<b><i>CCM3</i></b> Mutations Are Associated with Early-Onset Cerebral Hemorrhage and Multiple Meningiomas

Abstract

Mutations of <i>CCM3/PDCD10</i> cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of <i>CCM3</i>-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of <i>CCM3</i> patients. Molecular screening for point mutations and deletions was used to identify 54 <i>CCM3</i>-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 ± 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This ‘multiple meningiomas' phenotype is not associated with a specific <i>CCM3</i> mutation. Hence, <i>CCM3</i> mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas.