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Autosomal dominant Alport syndrome(ATS3A)

MedGen UID:
1648326
Concept ID:
C4746547
Disease or Syndrome
Synonyms: Alport syndrome 3, autosomal dominant; ALPORT SYNDROME 3A, AUTOSOMAL DOMINANT; Alport syndrome dominant type; ATS3A; 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
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): COL4A3 (2q36.3)
 
Monarch Initiative: MONDO:0007086
OMIM®: 104200
Orphanet: ORPHA88918

Disease characteristics

Excerpted from the GeneReview: Alport Syndrome
In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. 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 ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is 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 (ATS1; 301050). Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (ATS2, 203780; ATS3B, 620536); 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.  http://www.omim.org/entry/104200
From MedlinePlus Genetics
In late childhood or early adolescence, many people with Alport syndrome develop sensorineural hearing loss, which is caused by abnormalities of the inner ear. Affected individuals may also have misshapen lenses in their eyes (anterior lenticonus) and abnormal coloration of the retina, which is the light-sensitive tissue at the back of the eye. These eye abnormalities seldom lead to vision loss.



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 gradually lose their ability to efficiently remove waste products from the body, resulting in end-stage kidney disease (ESKD).

Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.  https://medlineplus.gov/genetics/condition/alport-syndrome

Clinical features

From HPO
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Disease or Syndrome
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
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Nephrotic syndrome
MedGen UID:
10308
Concept ID:
C0027726
Disease or Syndrome
Nephrotic syndrome is a collection of findings resulting from glomerular dysfunction with an increase in glomerular capillary wall permeability associated with pronounced proteinuria. Nephrotic syndrome refers to the constellation of clinical findings that result from severe renal loss of protein, with Proteinuria and hypoalbuminemia, edema, and hyperlipidemia.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Microscopic hematuria
MedGen UID:
65997
Concept ID:
C0239937
Finding
Microscopic hematuria detected by dipstick or microscopic examination of the urine.
Thickened glomerular basement membrane
MedGen UID:
488906
Concept ID:
C0445347
Finding
Prominent glomerular basement membrane (GBM), reflecting an increase in thickness (subjective estimate) of the basal lamina of the glomerulus of the kidney.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
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.
Glomerular basement membrane lamellation
MedGen UID:
1787773
Concept ID:
C5539416
Finding
Presence of abnormal additional layers of the basement membrane of the glomerulus.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Glomerulonephritis
MedGen UID:
6616
Concept ID:
C0017658
Disease or Syndrome
Inflammation of the renal glomeruli.
Nephritis
MedGen UID:
14328
Concept ID:
C0027697
Disease or Syndrome
The presence of inflammation affecting the kidney.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
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.
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.
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.
Early-onset anterior polar cataract
MedGen UID:
340806
Concept ID:
C1855179
Congenital Abnormality
A polar cataract that affects the anterior pole of the lens.

Professional guidelines

PubMed

Gibson JT, Huang M, Shenelli Croos Dabrera M, Shukla K, Rothe H, Hilbert P, Deltas C, Storey H, Lipska-Ziętkiewicz BS, Chan MMY, Sadeghi-Alavijeh O, Gale DP; Genomics England Research Consortium, Cerkauskaite A, Savige J
Sci Rep 2022 Feb 17;12(1):2722. doi: 10.1038/s41598-022-06525-9. PMID: 35177655Free PMC Article
Kashtan CE, Gross O
Pediatr Nephrol 2021 Mar;36(3):711-719. Epub 2020 Nov 6 doi: 10.1007/s00467-020-04819-6. PMID: 33159213
Ito M, Tanaka T, Nangaku M
Curr Opin Nephrol Hypertens 2020 Jan;29(1):128-135. doi: 10.1097/MNH.0000000000000556. PMID: 31592832

Curated

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

Zhou L, Xi B, Xu Y, Han Y, Yang Y, Yang J, Wang Y, Qiu L, Zhang Y, Zhou J
J Nephrol 2023 Jun;36(5):1415-1423. Epub 2023 Apr 25 doi: 10.1007/s40620-023-01570-7. PMID: 37097554
Uzzo M, Moroni G, Ponticelli C
Nephron 2023;147(7):383-391. Epub 2023 Mar 7 doi: 10.1159/000528243. PMID: 36882005
Furlano M, Martínez V, Pybus M, Arce Y, Crespí J, Venegas MDP, Bullich G, Domingo A, Ayasreh N, Benito S, Lorente L, Ruíz P, Gonzalez VL, Arlandis R, Cabello E, Torres F, Guirado L, Ars E, Torra R
Am J Kidney Dis 2021 Oct;78(4):560-570.e1. Epub 2021 Apr 7 doi: 10.1053/j.ajkd.2021.02.326. PMID: 33838161
Kamiyoshi N, Nozu K, Fu XJ, Morisada N, Nozu Y, Ye MJ, Imafuku A, Miura K, Yamamura T, Minamikawa S, Shono A, Ninchoji T, Morioka I, Nakanishi K, Yoshikawa N, Kaito H, Iijima K
Clin J Am Soc Nephrol 2016 Aug 8;11(8):1441-1449. Epub 2016 Jun 8 doi: 10.2215/CJN.01000116. PMID: 27281700Free PMC Article
Thorner PS
Nephron Clin Pract 2007;106(2):c82-8. Epub 2007 Jun 6 doi: 10.1159/000101802. PMID: 17570934

Diagnosis

Zhou L, Xi B, Xu Y, Han Y, Yang Y, Yang J, Wang Y, Qiu L, Zhang Y, Zhou J
J Nephrol 2023 Jun;36(5):1415-1423. Epub 2023 Apr 25 doi: 10.1007/s40620-023-01570-7. PMID: 37097554
Uzzo M, Moroni G, Ponticelli C
Nephron 2023;147(7):383-391. Epub 2023 Mar 7 doi: 10.1159/000528243. PMID: 36882005
Furlano M, Martínez V, Pybus M, Arce Y, Crespí J, Venegas MDP, Bullich G, Domingo A, Ayasreh N, Benito S, Lorente L, Ruíz P, Gonzalez VL, Arlandis R, Cabello E, Torres F, Guirado L, Ars E, Torra R
Am J Kidney Dis 2021 Oct;78(4):560-570.e1. Epub 2021 Apr 7 doi: 10.1053/j.ajkd.2021.02.326. PMID: 33838161
Kashtan CE, Gross O
Pediatr Nephrol 2021 Mar;36(3):711-719. Epub 2020 Nov 6 doi: 10.1007/s00467-020-04819-6. PMID: 33159213
Kamiyoshi N, Nozu K, Fu XJ, Morisada N, Nozu Y, Ye MJ, Imafuku A, Miura K, Yamamura T, Minamikawa S, Shono A, Ninchoji T, Morioka I, Nakanishi K, Yoshikawa N, Kaito H, Iijima K
Clin J Am Soc Nephrol 2016 Aug 8;11(8):1441-1449. Epub 2016 Jun 8 doi: 10.2215/CJN.01000116. PMID: 27281700Free PMC Article

Therapy

Tantisattamo E, Reddy UG, Ichii H, Ferrey AJ, Dafoe DC, Ioannou N, Xie J, Pitman TR, Hendricks E, Eguchi N, Kalantar-Zadeh K
Nephron 2022;146(2):220-226. Epub 2021 Dec 9 doi: 10.1159/000520150. PMID: 34883493Free PMC Article
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. doi: 10.1093/ndt/16.10.2008. PMID: 11572889

Prognosis

Uzzo M, Moroni G, Ponticelli C
Nephron 2023;147(7):383-391. Epub 2023 Mar 7 doi: 10.1159/000528243. PMID: 36882005
Rossanti R, Horinouchi T, Yamamura T, Nagano C, Sakakibara N, Ishiko S, Aoto Y, Kondo A, Nagai S, Okada E, Ishimori S, Nagase H, Matsui S, Tamagaki K, Ubara Y, Nagahama M, Shima Y, Nakanishi K, Ninchoji T, Matsuo M, Iijima K, Nozu K
Kidney360 2022 Mar 31;3(3):497-505. Epub 2021 Oct 13 doi: 10.34067/KID.0005252021. PMID: 35582193Free PMC Article
Mastrangelo A, Madeira C, Castorina P, Giani M, Montini G
Nephrol Dial Transplant 2022 Nov 23;37(12):2398-2407. doi: 10.1093/ndt/gfab334. PMID: 35090027
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
Thorner PS
Nephron Clin Pract 2007;106(2):c82-8. Epub 2007 Jun 6 doi: 10.1159/000101802. PMID: 17570934

Clinical prediction guides

Hirabayashi Y, Katayama K, Mori M, Matsuo H, Fujimoto M, Joh K, Murata T, Ito M, Dohi K
Genes (Basel) 2022 Oct 2;13(10) doi: 10.3390/genes13101779. PMID: 36292665Free PMC Article
Rossanti R, Horinouchi T, Yamamura T, Nagano C, Sakakibara N, Ishiko S, Aoto Y, Kondo A, Nagai S, Okada E, Ishimori S, Nagase H, Matsui S, Tamagaki K, Ubara Y, Nagahama M, Shima Y, Nakanishi K, Ninchoji T, Matsuo M, Iijima K, Nozu K
Kidney360 2022 Mar 31;3(3):497-505. Epub 2021 Oct 13 doi: 10.34067/KID.0005252021. PMID: 35582193Free PMC Article
Mastrangelo A, Madeira C, Castorina P, Giani M, Montini G
Nephrol Dial Transplant 2022 Nov 23;37(12):2398-2407. doi: 10.1093/ndt/gfab334. PMID: 35090027
Furlano M, Martínez V, Pybus M, Arce Y, Crespí J, Venegas MDP, Bullich G, Domingo A, Ayasreh N, Benito S, Lorente L, Ruíz P, Gonzalez VL, Arlandis R, Cabello E, Torres F, Guirado L, Ars E, Torra R
Am J Kidney Dis 2021 Oct;78(4):560-570.e1. Epub 2021 Apr 7 doi: 10.1053/j.ajkd.2021.02.326. PMID: 33838161
Horinouchi T, Yamamura T, Nagano C, Sakakibara N, Ishiko S, Aoto Y, Rossanti R, Nakanishi K, Shima Y, Morisada N, Iijima K, Nozu K
Kidney360 2020 Sep 24;1(9):936-942. Epub 2020 Jul 16 doi: 10.34067/KID.0000372019. PMID: 35369551Free PMC Article

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