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Page 2 of 5 Lee. Vessel Plus 2022;6:7 https://dx.doi.org/10.20517/2574-1209.2021.31

CHARACTERIZING THE PATIENT COMMUNITY
While Angioma Alliance serves the research community directly through its annual scientific meeting,
tissue bank, and patient registry, the organization views its most critical role as that of growing and
characterizing the known patient cohort with the goal of offering researchers and industry a critical resource
they might not be able to access independently. In 2009, replicating the efforts of many organizations,
Angioma Alliance launched a self-report patient registry that allows for efficient communication to
prospective clinical research participants. Beginning in 2016, Angioma Alliance enhanced its patient
outreach program by offering free clinical diagnostic genetic testing to those with multiple lesions that could
not be explained by a developmental venous anomaly or history of radiation. CCM is the result of an
autosomal dominant loss-of-function mutation on any one of three genes: CCM1 (KRIT1), CCM2, or
CCM3 (PDCD10) and can also be sporadic. A well-characterized patient cohort allows for a cleaner analysis
of between-group differences with less expense to any individual research project. To date, the Angioma
Alliance program has provided testing to more than 120 non-Hispanic index patients, representing well
over 600 total patients once affected family members are considered, and 290 patients at-risk for the CCM1
Common Hispanic Founder Mutation, representing more than 1000 total patients (more on this below). It
is believed that the Angioma Alliance program was the second-ever rare disease genotyping effort driven by
a patient advocacy organization; the first was offered by DuchenneConnect. More information on Angioma
Alliance programs is available at https://www.angioma.org.

EXCEPTIONALLY AGGRESSIVE CCM3 SYNDROME
Characterizing the patient cohort had precedent at Angioma Alliance as part of an outreach effort to special
populations. Before the biology of CCM3 mutations was well understood, it was clear to the patient
population and some providers that mutation of CCM3 resulted in proportionally more symptomatic
[1]
children who had a greater disease burden than those with the other genetic mutations . To assist in
phenotyping, from 2012 to 2016, Angioma Alliance joined with cerebrovascular neurosurgeon Issam Awad
at the University of Chicago to create a CCM3 Clinic at which every known patient could be seen, and their
travel and excess medical expenses were covered by the organization. By 2015, examinations at the CCM3
[2]
Clinic confirmed a more aggressive, multi-systemic phenotype . The finding allowed us to identify a
particular phenotype that should receive high priority for genetic testing - children with greater than 5
lesions, particularly those with no CCM family history as 50% of cases seen at the CCM3 Clinic were de
novo. Adults with high lesion burden, co-morbid benign brain tumors, and/or a history of scoliosis are also
prioritized. A significant amount of subsequent basic research has confirmed the uniqueness of CCM3
[3]
mutations, including the impairment of goblet cells in the gut . This 2017 finding points to the possibility
that individuals with CCM3 mutations may derive greater benefit from dietary changes, especially if made
early. Finally, in addition to extensive phenotyping, the CCM3 Clinic allowed families to form close bonds
with each other, ensuring a growing, invested patient community that is primed for clinical trials.

A COMMON HISPANIC FOUNDER MUTATION HISTORY & COMMUNITY
In 2017, Angioma Alliance began its most ambitious special population outreach to address the need to
engage those affected by the Common Hispanic Mutation, a founder mutation originating in the early
[4]
1600s in Mexico and New Mexico. The organization had been working in New Mexico since 2006 with only
moderate success in expanding patient participation in research or educational activities. Statistically, it is
expected that 30,000-40,000 individuals with the Common Hispanic Mutation continue to live in New
Mexico and surrounding states, but in 2016, only 300 patients were enrolled in clinical research programs at
the University of New Mexico (personal communication with Dr. Leslie Morrison, pediatric neurologist
and UNM Vice Chancellor emeritus). A rare disease elsewhere, CCM is a public health issue in New
Mexico. However, it was thought that mistrust of the medical system and a focus on a potentially