Aortic abnormalities in males with Alport syndrome

Abstract

Background: There have been isolated case reports of arterial disease in males with Alport syndrome (AS), a systemic disorder of Type IV collagen. In this paper, we describe five new cases of AS associated with significant aortic disease including dissection and aneurysm.

Methods: We present brief clinical descriptions of five males with AS and aortic disease. We performed immunohistochemical analysis of the expression of the α5 chain of Type IV collagen in skin basement membranes from a previously reported family with AS and associated aortic disease and in the aortic media of male mice with X-linked Alport syndrome (XLAS) due to a nonsense mutation in the COL4A5 gene.

Results: Three of the five patients exhibited aneurysm and dissection of the thoracic aorta, occurring at 25-32 years of age, while one had aortic dilatation and another had aortic insufficiency. All five men required renal replacement therapy by age 20. Immunohistochemistry of skin biopsy specimens in previously reported male siblings with aortic disease confirmed that they had XLAS. We further found that the α5 chain of Type IV collagen is abnormally absent from aortic media of transgenic mice with XLAS.

Conclusions: Early onset aortic disease may be an unusual feature of AS. Screening of men with AS for aortic abnormalities may be clinically indicated in some families.

Fig. 1

Computerized tomographic scan in Case 1 showing dissection involving the ascending aorta, aortic arch and descending aorta (white arrows indicate the false aortic lumen).

Fig. 2

Computerized tomographic scan in Case 5 showing dissection involving the ascending aorta and aortic arch (white and black arrows).

Fig. 3

Pedigree and results of skin biopsy immunostaining for α5(IV) in members of the family described by Tayel et al. [18]. The father was unaffected and exhibited continuous staining of EBM for α5(IV). Two of four affected sons underwent skin biopsies and showed absence of EBM staining for α5(IV), while normal staining was observed in an unaffected daughter. The mother was heterozygous for XLAS and displayed mosaic staining of EBV for α5(IV). Empty symbols indicate unaffected family members, filled boxes indicate affected males and the cross-hatched symbol indicates a heterozygous female. A colour version of this figure is available online.

Fig. 4

Results of immunostaining of aortic sections from wild-type mice and mice with XLAS due to a nonsense mutation in the col4a5 gene. In both wild-type and Alport mice, staining for α1(IV) is observed between autofluorescent elastic laminae. Similar localization of staining for α5(IV) is observed in wild-type mice, but staining for α5(IV) is negative in Alport mice. It is not clear whether the apparent contraction of the Alport aortic segment is related to the Type IV collagen abnormality or represents an artefact of tissue preparation. A colour version of this figure is available online.