ULTRASTRUCTURAL AND IMMUNOHISTOCHEMICAL FINDINGS IN ALPORTS-SYNDROME - A STUDY OF 108 PATIENTS FROM 97 ITALIAN FAMILIES WITH PARTICULAR EMPHASIS ON COL4A5 GENE MUTATION CORRELATIONS

A total of 108 patients affected by Alport's syndrome, taken from 97 f amilies, were enrolled in a genetic and ultrastructural study. Sixty-f our families (75 patients) were X-linked, seven autosomal recessive, t wo autosomal dominant, five uninterpretable, and 19 sporadic. The ultr astructural features were consistent with Alport's syndrome in 66, dou btful in 20, and not significant for Alport's syndrome in 22 patients in the X-linked, sporadic, and genetically uninterpretable groups (wit hout significant differences), as well as in the autosomal group. Muta tions of the COL4A5 gene were present in 36 patients in the first thre e groups, without significant differences. More severe mutations were more frequently present in patients with an ultrastructural pattern co nsistent with Alport's syndrome. Nevertheless, there seems to be no st rict correlation between mutation and ultrastructure, because a major rearrangement was found in a patient with no significant lesions, and different morphologic patterns were detected in patients belonging to the same family. Immunohistochemical investigation into 24 patients fo r alpha(IV) chains showed that both alpha 3(IV) and alpha 5(IV) were l acking in the glomerular basement membrane of 13 patients (five with m utations) and were expressed in another six (three with mutations and one in the autosomal group). On the contrary, in this study the retain ed expression of alpha 3(IV) chain was found, despite the lack of alph a 5(IV) in the glomerular basement membrane of five patients (two with mutation). These different patterns could be related to both the type and severity of the COL4A5 mutations. All of the ultrastructural patt erns were identified in all three immunohistochemical groups. Ultrastr uctural features and alpha 5(IV) chain production, even if an expressi on of a genetic mutation, do not strictly correlate. The combined use of analysis of collagen expression and electron microscopy made it pos sible to diagnose Alport's syndrome in 92% of the cohort, and therefor e this approach is advisable. A multidisciplinary approach is recommen ded in the study of Alport's syndrome in an attempt to achieve a bette r diagnostic definition of and insight into the pathogenetic mechanism s.