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Diagnose This (August 31, 2020)

Joel Murphy, MD
By Joel Murphy, MD

Sep 01, 2020

Alport Syndrome, COL4A5, COL4A3, COL4A4, Alport, X-linked, Hearing loss, GBM multilamellation

What is your diagnosis based on this IF staining pattern in a patient with hematuria and proteinuria?

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The immunofluorescence image is that of an Alport panel. The red staining highlights the alpha 2 subunit of collagen type IV while the green staining is that of the alpha 5 subunit of collagen type IV. The image shows segmental loss of the alpha 5 staining of type IV collagen along the glomerular basement membranes compatible with Alport syndrome. Alport syndrome is an inherited disease secondary to mutations in the alpha 3, 4, and 5 subunits of type IV collagen. The most common form of the mutation, comprising approximately 65-85% of mutations, occurs via X-linked inheritance and involves the COL4A5 gene. Interestingly, with this form of Alport syndrome, the nature of the mutation can have a significant influence on the phenotype in males while the disease in females is dependent not only the nature of the mutation but the degree of X-inactivation. Other forms of the disease demonstrate autosomal inheritance (dominant as well as recessive forms) and are secondary to mutations in COL4A3 and COL4A4 located on chromosome 2. By electron microscopy, typical features of the disease include multilamellation, splitting, and scalloping of the glomerular basement membranes. Additionally, the basement membranes can show areas of marked attenuation as well as areas of thickening typically with abrupt changes between the two. Ultimately, genetic testing is required for a confirmation of the underlying mutation.

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