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

Area of Science:

• Neuroscience
• Genetics
• Vascular Biology

Background:

• Familial cerebral cavernous malformations (FCCM) are inherited neurovascular disorders characterized by abnormal brain and spinal cord capillaries.
• Genetic disruptions in endothelial cell junctions, mechanotransduction, and kinase signaling are implicated in FCCM pathogenesis.
• FCCM serves as a model for studying vascular instability in the central nervous system.

Purpose of the Study:

• To synthesize current knowledge on FCCM pathophysiology, genetics, diagnostics, and therapeutics.
• To outline a framework for understanding FCCM as a disorder of endothelial signaling and neurovascular homeostasis.
• To highlight opportunities for advancing precision medicine in FCCM.

Main Methods:

• Review and synthesis of existing literature on FCCM.
• Analysis of genetic variants, molecular mechanisms, and signaling pathways.
• Integration of neuroimaging and circulating biomarker data.

Main Results:

• Pathogenic variants in FCCM lead to endothelial barrier dysfunction, iron deposition, inflammation, and lesion growth.
• Neuroimaging modalities are key biomarkers for detecting micro-lesions and iron accumulation.
• Circulating biomarkers like cytokines and microRNAs show potential for risk stratification.

Conclusions:

• FCCM is fundamentally a disorder of perturbed endothelial signaling and neurovascular homeostasis.
• Advances in diagnostics, including neuroimaging and biomarkers, improve disease detection and risk assessment.
• Understanding FCCM molecular mechanisms is crucial for developing targeted precision medicine strategies.