Clinical characteristics: 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.
Diagnosis/testing: The diagnosis of Alport syndrome is established in a proband with a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified on molecular genetic testing.
Management: Treatment of manifestations: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESRD; routine treatment of hypertension; renal transplantation for ESRD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Routine treatment of SNHL and cataracts; surgical intervention for symptomatic leiomyomas.
Agents/circumstances to avoid: Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise.
Surveillance: Follow up of all individuals with Alport syndrome with a nephrologist every six to 12 months; monthly monitoring of at-risk transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis for the first year post transplant; audiologic evaluation of children every one to two years beginning at age six to seven years; monitoring for ocular abnormalities; evaluation for aortic dilatation (for males with XLAS).
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.
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 pathogenic variant; 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 being affected.
In rare Alport families with digenic inheritance (pathogenic variants in two or more of the COL4A3, COL4A4, and COL4A5 genes), transmission patterns may not conform to mendelian expectations.
Molecular genetic testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.
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