In turn, the possibility that both NOTCH3 and PTEN variants contribute to CCM disease pathogenesis and severity is consistent with the recent discovery that NOTCH3 can transactivate PTEN and inhibit the PTEN downstream Akt/mTOR pathway [97], and the parallel identification of CCM causative mutations in genes involved in such a pathway, including PIK3CA and Akt [14,15,16]. This evidence concerns the gene PTEN and cerebral cavernous malformation.