"... Hereditary familial or congenital nephritis is a definite entity. Deafness is a marked feature in nearly all these cases. The male members of a family tend to develop nephritis and deafness and do not as a rule survive. The females have deafness and hematuria and live to old age..."
- A. Cecil Alport, 1927
Alport syndrome is mostly an X-linked disorder but autosomal recessive Alport syndrome has been described.
The defect is in the genes that code for Type IV collagen, which is ubiquitous in basement membranes.
All patients with Alport syndrome develop haematuria. Males with the X-linked form of this disease go on to develop proteinuria progressing to end-stage renal disease (ESRD), usually by the second or third decade of life. Females who are heterozygous for the X-linked Alport usually have a much more benign disease and most survive to old age with minimal renal impairment.
On renal biopsy, the glomeruli of patients with Alport syndrome have disorders of their glomerular basement membrane (GBM).
Deafness in Alport syndrome is frequently but not always associated with the renal lesion. Hearing loss whilst not congenital, is slowly progressive, bilateral and usually manifests clinically by adolescence. The damage seems to be to the cochlea.
Various ocular defects are also associated with Alport syndrome. These are less common than the hearing loss and tend to affect patients with juvenile type nephritis with hearing loss. Anterior lenticonus, the conical protrusion of the central portion of the lens into the anterior capsule, is virtually pathognomonic of Alport syndrome. Progression of anterior lenticonus causes increasing myopia. Ocular defects, if any, are not present at birth but develop over time and usually manifests by the second or third decade of life.
Criteria for the clinical diagnosis of Alport syndrome by Gregory et al, 1996
- Family history of nephritis of unexplained haematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.
- Persistent haematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy.
- Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30 years.
- A mutation in COL4An (where n = 3, 4 or 5).
- Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.
- Widespread GBM ultrastructural abnormalities, in particular thickening, thinning and splitting.
- Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
- Gradual progression to ESRD in the index case of at least two family members.
- Macrothrombocytopenia or granulocytic inclusions.
- Diffuse leiomyomatosis of esophagus or female genitalia, or both.
Four out of ten criteria should be fulfilled.
Sources:
http://www.cc.utah.edu/~cla6202/Chap.htm
Kashtan CE. Michael AF. Alport syndrome. Kidney International. 50(5):1445-63, 1996 Nov.
Tryggvason K. Heikkila P. Pettersson E. Tibell A. Thorner P. Can Alport syndrome be treated by gene therapy?. Kidney International. 51(5):1493-9, 1997 May.
Gregory MC et al: Alport syndrome clinical phenotypes, incidence and pathology, in Molecular Pathology and Genetics of Alport Syndrome (vol 117), edited by Tryggvason K, Basel, Karger, 1996, pp 1-28