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Autosomal recessive Alport syndrome(ATS2)

MedGen UID:
1648334
Concept ID:
C4746745
Disease or Syndrome
Synonyms: ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE; Alport syndrome recessive type; ATS2; COL4A4 Alport Syndrome and Thin Basement Membrane Nephropathy; Nephropathy and deafness
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): COL4A4 (2q36.3)
 
Monarch Initiative: MONDO:0008762
OMIM®: 203780
Orphanet: ORPHA88919

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
Autosomal recessive Alport syndrome-2 (ATS2) is a hereditary disorder of the basement membrane, resulting in a glomerulonephropathy causing renal failure. Progressive deafness and ocular anomalies may also occur (Mochizuki et al., 1994; Colville et al. (1997)). 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; autosomal dominant inheritance (ATS3A; 104200) is rare (van der Loop et al., 2000). See also benign familial hematuria (BFH; 141200), a similar but milder disorder.  http://www.omim.org/entry/203780
From MedlinePlus Genetics
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 gradually lose their ability to efficiently remove waste products from the body, resulting in end-stage kidney disease (ESKD).



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.  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).
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.
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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Nephritis
MedGen UID:
14328
Concept ID:
C0027697
Disease or Syndrome
The presence of inflammation affecting the kidney.
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.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Anterior lenticonus
MedGen UID:
473077
Concept ID:
C0344262
Congenital Abnormality
A conical projection of the anterior surface of the lens, occurring as a developmental anomaly.
Corneal erosion
MedGen UID:
97882
Concept ID:
C0392163
Disease or Syndrome
An erosion or abrasion of the cornea's outermost layer of epithelial cells.

Term Hierarchy

Professional guidelines

PubMed

Zhang Y, Böckhaus J, Wang F, Wang S, Rubel D, Gross O, Ding J
Pediatr Nephrol 2021 Sep;36(9):2719-2730. Epub 2021 Mar 27 doi: 10.1007/s00467-021-05040-9. PMID: 33772369Free 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
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

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

Savige J, Renieri A, Ars E, Daga S, Pinto AM, Rothe H, Gale DP, Aksenova M, Cerkauskaite A, Bielska O, Lipska-Zietkiewicz B, Gibson JT
Clin J Am Soc Nephrol 2022 Nov;17(11):1697-1706. Epub 2022 Jun 8 doi: 10.2215/CJN.03120322. PMID: 35675912Free PMC Article
Zhang Y, Böckhaus J, Wang F, Wang S, Rubel D, Gross O, Ding J
Pediatr Nephrol 2021 Sep;36(9):2719-2730. Epub 2021 Mar 27 doi: 10.1007/s00467-021-05040-9. PMID: 33772369Free PMC Article
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
Murata T, Katayama K, Oohashi T, Jahnukainen T, Yonezawa T, Sado Y, Ishikawa E, Nomura S, Tryggvason K, Ito M
Sci Rep 2016 Jul 5;6:29450. doi: 10.1038/srep29450. PMID: 27377778Free PMC Article
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

Diagnosis

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
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
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
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
Haas M
Arch Pathol Lab Med 2009 Feb;133(2):224-32. doi: 10.5858/133.2.224. PMID: 19195966

Therapy

Zhang Y, Böckhaus J, Wang F, Wang S, Rubel D, Gross O, Ding J
Pediatr Nephrol 2021 Sep;36(9):2719-2730. Epub 2021 Mar 27 doi: 10.1007/s00467-021-05040-9. PMID: 33772369Free PMC Article
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
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

Savige J, Renieri A, Ars E, Daga S, Pinto AM, Rothe H, Gale DP, Aksenova M, Cerkauskaite A, Bielska O, Lipska-Zietkiewicz B, Gibson JT
Clin J Am Soc Nephrol 2022 Nov;17(11):1697-1706. Epub 2022 Jun 8 doi: 10.2215/CJN.03120322. PMID: 35675912Free 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):1713-1720. Epub 2016 Jun 10 doi: 10.2215/CJN.00580116. PMID: 27287265Free PMC Article
Haas M
Arch Pathol Lab Med 2009 Feb;133(2):224-32. doi: 10.5858/133.2.224. PMID: 19195966
Thorner PS
Nephron Clin Pract 2007;106(2):c82-8. Epub 2007 Jun 6 doi: 10.1159/000101802. PMID: 17570934
Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY
Kidney Int 2003 Oct;64(4):1169-78. doi: 10.1046/j.1523-1755.2003.00234.x. PMID: 12969134

Clinical prediction guides

Savige J, Renieri A, Ars E, Daga S, Pinto AM, Rothe H, Gale DP, Aksenova M, Cerkauskaite A, Bielska O, Lipska-Zietkiewicz B, Gibson JT
Clin J Am Soc Nephrol 2022 Nov;17(11):1697-1706. Epub 2022 Jun 8 doi: 10.2215/CJN.03120322. PMID: 35675912Free PMC Article
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
Murata T, Katayama K, Oohashi T, Jahnukainen T, Yonezawa T, Sado Y, Ishikawa E, Nomura S, Tryggvason K, Ito M
Sci Rep 2016 Jul 5;6:29450. doi: 10.1038/srep29450. PMID: 27377778Free 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
Jefferson JA, Lemmink HH, Hughes AE, Hill CM, Smeets HJ, Doherty CC, Maxwell AP
Nephrol Dial Transplant 1997 Aug;12(8):1595-9. doi: 10.1093/ndt/12.8.1595. PMID: 9269635

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