X-linked Alport syndrome: Natural history in 195 families and genotype-phenotype correlations in males

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are respo nsible for the more common X-linked dominant form of the disease. Considera ble allelic heterogeneity has been observed. A "European Community Alport S yndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large nu mber of families. Data concerning 329 families, 250 of them with an X-linke d transmission, were collected. Characteristics of the 401 male patients be longing to the 195 families with COL4A5 mutation are presented. All male pa tients were hematuric, and the rate of progression to end-stage renal failu re and deafness was mutation-dependent. Large deletions, nonsense mutations , or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patien ts with missense or splice site mutation. The risk of developing hearing lo ss before 30 yr of age was approximately 60% in patients with missense muta tions, contrary to 90% for the other types of mutations. The natural histor y of X-linked AS and correlations with COL4A5 mutations have been establish ed in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.