Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management

Abstract

Cerebral cavernous (or capillary-venous) malformations (CCM) have a prevalence of about 0.1-0.5% in the general population. Genes mutated in CCM encode proteins that modulate junction formation between vascular endothelial cells. Mutations lead to the development of abnormal vascular structures.In this article, we review the clinical features, molecular and genetic basis of the disease, and management.

Figure 1

Functional domains of CCM proteins. Ankyrin, protein–protein interaction domain; FERM, four-point one ezrin radixin moesin domain; NLS, nuclear localization signal; NPxY/F, ICAP1α – Malcavernin binding site; PTB, phosphotyrosine-binding domain; S/T-KBP, serine/threonine kinase binding and phosphorylation domain.

Figure 2

Integrin signalling pathway. (a) Cell–cell adhesion. HEG1 receptor, heart of glass type 1 receptor; KRIT1, k-rev interaction trapped protein 1; PDCD10, programmed cell death 10; STK24/25, serine/threonine protein kinase; TCF, T-cell factor protein. (—∣) inhibition; ( → ) stimulation; (↔) interaction. (b) Cell-extracellular matrix adhesion. ICAP1α, α isoform of the β₁-integrin regulator integrin cytoplasmic adaptor protein 1; KRIT1, k-rev interaction trapped protein 1; PDCD10, programmed cell death 10; PTB, phosphotyrosine-binding domain. (—∣) inhibition; ( → ) stimulation; (↔) interaction.

Figure 3

Scheme for work-up of CCM patients at clinical presentation. Most patients (50–80%) with CCM are sporadic without a known family history of CCM. Solitary CCM lesions may be found in 8–19% of familial cases and roughly 75% of sporadic cases. Multiple lesions are indicative of familial forms of CCM.