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Alport syndrome, autosomal dominant(COL4A3)

MedGen UID:
339210
Concept ID:
C1567743
Disease or Syndrome
Synonyms: Alport syndrome dominant type; COL4A3; COL4A3 Alport Syndrome and Thin Basement Membrane Nephropathy; Renal failure and sensorineural hearing loss
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): COL4A3 (2q36.3)
OMIM®: 104200
Orphanet: ORPHA88918

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 classically comprises nephritis, often progressing to renal failure, and sensorineural hearing loss (Alport, 1927). For a general phenotypic description of Alport syndrome, see the X-linked dominant form (301050). Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance is rare (van der Loop et al., 2000). Also see benign familial hematuria (BFH; 141200), a similar but milder disorder also caused by mutation in the COL4A3 gene. An autosomal dominant disorder sharing the clinical features of Alport syndrome but with the addition of macrothrombocytopenia, known as Fechtner syndrome (153640), is caused by mutation in the MYH9 gene (160775) on chromosome 22q11.  http://www.omim.org/entry/104200
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

Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects nearby clearly, while objects in the distance appear blurry.
Lenticonus
MedGen UID:
116078
Concept ID:
C0239119
Congenital Abnormality
A conical projection of the anterior or posterior surface of the lens, occurring as a developmental anomaly.
Cataract 32
MedGen UID:
340806
Concept ID:
C1855179
Disease or Syndrome
A polar cataract that affects the anterior pole of the lens.
Hypertension
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is called diastolic pressure. . Your blood pressure reading uses these two numbers. Usually the systolic number comes before or above the diastolic number. A reading of. -119/79 or lower is normal blood pressure. -140/90 or higher is high blood pressure. -Between 120 and 139 for the top number, or between 80 and 89 for the bottom number is called prehypertension. Prehypertension means you may end up with high blood pressure, unless you take steps to prevent it. High blood pressure usually has no symptoms, but it can cause serious problems such as stroke, heart failure, heart attack and kidney failure. You can control high blood pressure through healthy lifestyle habits such as exercise and the DASH diet and taking medicines, if needed. . NIH: National Heart, Lung, and Blood Institute.
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
Hearing loss resulting from damage to the COCHLEA and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the AUDITORY NERVE and its connections in the BRAINSTEM.
Glomerulonephritis
MedGen UID:
6616
Concept ID:
C0017658
Disease or Syndrome
Inflammation of the renal glomeruli.
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Finding
The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
A condition characterized by calcification of the renal tissue itself. It is usually seen in distal RENAL TUBULAR ACIDOSIS with calcium deposition in the DISTAL KIDNEY TUBULES and the surrounding interstitium. Nephrocalcinosis causes RENAL INSUFFICIENCY.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
a kidney disease characterized by a high protein level in urine
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Thickening of the glomerular basement membrane
MedGen UID:
488906
Concept ID:
C0445347
Finding
Increase in thickness of the basal lamina of the glomerulus of the kidney.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Diffuse glomerular basement membrane lamellation
MedGen UID:
479937
Concept ID:
C3278307
Finding
Presence of abnormal additional layers of the basement membrane of the glomerulus.
Glomerulonephritis
MedGen UID:
6616
Concept ID:
C0017658
Disease or Syndrome
Inflammation of the renal glomeruli.
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Finding
The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Pathologic Function
An abnormally decreased phosphate concentration in the blood.
Azotemia
MedGen UID:
116608
Concept ID:
C0242528
Disease or Syndrome
An increased concentration of nitrogen compounds in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Alport syndrome, autosomal dominant 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

Recent clinical studies

Etiology

Deng S, Xu H, Yuan J, Xiao J, Yuan L, Deng X, Guan L, Zhu A, Rong P, Zhang J, Deng H
Indian J Med Res 2016 Aug;144(2):200-205. doi: 10.4103/0971-5916.195026. PMID: 27934798Free PMC Article
Yefet E, Tovbin D, Nachum Z
Arch Gynecol Obstet 2016 Apr;293(4):739-47. Epub 2015 Sep 28 doi: 10.1007/s00404-015-3893-9. PMID: 26411580
Rosado C, Bueno E, Felipe C, Valverde S, González-Sarmiento R
Kidney Blood Press Res 2015;40(4):435-42. Epub 2015 Jul 31 doi: 10.1159/000368519. PMID: 26277931
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, Miglietti N, Antonucci MF, Cetta F, Sayer JA, van den Wijngaard A, Yau S, Mari F, Bruttini M, Ariani F, Dahan K, Smeets B, Antignac C, Flinter F, Renieri A
J Med Genet 2015 Mar;52(3):163-74. Epub 2015 Jan 9 doi: 10.1136/jmedgenet-2014-102822. PMID: 25575550
Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombolà G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F
Nephrol Dial Transplant 2009 May;24(5):1464-71. Epub 2009 Jan 7 doi: 10.1093/ndt/gfn681. PMID: 19129241

Diagnosis

Deng S, Xu H, Yuan J, Xiao J, Yuan L, Deng X, Guan L, Zhu A, Rong P, Zhang J, Deng H
Indian J Med Res 2016 Aug;144(2):200-205. doi: 10.4103/0971-5916.195026. PMID: 27934798Free PMC Article
Yefet E, Tovbin D, Nachum Z
Arch Gynecol Obstet 2016 Apr;293(4):739-47. Epub 2015 Sep 28 doi: 10.1007/s00404-015-3893-9. PMID: 26411580
Rosado C, Bueno E, Felipe C, Valverde S, González-Sarmiento R
Kidney Blood Press Res 2015;40(4):435-42. Epub 2015 Jul 31 doi: 10.1159/000368519. PMID: 26277931
Fallerini C, Dosa L, Tita R, Del Prete D, Feriozzi S, Gai G, Clementi M, La Manna A, Miglietti N, Mancini R, Mandrile G, Ghiggeri GM, Piaggio G, Brancati F, Diano L, Frate E, Pinciaroli AR, Giani M, Castorina P, Bresin E, Giachino D, De Marchi M, Mari F, Bruttini M, Renieri A, Ariani F
Clin Genet 2014 Sep;86(3):252-7. Epub 2013 Oct 17 doi: 10.1111/cge.12258. PMID: 24033287
Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombolà G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F
Nephrol Dial Transplant 2009 May;24(5):1464-71. Epub 2009 Jan 7 doi: 10.1093/ndt/gfn681. PMID: 19129241

Therapy

Zhang Y, Wang F, Ding J, Zhang H, Liu X, Wang S, Xiao H, Yao Y, Liu J, Zhong X, Guan N, Su B, Wu G, Yu L
Pediatr Nephrol 2016 Jan;31(1):67-72. Epub 2015 Aug 7 doi: 10.1007/s00467-015-3184-5. PMID: 26248473
Webb NJ, Shahinfar S, Wells TG, Massaad R, Gleim GW, McCrary Sisk C, Lam C
Pediatr Nephrol 2013 May;28(5):737-43. Epub 2012 Dec 4 doi: 10.1007/s00467-012-2372-9. PMID: 23207876
Noone D, Licht C
Pediatr Nephrol 2013 Jul;28(7):1025-36. Epub 2012 Aug 18 doi: 10.1007/s00467-012-2272-z. PMID: 22903660
Ars E, Tazón-Vega B, Ruiz P, Nogués C, Arnedo N, Rajmil O, Torra R
Eur J Hum Genet 2005 Sep;13(9):1040-6. doi: 10.1038/sj.ejhg.5201452. PMID: 15957001
Ciccarese M, Casu D, Ki Wong F, Faedda R, Arvidsson S, Tonolo G, Luthman H, Satta A
Nephrol Dial Transplant 2001 Oct;16(10):2008-12. PMID: 11572889

Prognosis

Yefet E, Tovbin D, Nachum Z
Arch Gynecol Obstet 2016 Apr;293(4):739-47. Epub 2015 Sep 28 doi: 10.1007/s00404-015-3893-9. PMID: 26411580
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, Miglietti N, Antonucci MF, Cetta F, Sayer JA, van den Wijngaard A, Yau S, Mari F, Bruttini M, Ariani F, Dahan K, Smeets B, Antignac C, Flinter F, Renieri A
J Med Genet 2015 Mar;52(3):163-74. Epub 2015 Jan 9 doi: 10.1136/jmedgenet-2014-102822. PMID: 25575550
Rosado C, Bueno E, Fraile P, García-Cosmes P, González-Sarmiento R
Eur J Med Genet 2015 Jan;58(1):35-8. Epub 2014 Oct 28 doi: 10.1016/j.ejmg.2014.10.003. PMID: 25450602
Marcocci E, Uliana V, Bruttini M, Artuso R, Silengo MC, Zerial M, Bergesio F, Amoroso A, Savoldi S, Pennesi M, Giachino D, Rombolà G, Fogazzi GB, Rosatelli C, Martinhago CD, Carmellini M, Mancini R, Di Costanzo G, Longo I, Renieri A, Mari F
Nephrol Dial Transplant 2009 May;24(5):1464-71. Epub 2009 Jan 7 doi: 10.1093/ndt/gfn681. PMID: 19129241
Hood JC, Dowling J, Bertram JF, Young RJ, Huxtable C, Robinson W, Savige J
Nephrol Dial Transplant 2002 Nov;17(11):1897-908. PMID: 12401844

Clinical prediction guides

Rosado C, Bueno E, Felipe C, Valverde S, González-Sarmiento R
Kidney Blood Press Res 2015;40(4):435-42. Epub 2015 Jul 31 doi: 10.1159/000368519. PMID: 26277931
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, Miglietti N, Antonucci MF, Cetta F, Sayer JA, van den Wijngaard A, Yau S, Mari F, Bruttini M, Ariani F, Dahan K, Smeets B, Antignac C, Flinter F, Renieri A
J Med Genet 2015 Mar;52(3):163-74. Epub 2015 Jan 9 doi: 10.1136/jmedgenet-2014-102822. PMID: 25575550
Rosado C, Bueno E, Fraile P, García-Cosmes P, González-Sarmiento R
Eur J Med Genet 2015 Jan;58(1):35-8. Epub 2014 Oct 28 doi: 10.1016/j.ejmg.2014.10.003. PMID: 25450602
Vizjak A, Ferluga D
Srp Arh Celok Lek 2008 Dec;136 Suppl 4:323-6. PMID: 20804103
Hood JC, Dowling J, Bertram JF, Young RJ, Huxtable C, Robinson W, Savige J
Nephrol Dial Transplant 2002 Nov;17(11):1897-908. PMID: 12401844

Recent systematic reviews

Mora A, Michalickova K, Donaldson IM
BMC Bioinformatics 2013 Feb 11;14:47. doi: 10.1186/1471-2105-14-47. PMID: 23398688Free 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
Kashtan CE, Ding J, Gregory M, Gross O, Heidet L, Knebelmann B, Rheault M, Licht C; Alport Syndrome Research Collaborative.
Pediatr Nephrol 2013 Jan;28(1):5-11. Epub 2012 Mar 30 doi: 10.1007/s00467-012-2138-4. PMID: 22461141Free PMC Article
Savige J
Nat Rev Nephrol 2012 May 29;8(7):375-6. doi: 10.1038/nrneph.2012.109. PMID: 22641079
Morzaria S, Westerberg BD, Kozak FK
J Otolaryngol 2005 Oct;34(5):297-303. PMID: 16181590

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