Cavernous malformations: Genetics, molecular biology, and familial forms

Cavernous malformations are compact lesions composed of sinusoidal vascular channels that resemble dilated capillaries. They are found throughout the central nervous system with an estimated incidence in the general population of about 0.4%. Cavernous malformations occur as a sporadic form in which lesions tend to be solitary and as a familial form characterized by multiple lesions and a strong family history of seizures. The familial forms of this disease are inherited in an autosomal dominant mode. Genetic studies have identified three distinct loci associated with the familial forms of this disease - which have been termed cerebral cavernous malformations (CCM): CCM1 located on the long arm of chromosome 7 (7q21 to 7q22), CCM2 on the short arm of chromosome 7 (7p13-p15), and CCM3 on the long arm of chromosome 3 (3q25 to 3q27). In the CCM population, 40% of families link to CCM1, 20% to CCM2, and 40% to CCM3. Further analysis has demonstrated that mutations in the KRIT1 gene are responsible for CCM1. KRIT1 is a binding protein that interacts with Krev-1/rap1a, a member of the Ras family of GTPases with tumor-suppressing activity for the Ras oncogenes. These findings, along with the evidence from magnetic resonance imaging (MRI) studies that the de novo appearance of new lesions is relatively common, suggest that cavernous malformations should be reclassified as benign vascular tumors. 2002, Elsevier Science (USA). All rights reserved.