Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the central nervous system that can lead to seizure, hemorrhage, and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analyzed whole-exome sequencing data for patients with CCM and found that ∼40% of them have a single, specific MAP3K3 mutation (c.1323C>G [p.Ile441Met]) but not any other known mutations in CCM-related genes. We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the central nervous system. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labeling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood-brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1/2/3 and/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.

Dural arteriovenous fistulas of the hypoglossal canal (HCDAVFs) involving the anterior condylar confluence (ACC) and anterior condylar vein (ACV) are infrequent. Although transvenous embolization through the internal jugular vein (IJV) is the preferred treatment option for type I and II fistulas, it can be difficult if the IJV is unavailable. Here we report a rare case of HCDAVF in which the most common transvenous embolization access via IJV was not available. The patient underwent transarterial and transvenous onyx embolization. Transarterial embolization (TAE) aimed at controlling the arterial inflow and subsequently TVE was performed via the external jugular vein (EJV), the facial vein, the ophthalmic vein, the cavernous sinus, ACC, and ultimately to the fistula pouch. Complete obliteration of the HCDAVF was achieved without complications. We suggest that transvenous embolization (TVE) via the EJV and the facial vein can be effective in cases where trans-IJV is not possible.