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Page 4 of 8 Rigamonti et al. Vessel Plus 2021;5:47 https://dx.doi.org/10.20517/2574-1209.2021.65

More than 350 distinct CCM1/CCM2/CCM3 mutations have been published to date, and, 15 years after the
identification of CCM3, no additional genes have been correlated to the remaining almost 5%-15% of cases
that are not associated with any of the three [59-62] .

CCM protein products collectively interact with each other, as well as with other molecules, proteins, and
kinases to regulate various cellular processes, including angiogenesis and intercellular communication.
Mutations in any of the genes impairs the functionality of the CCM complex, including the Rho family of
the GTPases, which specifically regulate the endothelial barrier leading to altered development and
maintenance of the vascular permeability. However, data on why mutations in CCM genes commonly affect
the cerebral and spinal vasculature remain unclear [63-80] .

Research on CCM proteins and their influence on the cellular and molecular pathways and their influence
on the disease has been the focus of intense research and controversies that have greatly enhanced our
knowledge to the point where several pharmacological therapeutic candidates are under preclinical
investigation with promising results in the prevention of lesion formation, maturation, and hemorrhage
such as mTOR and ROCK inhibitors, among others [81-84] .

Pending questions include why mutations in CCM genes predominantly affect blood vessels in the brain
and spinal cord, further understanding of lesions without CCM1-3 mutations; use of laser ablation as a
minimally invasive surgical treatment, as well as radiation therapy for deep-seated lesions, and those located
in eloquent cortex; and additional clarification regarding the use of antithrombotic/anticoagulant agents for
each type and risk of hemorrhage as well as clearer recommendations for the treatment of comorbidities.

There are still many gaps that need to be addressed to include medical therapies as part of the therapeutic
options, and, for this reason, as of today, CCMs remain a surgical disease.

CCM patients and their families formed the Angioma Alliance in the United States, which has inspired and
funded further research and has helped standardize the management of this condition. Following its
[85]
stimulating example, similar associations have been established and organized around the world .

CONCLUSIONS
Our knowledge of the clinical and epidemiological characteristics of CCMs has been tremendously
enhanced with the advent of MRI. Because this imaging modality is very sensitive in regard to the
visualization of even the smallest CCMs and specific, epidemiology and clinical features of CCMs were
prospectively studied and elucidated. Furthermore, understanding the molecular biology of CCMs and the
development of the vascular system in the human patient has allowed for the development of novel
biomarkers and therapeutic markers, with the potential to offer medical treatment in the years to come.

DECLARATIONS
Acknowledgments
The author acknowledges the enduring support provided by the Salisbury Family Foundation.

Authors’ contributions
Contributed to the planification, literature review, redaction, and critical revision of this manuscript:
Rigamonti D, Vivas-Buitrago T