Alport Syndrome (AS)

At a glance

Generalized inherited disorder of basement membranes that involves Type IV collagen, characterized by hematuria and progressive neurosensory hearing loss. Predominantly affects males. Ocular signs can be present. Renal failure occurs frequently.

Synonym

Familial Hematuric Nephritis with Neurosensory Deafness.

History

First described in 1902 by the English physician L.B. Guthrie. However, it was not before 1927 that the South African physician Arthur Cecil Alport recognized the association of renal failure and progressive deafness.

Incidence

It is the most common form of hereditary glomerular disease and estimated to account for approximately 2.5 to 3% of all cases of pediatric end-stage renal disease. Males are affected more often and more severely than females as the majority of cases are X-linked inherited, which usually affects females only mildly. Prevalence for the X-linked version is approximately 1 in 10,000 and 1 in 50,000 for the autosomal recessive form.

Genetic inheritance

Caused by mutations in the COL4A3 (Collagen, Type IV, Alpha-3), COL4A4, and COL4A5 genes, which encode the α3, α4, and α5 chains, respectively, of Collagen Type IV. In 85% of patients, inheritance is X-linked and caused by mutations in the COL4A5-gene on chromosome Xq22.3 affecting the α5 chain of basement membrane collagen (see “Pathophysiology”). In the remaining 15% of patients, inheritance is autosomal recessive and caused by mutations in either the COL4A3 or COL4A4 gene, which have been mapped to chromosome 2q36-q37 and 2q36-q37, respectively. Autosomal dominant inheritance may have occurred in a few isolated cases.

Pathophysiology

In the early stages of AS, the glomeruli show segmental proliferation and/or sclerosis. An increase in the mesangial matrix is often combined with a foamy appearance of the glomerular and tubular epithelial cells secondary to intracellular depositions of fat and mucopolysaccharides. Progression of the disease results in extensive glomerulosclerosis, podocyte effacement, tubular atrophy, and tubulointerstitial fibrosis. Electron microscopy reveals splitting and irregular thickening of the glomerular and tubular basement membranes. One of the main components of these basement membranes is Collagen Type IV, which consists of six subunits, α1 to α6. In AS, depending on the mode of inheritance, subunits α3, α4, or α5 are abnormal. Normally, these subunits form a heterotrimer (triple helix), which in the glomerular basement membrane is produced by the podocytes. These heterotrimers occur almost exclusively in the basement membranes of the kidneys, the cochlea and the eye. The distribution of this abnormal heterotrimer structure in the body explains the unique scattering of the disease in AS.

Diagnosis

Based on the presence of three of the four major signs: (1) family history of microhematuria, (2) typical lesions of the glomerular basement membrane, (3) sensorineural deafness, and (4) characteristic ocular abnormalities (anterior lenticonus, spherophakia, ...