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Page 2 of 9 Finetti et al. Vessel Plus 2021;5:29 https://dx.doi.org/10.20517/2574-1209.2021.49

INTRODUCTION
Cerebral cavernous malformation (CCM), is a rare disease characterized by “mulberry-like” vascular lesions
present in the brain (caverns) with abnormal ultrastructural features of vessels. The thin vessel wall is
enlarged and leaky and composed of amorphous material lacking endothelial support and devoid of normal
[1]
and intact tight junctions and vessel structural components, such as pericytes and astrocyte foot processes .

CCM lesions are predominantly found in the central nervous system (CNS) but can be present also in the
retina, skin, and liver. In the brain, CCM lesions can occur as single or multiple (even hundreds) lesions,
[2]
with sizes varying from a few millimeters to a few centimeters, depending on the pathogenesis .
Despite the high prevalence of CCM lesions, the development of clinical symptoms is extremely variable,
and approximately only 30% of affected people show headaches, focal neurological deficits (25%), seizures
(50%), and symptomatic hemorrhage (25%) . Symptoms may occur at any age, although the typical age of
[3]
onset is between the second and fifth decade of life and without sex predominance, even though the
available data are conflicting. Moreover, the majority of CCM lesions remain clinically and biologically
[4-6]
quiescent during the most of the host’s lifetime . To date, diagnosis is made only by magnetic resonance
imaging (MRI), and it is mainly possible only when lesions become symptomatic . The most commonly
[3]
used classification of CCMs in the literature was proposed by Zabramski et al. . Individual cavernous
[7]
malformations are divided into four categories on the basis of pathological correlations and magnetic
resonance signal characteristics: Type I, characterized by the presence of subacute hemorrhage; Type II,
with loculated areas of hemorrhage and thrombosis of varying age; Type III, with chronic areas of
hemorrhage; and Type IV, with small multiple punctate microhemorrhagies .
[7]

CCM is a disease of proven genetic origin (OMIM 116860) that may arise sporadically or can be inherited as
an autosomal dominant condition, with incomplete penetrance and variable expressivity. The sporadic form
accounts for up to 80% of cases and is characterized by a lack of family history of the disease and the
presence of a single lesion on MRI. The familial form accounts for at least 20% of cases and is generally
characterized by the presence of multiple CCM lesions in the brain associated with cutaneous and retinal
[8]
vascular lesions in 9% and 5% of familial CCM cases . Human genetic studies have so far identified three
genes whose heterozygous loss-of-function mutations are associated with CCM disease: KRIT1 (CCM1),
MGC4607 (CCM2), and PDCD10 (CCM3). The mutation rates for each gene range between 53% and 65%
for KRIT1/CCM1, 15% and 19% for CCM2, and 10% and 16% for CCM3 [9,10] . However, genotype does not
entirely explain the large clinical variability of CCM disease, even among family members carrying the same
mutation, suggesting that genetic and environmental modifiers can contribute to CCM disease . Despite
[11]
the differences between families, some genotype-phenotype correlations are delineated. While CCM1 and
CCM2 induce similar characteristics with later manifestation, mutations on CCM3 drive an early age,
aggressive phenotype, with higher risk for cerebral hemorrhage and propensity to multiple meningiomas .
[2]

At the molecular level, CCM gene loss induces the activation of different signaling pathways [12-14] . In
particular CCM deficiency have been associated with hyperactivation of the MEKK3-MEK5-ERK5 kinase
cascade, that leads to KLF2 and KLF4 upregulation and subsequent altered expression of bone morphogenic
protein 6 (BMP6), thrombomodulin (TM), and thrombospondin 1 [15-18] , with activation of RhoA-ROCK
signaling, and with alteration of the junctional signaling including VE-cadherin and β-catenin [19,20] . A
significant alteration of reactive oxygen species balance has been also extensively described [13,21-23] .

At present, the pharmaceutical therapy available for the treatment of CCM is very restricted and limited to
the treatment of clinical symptoms, as headaches, seizures and epilepsy. The clinical approach to CCM