Stroke is the third leading cause of death worldwide and the most common cause of disability in developed nations. Intracranial hemorrhage (ICH) accounts for 10 percent of stroke and is a particularly severe form of the disease, associated with high rates of death and long-term disability. A substantial number of individuals have inherited ICH disorders caused by mutations in one of three CCM (cerebral cavernous malformation) genes. The incidence of stroke is highly variable within affected families, and the factors that trigger ICH in either inherited or sporadic forms of the disease are unknown. Limited understanding of the genetic contributors to this disease has hampered treatment and there is currently no effective prophylactic drug therapy for ICH.

This study is the first definitive demonstration that ICH can be triggered by a combination of very minor defects in CCM proteins or in their effectors. By injecting specialized antisense oligonucleotides into zebrafish, the authors simultaneously inhibited the expression of multiple CCM pathway genes in various combinations. They show that a subtle decrease in each of these genes alone caused little or no effect independently, but when combined resulted in very high frequencies of ICH.

These findings have important implications for the diagnosis and treatment of hemorrhagic stroke. Single mutations in CCM proteins may not be enough to induce stroke, but accompanying subtle secondary mutations may have significant consequences. In addition, mutations to effectors in the CCM pathway may initiate lesions, contributing to the highly variable penetrance of familial CCM disorders. In humans, subtle genetic second hits in individuals that are outwardly normal, but genetically ‘sensitized’ by minor deficits in CCM pathway genes, could lead to sporadic forms of hemorrhagic stroke. Besides the potential for improved diagnostics for stroke predisposition, these results also suggest that downstream manipulation of CCM signaling could be useful for future development of effective pharmacologic therapies for treatment and prevention of ICH.

2008