A review of clinical characteristics and genetic backgrounds in Alport syndrome

Abstract

Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

Keywords: ACE inhibitor; Bardoxolone; Genotype–phenotype correlation; Thin basement membrane.

Fig. 1

Glomerular basement membrane (GBM) change in Alport syndrome (AS) observed by electron microscopy. A Thin basement membrane, which is typically observed in milder cases, including female X-linked AS and autosomal dominant AS. B Diffuse thickening and lamellation, which are specific findings of AS

Fig. 2

Immunohistochemical analysis of type IV collagen α5 chain in glomerulus. A Normal control shows full expression in both glomerular basement membrane (GBM) and Bowman’s capsule (BC). B Male X-linked Alport syndrome (XLAS) case shows completely negative expression in both GBM and BC. C Female XLAS case shows a mosaic pattern of expression in both GBM and BC due to the mechanisms of X-chromosome inactivation that occur in female cells. D Autosomal recessive Alport syndrome case shows negative expression only on GBM and positivity on BC, because BC consists of the α5–α5–α6 triple helix. E Schema for X-chromosome inactivation (XCI). In all female cells, either of the two X chromosomes is randomly inactivated. When the wild-type chromosome has been inactivated, the cell will not produce α5. Then, GBM and BC will be stained with a mosaic pattern

Fig. 3

Immunohistochemical analysis of type IV collagen α5 chain on epidermal basement membrane (EBM). A Male X-linked Alport syndrome (XLAS) case shows completely negative expression on EBM. B Female XLAS case shows a mosaic pattern of expression on EBM due to the mechanisms of X-chromosome inactivation that occur in female cells. C Normal control shows full α5 expression on EBM; however, decreased α5 expression can be observed in the bottom of papillary EBM in the normal skin. D Normal control shows full α2 expression on EBM, even at the bottom of papillary EBM

Fig. 4

Schema of genetic mosaicism. When gene mutation occurs after repeated cycles of cell division in fertilized eggs, cells with a normal gene and cells with an abnormal gene coexist; this is known as mosaicism. When this status occurs in somatic cells, it is recognized as somatic mosaicism; in gonadal cells, it is known as germline mosaicism