Generalized inherited disorder of basement membranes
that involves type IV collagen, characterized by hematuria and progressive
neurosensory deafness. Predominant in males. Ocular signs can be present.
Renal failure occurs frequently.
Familial Hematuric Nephritis with Neurosensory Deafness.
First described in 1902 by L.B. Guthrie, the English
Physician. It was not until 1927 that Arthur Cecil Alport, a South African
physician, recognized the association of renal failure and progressive
Geographic variability. It is the most common form of
hereditary glomerular disease and is 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.
In 85% of patients, inheritance is X-linked
caused by mutation on Xq22.3 affecting the gene encoding the α-5
chain of basement membrane collagen COL4A5 (see Pathophysiology). In the remaining 15%,
inheritance is autosomal recessive (caused by mutation in either the COL4A3
or COL4A4 gene, which have been mapped to 2q36-q37 and 2q36-q37,
respectively. Autosomal dominant inheritance has been described in isolated
In the early stages of Alport syndrome, the
glomeruli show segmental proliferation and/or sclerosis. An increase in
mesangial matrix often is combined with a foamy appearance of glomerular and
tubular epithelial cells secondary to intracellular depositions of fat and
mucopolysaccharides. Progression of the disease results in extensive
glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis.
Electron microscopy allows detection of irregular thickening of the
glomerular and tubular basement membrane. One of the main components of the
basement membranes is type IV collagen, which consists of six subunits, a1
to a6. In Alport syndrome, depending on the mode of inheritance, subunit a3,
a4, or a5 is altered, which all occur almost exclusively in basement
membranes of the kidney, the cochlea, and the eye. This situation explains
the unique distribution of the disease.
Based on the presence of three of the four major signs:
familial history of microhematuria, typical lesions of the glomerular
basement membrane, sensorineural deafness, and characteristic ocular
abnormalities (anterior lenticonus, spherophakia, cataract, perimacular
Generally, the disorder is more severe in males.
Initially, patients most often present only with persistent hematuria
(microhematuria with intermittent gross hematuria) starting in early
childhood and a positive family history for hematuria. Other renal features
include proteinuria, hypertension, and renal failure (occurs in >90% of
male patients but only 3% of female patients after age 25 years).
However, the typical histologic findings may not yet be present in young
children. End-stage renal failure, sensorineural, high-frequency hearing
loss (in >80% of males and >50% of females), and ophthalmic lesions
appear later in life (usually between age 20 and 40 years). Other features
may include hypoparathyroidism, thrombocytopenia, ichthyosis, and diffuse
leiomyomatosis. This diffuse leiomyomatosis is typical in a subgroup of
patients with the X-linked form of Alport syndrome, occurs ...