Cerebral cavernous malformation (CCM; MIM 116860) is a common disorder that is found in 0.1 to 0.5% of the population and represents~ 10 to 20% of cerebral vascular lesions. 1 However, symptomatic disease is considerably less common. The lesions, which affect the brain vasculature, are characterized by abnormally enlarged capillary cavities in the brain without intervening normal parenchyma. 2 Most often, CCM occurs sporadically, and individuals develop only one malformation. In familial CCM, the disorder is dominantly inherited, and individuals often develop multiple malformations. Symptoms include focal neurologic signs, hemorrhagic strokes, seizures, headaches, or sometimes death. 1 Patients are treated conservatively or with surgical resection when lesions cause recurrent hemorrhage or seizures. Three genetic loci have been defined: 3 CCM1 on chromosome 7q21-q22 accounting for 40% of all familial cases, CCM2 on 7p13-p15 accounting for 20%, and CCM3 on 3q25. 2-q27 for 40%. Subsequently, the CCM1 gene has been identified and has been shown to encode the Krit1 protein. 4 More recently in CCM2 families, a novel gene, MGC4607, has been found that encodes malcavernin, a protein with a phosphotyrosine-binding domain. We previously screened the CCM1 gene in a cohort of 21 sporadic cases with a single malformation and 14 sporadic cases with multiple malformations. 5 Of the 14 cases with multiple malformations, 4 cases had a mutation leading to a truncated protein, which suggested that sporadic cases with multiple malformations seem to harbor CCM1 mutations in approximately the same proportion that familial cases harbor CCM1 mutations. In contrast, none of the 21 sporadic cases with a single malformation had a mutation, suggesting that the malformation may have been caused by a one-time random mutational event in one of the CCM genes.

Mutations in the MGC4607 gene recently were found in CCM families, which show linkage to the CCM2 locus. 6 Therefore, we decided to screen the CCM2 gene for mutation in the 21 sporadic cases with one malformation and the remaining 10 sporadic cases with multiple malformations.