Genotype-phenotype correlations in cerebral cavernous malformations patients

Objective To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers. Methods A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed. Results A deleterious mutation was detected in 128 probands. Three hundred thirty‐three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety‐four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2‐weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient‐echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient‐echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05). Interpretation Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient‐echo sequence lesions with age differs between CCM1 and CCM2 patients. Ann Neurol 2006