Familial Cerebral Cavernous Malformations: Pathophysiology, Genetics, Biomarkers, and Treatment Perspectives

Familial cerebral cavernous malformations (FCCM) are a heritable neurovascular disorder defined by clusters of dilated, thin-walled capillaries in the brain and spinal cord. Although rare, FCCM offers a tractable model for understanding how genetic disruptions in endothelial junction biology, mechanotransduction, and kinase signaling drive vascular instability in the central nervous system. Pathogenic loss-of-function variants converge on signaling abnormalities that promote barrier dysfunction, iron deposition, inflammation, and progressive lesional growth. Clinically, FCCM may manifest with seizures, headaches, focal deficits, or intracerebral hemorrhage, yet many carriers remain asymptomatic owing to incomplete and age-dependent penetrance. Advances in neuroimaging have enhanced the detection of micro-lesions and iron accumulation, establishing these modalities as central biomarkers of disease expression. Complementing imaging, emerging circulating biomarkers, including inflammatory cytokines and plasma microRNAs associated with mutation status, may improve individualized risk stratification. This primer synthesizes current knowledge on FCCM pathophysiology, genetics, diagnostic strategies, and therapeutic perspectives. By integrating molecular mechanisms with clinical relevance, it outlines a framework for understanding FCCM as a disorder of perturbed endothelial signaling and neurovascular homeostasis, and highlights opportunities to advance precision medicine for this challenging condition.