Alport syndrome

Alport syndrome (AS) is a progressive hereditary nephropathy with extrarenal manifestations. Initial clinical signs include proteinuria and hematuria; as the disease progresses, patients develop end-stage renal disease (ESRD). In addition, extrarenal manifestations such as inner ear hearing loss (60–80% of Alport patients) and ocular changes (anterior lenticonus; 25–40% of Alport patients) are observed. For the COL4A3 and COL4A4 genes, both autosomal recessive and autosomal dominant inheritance have been described. Pathogenic variants in COL4A5 cause X-linked AS, which is the most prevalent form of hereditary nephritis. Characteristic findings in males include microscopic hematuria in 100%, gross hematuria in 60–70%, proteinuria in 90%, hearing loss in 90%, and ocular abnormalities in 35%. Although male patients are generally more severely affected due to X-linked inheritance, many women with heterozygous pathogenic COL4A5 variants also show symptoms of AS. Microhematuria is found in over 95% of affected women, proteinuria is common from early adulthood and 15-30% develop kidney failure by the age of 60. Autosomal recessive AS is similar to X-linked AS in men, but shows no gender-specific differences in terms of disease course and family history. The clinical presentation of autosomal dominant AS ranges from an asymptomatic course (which usually manifests as familial benign hematuria) to proteinuria and focal segmental glomerulosclerosis (in cases without hematuria or when hematuria is not the initial symptom). Progression to end-stage renal failure is generally slower than in X-linked AS, and extrarenal manifestations occur less frequently.

The estimated prevalence of AS is 1/5,000 to 1/50,000. Population sequencing of gnomAD suggests a substantially higher carrier frequency of predicted pathogenic COL4A3 or COL4A4 variants, around 1/106.

AS is caused by germline pathogenic variants in three type IV collagen genes: COL4A5 (Xq22.3; 80-85% of families), COL4A3 (2q36.3; 12-15%), and COL4A4 (2q36.3; 5-8%). These variants disrupt assembly of the type IV collagen α3α4α5 triple helix that forms the mature glomerular, cochlear, and ocular basement membranes; absence or under-expression of these chains renders the resulting networks defective, underlying the kidney, hearing, and ocular manifestations.

AS is inherited in an X-linked, autosomal recessive, or autosomal dominant manner, depending on the gene involved. Approximately 10-15% of male probands with X-linked disease carry a de novo COL4A5 pathogenic variant. Recurrence risk for offspring follows the respective Mendelian mode and is addressed in genetic counselling. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

AS is diagnosed primarily by molecular genetic testing of the type IV collagen genes. Where molecular testing is unavailable or inconclusive, kidney biopsy with immunohistochemical staining for collagen IV α3, α4, and α5 chains, together with electron microscopy demonstrating glomerular basement membrane thinning, lamellation (basket-weave splitting of the lamina densa), and thickening, can establish the diagnosis. Skin biopsy with monoclonal antibody staining for the collagen IV α5 chain provides an alternative confirmatory tool in suspected X-linked disease.

Main differential diagnoses include:

• C3 glomerulopathy: haematuria and proteinuria with hypocomplementaemia and complement-mediated rather than collagen-related glomerular injury; C3, CFH and others
• MYH9-related disease: combined nephritis and sensorineural hearing loss with macrothrombocytopenia, occasionally with glomerular ultrastructural changes reminiscent of AS; MYH9
• : hearing loss with branchial fistulae, external-ear anomalies, and kidney failure; EYA1, SIX1

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for informed counselling of the affected individual and the family.
• Identification of the causative variant enables specific and individualized surveillance, in particular early detection of microalbuminuria and proteinuria through regular monitoring, and is a prerequisite for targeted medical care.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives is technically possible and supports informed reproductive and clinical decision-making.

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