Alport Syndrome: Clinical Spectrum and Therapeutic Advances

Abstract

Alport syndrome is a hereditary disorder characterized by kidney disease, ocular abnormalities, and sensorineural hearing loss. Work in understanding the cause of Alport syndrome and the molecular composition of the glomerular basement membrane ultimately led to the identification of COL4A3, COL4A4 (both on chromosome 2q36), and COL4A5 (chromosome Xq22), encoding the α3, α4, and α5 chains of type IV collagen, as the responsible genes. Subsequent studies suggested that autosomal recessive Alport syndrome and males with X-linked Alport syndrome have more severe disease, whereas autosomal dominant Alport syndrome and females with X-linked Alport syndrome have more variability. Variant type is also influential-protein-truncating variants in autosomal recessive Alport syndrome or males with X-linked Alport syndrome often present with severe symptoms, characterized by kidney failure, extrarenal manifestations, and lack of the α3-α4-α5(IV) network. By contrast, mild-moderate forms from missense variants display α3-α4-α5(IV) in the glomerular basement membrane and are associated with protracted kidney involvement without extrarenal manifestations. Regardless of type, therapeutic intervention for kidney involvement is focused on early initiation of angiotensin-converting enzyme inhibitors. There are several therapies under investigation including sodium/glucose cotransporter 2 inhibitors, aminoglycoside analogs, endothelin type A antagonists, lipid-modifying drugs, and hydroxychloroquine, although targeting the underlying defect through gene therapy remains in preclinical stages.

Keywords: ACEi; Alport syndrome; angiotensin-converting enzyme inhibitor; gene editing; glomerular basement membrane; investigational therapeutics; type IV collagen.

Figure 1

Type IV collagen from gene to protein trimerization to disease. The 6 collagens are arranged in a head-to-head configuration, with COL4A1 and COL4A2 on chromosome 13, COL4A3 and COL4A4 on chromosome 2, and COL4A5 and COL4A6 on chromosome X. The arrow above each gene indicates the direction in which transcription takes place. The collagen monomers come together to form heterotrimers, with the α1-α1-α2 (IV) expressed in the glomerular basement membrane during development, which later switches to the α3-α4-α5 (IV) in adulthood. Uniquely, the α5-α5-α6 (IV) heterotrimer is expressed in the basement membrane of Bowman’s capsule. Pathogenic variants in these genes can lead to congenital abnormalities of the kidney and urinary tract (CAKUT) (COL4A1), autosomal recessive Alport syndrome (COL4A3 or COL4A4), autosomal dominant Alport syndrome (COL4A3 or COL4A4), digenic Alport syndrome (COL4A3 and COL4A4 or COL4A3/COL4A4 and COL4A5), or diffuse leiomyomatosis accompanying X-linked Alport syndrome (COL4A5 and COL4A6). ADAS, autosomal dominant Alport syndrome; ARAS, autosomal recessive Alport syndrome; AS, Alport syndrome; XLAS, X-linked Alport syndrome.

Figure 2

Clinical characteristics and GBM features observed in Alport syndrome. There is wide clinical variability in Alport syndrome. Stages of progression for the most severe forms are shown. eGFR, estimated glomerular filtration rate; GBM, glomerular basement membrane.

Figure 3

Factors that affect disease severity. The severity of Alport syndrome is influenced by the type of pathogenic variant(s) in COL4A3/COL4A4/COL4A5 and pattern of inheritance, which in turn affects the levels of α3-α4-α5 (IV) expression in the glomerular basement membrane. The combination of these factors contributes to the broad spectrum of disease observed clinically. ADAS, autosomal dominant Alport syndrome; ARAS, autosomal recessive Alport syndrome; AS, Alport syndrome; CAKUT, congenital abnormalities of the kidney and urinary tract; XLAS, X-linked Alport syndrome.