scholarly journals Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Rosalia D’Angelo ◽  
Concetta Alafaci ◽  
Concetta Scimone ◽  
Alessia Ruggeri ◽  
Francesco Maria Salpietro ◽  
...  
Keyword(s):  
Mutation Screening ◽  
Neurological Deficits ◽  
Vascular Lesions ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition ◽  
Italian Cohort ◽  
New Mutations

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes:CCM1(K-Rev interaction trapped 1 (KRIT1)),CCM2(MGC4607), andCCM3(PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM.

scholarly journals Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
Author(s):  
Gwénola Boulday ◽  
Noemi Rudini ◽  
Luigi Maddaluno ◽  
Anne Blécon ◽  
Minh Arnould ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Vascular Lesions ◽  
Developmental Timing ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

Effective surgical treatment of cerebral cavernous malformations: a multicenter study of 79 pediatric patients

2011 ◽  
Vol 8 (5) ◽  
pp. 522-525 ◽  
Author(s):  
Michael Hugelshofer ◽  
Nicola Acciarri ◽  
Ulrich Sure ◽  
Dimitrios Georgiadis ◽  
Ralf W. Baumgartner ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Refractory Epilepsy ◽  
Epileptic Seizures ◽  
Neurological Deficits ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Persistent Symptoms ◽  
The Mean ◽  
The Brain

Object Cerebral cavernous malformations (CCMs) are common vascular lesions in the brain, affecting approximately 0.5% of the population and representing 10%–20% of all cerebral vascular lesions. One-quarter of all CCMs affect pediatric patients, and CCMs are reported as one of the main causes of brain hemorrhage in this age group. Symptoms include epileptic seizures, headache, and focal neurological deficits. Patients with symptomatic CCMs can be treated either conservatively or with resection if lesions cause medically refractory epilepsy or other persistent symptoms. Methods The authors retrospectively analyzed 79 pediatric patients (41 boys and 38 girls) from 3 different centers, who were surgically treated for their symptomatic CCMs between 1974 and 2004. The mean age of the children at first manifestation was 9.7 years, and the mean age at operation was 11.3 years. The main goal was to compare the clinical outcomes with respect to the location of the lesion of children who preoperatively suffered from epileptic seizures. Results Of these patients, 77.3% were seizure free (Engel Class I) after the resection of the CCM. Significant differences in the outcome between children who harbored CCMs at different locations were not found. Conclusions Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.

scholarly journals The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications

2010 ◽  
Vol 29 (3) ◽  
pp. E2 ◽  
Author(s):  
Khaled M. Krisht ◽  
Kevin J. Whitehead ◽  
Toba Niazi ◽  
William T. Couldwell
Keyword(s):  
Neurological Deficits ◽  
Therapeutic Modality ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Mice Model ◽  
Genetic Studies ◽  
Cavernous Malformations ◽  
Therapeutic Implications ◽  
Model Studies ◽  
Shed Light

Cerebral cavernous malformations (CCMs) are common vascular lesions of the CNS that may lead to seizures, focal neurological deficits, and fatal hemorrhagic stroke. Human genetic studies have identified 3 genes associated with CCM, and biochemical and molecular studies in mice have elucidated signaling pathways with important therapeutic implications. In this review, the authors shed light on the 3 discovered CCM genes as well as their protein products, with particular emphasis on their signal transduction pathways and their interaction with one another. Close focus is directed at mice model studies involving the Ccm2 gene product signaling pathway, revealing an important role for the use of simvastatin or other RhoA inhibitors as a therapeutic modality in the treatment of CCM. The remaining challenges to creating a more faithful CCM animal model as well as future clinical and research implications are reviewed.

scholarly journals Cerebral Cavernous Malformations, Developmental Venous Anomaly, and Its Coexistence: A Review

2020 ◽  
Vol 83 (4) ◽  
pp. 360-368 ◽  
Author(s):  
Pretty Sara Idiculla ◽  
Dhineshreddy Gurala ◽  
Jobin Philipose ◽  
Kartikeya Rajdev ◽  
Prateek Patibandla
Keyword(s):  
English Language ◽  
Vascular Malformations ◽  
Incidental Finding ◽  
Neurological Deficits ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Developmental Venous Anomaly ◽  
Venous Anomaly ◽  
Cavernous Malformations ◽  
Acute Thrombosis

Background: Cerebral cavernous malformations (CCMs) are intracranial vascular malformations that can exist as a single lesion or mixed vascular lesions. The most common mixed form is the coexistence of CCM with an associated developmental venous anomaly (DVA). In this paper, we aim to give a comprehensive review of CCM, DVA, and their coexistence as mixed lesions. A PubMed search using the keywords “Cerebral cavernous malformations, Developmental venous anomaly, Mixed Cerebral cavernous malformations with Developmental venous anomaly” was done. All studies in the English language in the past 10 years were analyzed descriptively for this review. Summary: The search yielded 1,249 results for “Cerebral cavernous malformations,” 271 results for “Developmental venous anomaly,” and 5 results for “Mixed Cerebral cavernous malformations with Developmental venous anomaly.” DVA is the most common intracranial vascular malformation, followed by CCM. CCM can have a wide array of clinical presentations like hemorrhage, seizures, or focal neurological deficits or can also be an incidental finding on brain imaging. DVAs are benign lesions by nature; however, venous infarction can occur in a few patients due to acute thrombosis. Mixed CCM with DVA has a higher risk of hemorrhage. CCMs are angiographically occult lesion, and cerebral digital subtraction angiography is the gold standard for the diagnosis of DVA. Mixed lesions, on the other hand, are best diagnosed with magnetic resonance imaging, which has also been effective in detecting specific abnormalities. Asymptomatic lesions are treated through a conservative approach, while clinically symptomatic lesions need surgical management. Conclusion: Individual CCM or DVA lesions have a benign course; however, when they coexist in the same individual, the hemorrhagic risk is increased, which prompts for rapid diagnosis and treatment.

Abstract 159: Exceptional Aggressiveness of CCM3 Phenotype

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tania J Rebeiz ◽  
Abdul Ghani Mikati ◽  
Darlene Simkhin ◽  
Cornelia Lee ◽  
Amy Akers ◽  
...  
Keyword(s):  
Spontaneous Mutation ◽  
Mutation Screening ◽  
High Sensitivity ◽  
Skin Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cognitive Disability ◽  
Cavernous Malformations ◽  
Patient Advocacy Group ◽  
Sporadic Cases

Introduction: Familial forms of cerebral cavernous malformations (CCM) account for about 1/3 of cases, involving autosomal dominant inheritance at 1 of 3 gene loci. Few studies have examined any special features of the rarest cases with CCM3 (PDCD10 ) mutation at q3, constituting <15 % of probands genotyped by sequential mutation screening, and <2% of CCM cases at large. Hypothesis: We hypothesize that CCM3 cases have unique phenotypic features not recognized in the more common CCM1 and 2 families, or in sporadic cases. Methods: Twelve probands including 17 subjects with confirmed CCM3 mutations were prospectively enrolled through systematic facilitated referral by the patient advocacy group Angioma Alliance. Clinical features were catalogued, including high sensitivity susceptibility weighted imaging (SWI). Rates of overt hemorrhage were determined based on adjudicated criteria. Comparisons were made to systematic literature review of natural history data on non-CCM3 cases. Results: The first overt hemorrhage occurred most often in the 1st decade of life (mean age 5.8). Nine of 17 subjects (52%) suffered 30 overt hemorrhages, with an estimated incidence of 6.7 % /patient/year based on exposure risk since birth, and 17% /patient/year based on risk since first symptom onset. Lesion burden on SWI was exceptionally high, >100 lesions in 28%, and > 20 lesions in 72% of cases, respectively. Adjusted bleed rate was <0.5% /lesion/year. New SWI lesions formed at a rate of 2.7/patient/year in prospective follow-up, and 1.8/patient/year based on years since birth. Scoliosis was found in 47% (an association not recognized previously), skin lesions in 29.4%, and brain tumors in 29.4% of cases, respectively. Cognitive disability affected 47% of cases, mostly in association with high lesion burden. Six of 15 cases with parental screening (40%) represented a spontaneous mutation. Conclusion: CCM3 is exceptionally aggressive compared to other familial and sporadic CCM. High risks of bleeding and cognitive disability mostly reflect severe lesion burden early in life, rather than a higher risk per lesion. These results will inform the design of clinical trials, urgently needed to address this unique CCM cohort.

Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes

2021 ◽  
Vol 30 (12) ◽  
pp. 106130
Author(s):  
Pablo Iruzubieta ◽  
David Campo-Caballero ◽  
Jon Equiza ◽  
Inés Albajar ◽  
Naroa Sulibarría ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Familial Cerebral Cavernous Malformations ◽  
New Mutations

scholarly journals Supratentorial cerebral cavernous malformations: clinical, surgical, and genetic involvement

2006 ◽  
Vol 21 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Vincenzo Antonio D'Angelo ◽  
Costanzo De Bonis ◽  
Rosina Amoroso ◽  
Alessandro Calì ◽  
Leonardo D'Agruma ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Family Members ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Psychological Burden ◽  
Management Algorithm ◽  
Screening Protocol

Object Although there is general agreement on the methods of treatment for symptomatic supratentorial cerebral cavernous malformations (CMs) located in noneloquent areas, some controversy exists regarding the management of cerebral CMs that are asymptomatic and/or located in eloquent or deep areas. Moreover, recent advances in genetic findings could influence both standard clinical management and the follow-up strategy in affected individuals. Thus, the objective of this study was to develop, based on the authors' experience and a literature review, a management algorithm to deal with supratentorial cerebral CMs. Methods The authors retrospectively reviewed the clinical data related to 118 patients who underwent surgery for symptomatic supratentorial cerebral CMs at their institution. Twenty-eight of 118 patients harbored multiple lesions, and nine of these 28 patients had a clinically positive familial history. Genetic investigations were performed in 89 patients (75%). Conclusions Surgery for supratentorial cerebral CMs in noneloquent locations is safe and curative. In cerebral CMs located in deep and eloquent areas and with symptoms including progressive neurological deficits, evidence of hemorrhage, and uncontrolled seizures, surgical treatment according to an integrated plan based on frameless stereotactic guidance and functional magnetic resonance imaging is recommended and results in acceptably low morbidity. The data support the need for long-term imaging follow up in all patients, careful preoperative vascular studies to detect associated venous anomalies, and the importance of genetic mutational analysis. The DNA screening protocol will change the care of family members of patients with familial forms of cerebral CMs, because affected asymptomatic family members may benefit by early detection of lesions. At the same time, the exclusion of family members who are not carriers of the mutation as members of the population at risk reduces the economic and psychological burden of clinical and instrumental monitoring.

scholarly journals A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

2021 ◽  
Vol 14 ◽  
Author(s):  
Guoqing Han ◽  
Li Ma ◽  
Huanhuan Qiao ◽  
Lin Han ◽  
Qiaoli Wu ◽  
...  
Keyword(s):  
Vascular Malformations ◽  
Case Reports ◽  
Chinese Family ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Cavernous Malformations ◽  
Direct Dna Sequencing ◽  
Number Of Patients

Cerebral cavernous malformations (CCMs) are common vascular malformations in the central nervous system. Familial CCMs (FCCMs) are autosomal dominant inherited disease with incomplete penetrance and variable symptoms. Mutations in the KRIT1, CCM2, and PDCD10 genes cause the development of FCCM. Approximately 476 mutations of three CCM-related genes have been reported, most of which were case reports, and lack of data in stable inheritance. In addition, only a small number of causative missense mutations had been identified in patients. Here, we reported that 8/20 members of a Chinese family were diagnosed with CCMs. By direct DNA sequencing, we found a novel variant c.331G &gt; C (p.A111P) in exon 4 of the CCM2 gene, which was a heterozygous exonic variant, in 7/20 family members. We consider this variant to be causative of disease due to a weaken the protein–protein interaction between KRIT1 and CCM2. In addition, we also found the exon 13 deletion in KRIT1 coexisting with the CCM2 mutation in patient IV-2, and this was inherited from her father (patient III-1H). This study of a Chinese family with a large number of patients with CCMs and stable inheritance of a CCM2 mutation contributes to better understanding the spectrum of gene mutations in CCMs.

scholarly journals The natural history of cerebral cavernous malformations in children

2016 ◽  
Vol 17 (2) ◽  
pp. 123-128 ◽  
Author(s):  
Bradley A. Gross ◽  
Rose Du ◽  
Darren B. Orbach ◽  
R. Michael Scott ◽  
Edward R. Smith
Keyword(s):  
Risk Factors ◽  
Family History ◽  
Natural History ◽  
Significant Risk ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Similar Data ◽  
Cavernous Malformations ◽  
Neurological Morbidity ◽  
History Of

OBJECT Cerebral cavernous malformations (CMs) are a source of neurological morbidity from seizures and focal neurological deficits due to mass effect and hemorrhage. Although several natural history reports exist for adults with CMs, similar data for pediatric patients are limited. METHODS The authors reviewed hospital databases to identify children with CMs who had not been treated surgically and who had clinical and radiological follow-up. Annual hemorrhage rates were calculated in lesion-years, and risk factors were assessed using the Cox proportional hazards model. RESULTS In a cohort of 167 patients with 222 CMs, the mean patient age at the time of diagnosis was 10.1 years old (SD 6.0). Ninety patients (54%) were male. One hundred four patients (62%) presented with hemorrhage from at least 1 CM, 58 (35%) with seizures with or without CM hemorrhage, and 43 (26%) with incidental lesions. Twenty-five patients (15%) had multiple CMs, 17 (10%) had a family history of CMs, and 33 (20%) had radiologically apparent developmental venous anomalies (DVAs). The overall annual hemorrhage rate was 3.3%. Permanent neurological morbidity was 29% per hemorrhage, increasing to 45% for brainstem, thalamic, or basal ganglia CM and decreasing to 15% for supratentorial lobar or cerebellar lesions. The annual hemorrhage rate for incidental CMs was 0.5%; for hemorrhagic CMs, it was 11.3%, increasing to 18.2% within the first 3 years. Hemorrhage clustering within 3 years was statistically significant (HR 6.1, 95% CI 1.72–21.7, p = 0.005). On multivariate analysis, hemorrhagic presentation (HR 4.63, 95% CI 1.53–14.1, p = 0.007), brainstem location (HR 4.42, 95% CI 1.57–12.4, p = 0.005), and an associated radiologically apparent DVA (HR 2.91, 95% CI 1.04–8.09, p = 0.04) emerged as significant risk factors for hemorrhage, whereas age, sex, CM multiplicity, and CM family history did not. CONCLUSIONS Prior hemorrhage, brainstem location, and associated DVAs are significant risk factors for symptomatic hemorrhage in children with CMs. Hemorrhage clustering within the first 3 years of a bleed can occur, a potentially important factor in patient management and counseling.

Bringing CCM into a dish: cell culture models for cerebral cavernous malformations

2021 ◽  
Vol 33 (3) ◽  
pp. 251-259
Author(s):  
Dariush Skowronek ◽  
Robin A. Pilz ◽  
Konrad Schwefel ◽  
Christiane D. Much ◽  
Ute Felbor ◽  
...  
Keyword(s):  
Neurological Complications ◽  
Cell Junctions ◽  
Vascular Lesions ◽  
Disease Genes ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
High Throughput Drug Screening ◽  
Culture Models ◽  
Cell Culture Models

Abstract Cerebral cavernous malformations (CCMs) are vascular lesions that can cause severe neurological complications due to intracranial hemorrhage. Although the CCM disease genes, CCM1, CCM2, and CCM3, have been known for more than 15 years now, our understanding of CCM pathogenesis is still incomplete. CCM research currently focuses on three main disease mechanisms: (1) clonal expansion of endothelial cells with biallelic inactivation of CCM1, CCM2, or CCM3, (2) recruitment of cells with preserved CCM protein expression into the growing lesion, and (3) disruption of endothelial cell–cell junctions in CCMs. We here describe novel CRISPR/Cas9-based in vitro models of CCM and discuss their strengths and limitations in the context of high-throughput drug screening and repurposing approaches.

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