Diagnostic evaluation for Alport syndrome

C3: complement component 3; IgA: immunoglobulin A; NG: next-generation; DNA: deoxyribonucleic acid; GBM: glomerular basement membrane.

* Alport syndrome (hereditary nephritis) presents with persistent glomerular hematuria and is caused by mutations of the COL4 gene, which encodes the collagen IV protein. So-called thin basement membrane nephropathy has also been associated with heterozygous mutations of the type IV collagen genes COL4A3 and COL4A4. This algorithm reflects the diagnostic evaluation based on the author's approach for the UpToDate topic on clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis).

¶ Ocular findings characteristic of Alport syndrome include anterior lenticonus, dot and fleck retinopathy, and corneal changes (posterior polymorphous dystrophy and recurrent corneal erosion). Refer to the UpToDate topic on clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis) for more details.

Δ If genetic testing has previously confirmed a COL4 gene mutation in any of the patient's family members, targeted mutational analysis is the preferred diagnostic test.

◊ NG DNA sequencing is the preferred diagnostic test for patients with a likely or high probability of having a COL4 mutation. However, this may not be available for some patients and families, and renal or skin biopsy is an alternate diagnostic procedure. A skin biopsy is a less invasive diagnostic tool. It uses a monoclonal antibody against the alpha-5(IV) chain. If there is absent protein in a male patient or a mosaic pattern in a female patient, the diagnosis of X-linked Alport syndrome is confirmed. However, a renal biopsy may provide pathologic diagnostic findings of another glomerular disorder.

§ Renal biopsy is the best diagnostic test in this clinical setting to determine the underlying glomerular disorder as there is a similar likelihood of renal disease due to COL4 mutation or IgA nephropathy.

¥ The diagnostic findings for Alport syndrome on renal biopsy are longitudinal splitting of the lamina densa of the GBM detected by electron microscopy and immunostaining pattern for type IV collagen, demonstrating absence or an abnormal distribution of the alpha-3, alpha-4, and/or alpha-5(IV) chains of the GBM.