Temporal bone histopathology in alport syndrome.
OBJECTIVE
To determine the histopathologic abnormalities within the cochlea in Alport syndrome.


BACKGROUND
Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen. The proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL.


METHODS
We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen proportional, variant5 chain gene.


RESULTS
By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal.


CONCLUSIONS
The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.
Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA. snm@epl.meei.harvard.edu
Saumil N
SN
Merchant
Barbara J
BJ
Burgess
Joe C
JC
Adams
Clifford E
CE
Kashtan
Martin C
MC
Gregory
Peter A
PA
Santi
Robert
R
Colvin
Bernie
B
Collins
Joseph B
JB
Nadol
D000293:Adolescent; D000328:Adult; D001485:Basement Membrane / Q000473:pathology; D001489:Basilar Membrane / Q000473:pathology; D041321:Chromosomes, Human, X; D003051:Cochlea / Q000473:pathology*; D024141:Collagen Type IV / Q000235:genetics; D004252:DNA Mutational Analysis; D005110:Extracellular Space; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007760:Labyrinth Supporting Cells / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009394:Nephritis, Hereditary / Q000235:genetics / Q000473:pathology*; D009925:Organ of Corti / Q000473:pathology; D012729:Sex Chromosome Aberrations; D013701:Temporal Bone / Q000473:pathology*
C478159:COL4A5 protein, human; D024141:Collagen Type IV