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X-linked Alport syndrome(ATS1)

MedGen UID:
1648433
Concept ID:
C4746986
Disease or Syndrome
Synonyms: Alport syndrome 1, X-linked recessive; Alport Syndrome and Thin Basement Membrane Nephropathy; ATS1; NEPHROPATHY AND DEAFNESS, X-LINKED
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: 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.
 
Gene (location): COL4A5 (Xq22.3)
 
Monarch Initiative: MONDO:0010520
OMIM®: 301050
Orphanet: ORPHA88917

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 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). Genetic Heterogeneity of Alport Syndrome 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 (ATS2, 203780; ATS3B, 620536); autosomal dominant inheritance (ATS3A; 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 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
Diffuse leiomyomatosis
MedGen UID:
870536
Concept ID:
C4024984
Neoplastic Process
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.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Nephritis
MedGen UID:
14328
Concept ID:
C0027697
Disease or Syndrome
The presence of inflammation affecting the kidney.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
An abnormality of the skin characterized the presence of excessive amounts of dry surface scales on the skin resulting from an abnormality of keratinization.
Reduced epidermal collagen IV alpha 5 chain staining
MedGen UID:
1052767
Concept ID:
CN378378
Finding
Diminished or absent collagen alpha5(IV) chain staining pattern in the epidermal basement membrane.
Hypoparathyroidism
MedGen UID:
6985
Concept ID:
C0020626
Disease or Syndrome
A condition caused by a deficiency of parathyroid hormone characterized by hypocalcemia and hyperphosphatemia.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
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.
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.

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
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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

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

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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

Clinical prediction guides

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