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Alport Syndrome and Thin Basement Membrane Nephropathy.

Authors

Kashtan CE1.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2001 Aug 28 [updated 2015 Nov 25].

Author information

1
Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Excerpt

CLINICAL 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.

DIAGNOSIS/TESTING:

The diagnosis of Alport syndrome and thin basement membrane nephropathy rests on: History and physical examination, which may include audiologic, renal, and ophthalmic evaluation; Detailed family history and possibly urinalyses on first- and second-degree relatives; Immunohistochemical analysis of basement membrane type IV collagen expression, using skin and/or renal biopsy specimens; and Examination of renal biopsy specimens by electron microscopy. With these tools, the diagnosis can be confirmed in most cases. AS and many cases of TBMN are caused by mutation of the type IV collagen genes COL4A3, COL4A4, and COL4A5.

MANAGEMENT:

Treatment of manifestations: Alport syndrome: angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker in proteinuric individuals; potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Routine treatment of hypertension; renal transplantation for ESRD. Routine treatment of SNHL and cataracts; surgical intervention for symptomatic leiomyomas. Prevention of secondary complications: Protect corneas of those with recurrent corneal erosions from minor trauma. Minimize exposure to loud noise. Surveillance: Follow up of all individuals with Alport syndrome and thin basement membrane nephropathy with a nephrologist; monitoring of females with XLAS with measurement of blood pressure and renal function; audiologic evaluation of children with Alport syndrome every one to two years beginning at age six to seven years; monitoring of transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis. Evaluation of relatives at risk: Evaluate at-risk family members either by urinalysis or, if the pathogenic variant(s) in the family are known, by molecular genetic testing.

GENETIC COUNSELING:

Three modes of inheritance are recognized for Alport syndrome: X-linked, autosomal recessive, and autosomal dominant. Currently, TBMN is known to be inherited in an autosomal dominant manner only. In families with X-linked inheritance, mothers heterozygous for a COL4A5 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy; sons who inherit the pathogenic variant will be affected with Alport syndrome and will eventually develop ESRD and, in most cases, deafness; daughters who inherit the pathogenic variant will typically have asymptomatic hematuria but may have more severe renal disease. Affected males will pass the pathogenic variant to all of their daughters and none of their sons. In families with autosomal recessive inheritance, the parents of an affected child are obligate heterozygotes and carry one mutant allele; at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier who may or may not be symptomatic, and a 25% chance of being unaffected and not a carrier. In families with autosomal dominant inheritance, each child of an affected individual has a 50% chance of inheriting the pathogenic variant and having a collagen IV disorder (autosomal dominant AS or TBMN). Molecular genetic testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.

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