Overview
People with a CCM3 (also called PDCD10) genetic mutation have an increased risk of developing multiple cavernous malformations, scoliosis, and benign brain tumors. Mutations in the CCM3 gene cause symptoms outside of the vascular system because the gene is active in additional molecular pathways not shared by the CCM1 and CCM2 genes.
Mutations in the CCM3 gene account for about 10-16% of familial cavernous malformation cases.
Symptoms
- Earlier onset: At least half of those identified with a CCM3 mutation began to exhibit serious symptoms, including multiple brain hemorrhages, in childhood (before age 15 years old)
- More CCMs: People with a CCM3 mutation develop more CCM lesions than those with CCM1 or CCM2 mutations.
- Scoliosis: In one study of 18 people with CCM3 mutations, about 1 in 3 people had scoliosis (39%).
- Benign brain tumors (meningiomas, acoustic neuroma, and cerebellar astrocytoma): In the same study of 18 people, about 1 in 4 people had benign brain tumors (28%).
- The more severe aspects of the illness, such as hemorrhage, appear to diminish with age.
CCM3 and the Microbiome
In 2019, researchers at the University of Pennsylvania identified a unique role of the CCM3 gene in the creation of the mucous lining of the gut. Mice with CCM3 mutations developed impaired goblet cells in the gut. The goblet cells are responsible for producing the mucous lining that helps to keep bacteria inside the gut. The mucous lining was reduced by 25-50% in these mutated mice. This is an effect similar to what might be expected by consuming a diet high in preservatives and emulsifiers. Leakage of gram-negative bacteria from the gut, causing an inflammatory response, has been implicated in the development of cavernous malformation lesions. The compromised gut lining observed in CCM3 patients may explain their greater lesion burden. Additional microbiome research is underway. Visit the Microbiome and Gut Health in CCM webpage for more information.
Join Our CCM3 Community
Alliance to Cure Cavernous Malformation has established a Facebook group for families affected by this mutation and offers an annual global video meeting. If you have been diagnosed with a CCM3 gene mutation, please contact us at info@alliancetocure.org to learn more about our community.
References
Flemming K, et al. Familial Cerebral Cavernous Malformations. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Last Update July 27, 2023.
Shenkar R, et al. Exceptional Aggressiveness of Cerebral Cavernous Malformation Disease Associated with PDCD10 Mutations. Genet Med. 2015 Mar; 17(3): 188–196.
Tang AT, et. al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 18; 545(7654): 305–310.
Tang AT, et. al. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27; 11(520).
Wang K, Zhou HJ, Wang M. CCM3 and cerebral cavernous malformation disease. Stroke Vasc Neurol. 2019 Jun; 4(2): 67–70.
Updated 2.20.26
