Genetic Genealogy Uncovers a Founder Deletion Mutation in the Cerebral Cavernous Malformations 2 Gene

Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700’s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.

Displacement of Gray Matter and Incidence of Seizures in Patients with Cerebral Cavernous Malformations

Seizures are the most common presentation in patients with cerebral cavernous malformations (CCMs). Based on the hypothesis that the volume or proportion of gray matter (GM) displaced by CCMs is associated with the risk of seizure, we developed an algorithm by which to quantify the volume and proportion of displaced GM and the risk of seizure. Image analysis was conducted on 111 patients with solitary CCMs (divided into seizure and nonseizure groups) from our gamma knife radiosurgery (GKRS) database from February 2005 and March 2020. The CCM algorithm proved effective in quantifying the GM and CCM using T1WI MRI images. In the seizure group, 11 of the 12 patients exhibited seizures at the initial presentation, and all CCMs in the seizure group were supratentorial. The location of the limbic lobe within the CCM was significantly associated with the risk of seizure (OR = 19.6, p = 0.02). The risk of seizure increased when the proportion of GM displaced by the CCM exceeded 31%. It was also strongly correlated with the volume of displaced GM. The volume and proportion of displaced GM were both positively correlated with the risk of seizure presentation/development and thus could be used to guide seizure prophylaxis in CCM patients.

Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study

Background and Purpose: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. Methods: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. Results: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15−8.63], P =0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04−5.86], P= 0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18−8.99], P= 0.022 and odds ratio, 2.53 [95% CI, 1.07−5.98], P =0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80−110.39], P= 0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%−23.6%) for the entire cohort, 30.2% (20.2%−42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%−51.1%) for children with brain stem CCM. Conclusions: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

The role of MRI in assessing the effectiveness of cerebral cavernous malformations stereotaxic radiosurgical treatment

.