tamary H, Zaft T, Bazak L, Meyerovitch J, Pelli T, Botchan S, Farberov L, Weissglas-Volkov D, Shomron N
Gene 2017 Mar 30;606:47-52. Epub 2017 Jan 9 doi: 10.1016/j.gene.2017.01.001. PMID: 28089922
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F
Clin J Am Soc Nephrol 2016 Sep 7;11(9):1713-20. Epub 2016 Jun 10 doi: 10.2215/CJN.00580116. PMID: 27287265Free PMC Article
Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J
Pediatr Nephrol 2014 Mar;29(3):391-6. Epub 2013 Nov 2 doi: 10.1007/s00467-013-2643-0. PMID: 24178893
Temme J, Peters F, Lange K, Pirson Y, Heidet L, Torra R, Grunfeld JP, Weber M, Licht C, Müller GA, Gross O
Kidney Int 2012 Apr;81(8):779-83. Epub 2012 Jan 11 doi: 10.1038/ki.2011.452. PMID: 22237748

Clinical prediction guides

Basel-Vanagaite L, Pillar N, Isakov O, Smirin-Yosef P, Lagovsky I, Orenstein N, Salmon-Divon M, Tamary H, Zaft T, Bazak L, Meyerovitch J, Pelli T, Botchan S, Farberov L, Weissglas-Volkov D, Shomron N
Gene 2017 Mar 30;606:47-52. Epub 2017 Jan 9 doi: 10.1016/j.gene.2017.01.001. PMID: 28089922
Savige J, Storey H, Il Cheong H, Gyung Kang H, Park E, Hilbert P, Persikov A, Torres-Fernandez C, Ars E, Torra R, Hertz JM, Thomassen M, Shagam L, Wang D, Wang Y, Flinter F, Nagel M
PLoS One 2016;11(9):e0161802. Epub 2016 Sep 14 doi: 10.1371/journal.pone.0161802. PMID: 27627812Free PMC Article
Nishizawa Y, Takei T, Miyaoka T, Kamei D, Mochizuki T, Nitta K
J Obstet Gynaecol Res 2016 Mar;42(3):331-5. Epub 2015 Dec 2 doi: 10.1111/jog.12897. PMID: 26628290
Wang Y, Sivakumar V, Mohammad M, Colville D, Storey H, Flinter F, Dagher H, Savige J
Pediatr Nephrol 2014 Mar;29(3):391-6. Epub 2013 Nov 2 doi: 10.1007/s00467-013-2643-0. PMID: 24178893
Anazi S, Al-Sabban E, Alkuraya FS
Clin Genet 2014 Mar;85(3):278-81. Epub 2013 Apr 22 doi: 10.1111/cge.12156. PMID: 23551117

Recent systematic reviews

Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F
J Am Soc Nephrol 2013 Feb;24(3):364-75. Epub 2013 Jan 24 doi: 10.1681/ASN.2012020148. PMID: 23349312

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