Familial form of cerebral cavernous malformations: evaluation of gradient-spin-echo (GRASE) imaging in lesion detection and characterization at 1.5 T

2001 ◽  
Vol 43 (11) ◽  
pp. 973-979 ◽  
Author(s):  
L. Brunereau ◽  
C. Leveque ◽  
P. Bertrand ◽  
F. Tranquart ◽  
Y. Cordoliani ◽  
...  
Keyword(s):  
Spin Echo ◽  
Lesion Detection ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Familial Form

scholarly journals Molecular genetics of familial cerebral cavernous malformations

2006 ◽  
Vol 21 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Shervin R. Dashti ◽  
Alan Hoffer ◽  
Yin C. Hu ◽  
Warren R. Selman
Keyword(s):  
Molecular Genetics ◽  
Cerebral Cavernous Malformations ◽  
Pathological Findings ◽  
Cavernous Malformations ◽  
Molecular Events ◽  
Familial Form ◽  
Hispanic Patients ◽  
Caucasian Patients ◽  
Vascular Channels ◽  
Familial Cerebral Cavernous Malformations

✓Cerebral cavernous malformations (CMs) are angiographically occult neurovascular lesions that consist of enlarged vascular channels without intervening normal parenchyma. Cavernous malformations can occur as sporadic or auto-somal-dominant inherited conditions. Approximately 50% of Hispanic patients with cerebral CMs have the familial form, compared with 10 to 20% of Caucasian patients. There is no difference in the pathological findings or presentation in the sporadic and familial forms. To date, familial CMs have been attributed to mutations at three different loci: CCM1 on 7q21.2, CCM2 on 7p15-p13, or CCM3 on 3q25.2-q27. The authors summarize the current understanding of the molecular events underlying familial CMs.

scholarly journals Accuracy of SWI sequences compared to T2*-weighted gradient echo sequences in the detection of cerebral cavernous malformations in the familial form

2016 ◽  
Vol 29 (5) ◽  
pp. 326-335 ◽  
Author(s):  
Gianvincenzo Sparacia ◽  
Claudia Speciale ◽  
Aurelia Banco ◽  
Francesco Bencivinni ◽  
Massimo Midiri
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Gradient Echo ◽  
Cavernous Malformations ◽  
Familial Form

De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families

2000 ◽  
Vol 53 (5) ◽  
pp. 475-483 ◽  
Author(s):  
Laurent Brunereau ◽  
Claude Levy ◽  
Sophie Laberge ◽  
Jean-Pierre Houtteville ◽  
Pierre Labauge
Keyword(s):  
De Novo ◽  
Cerebral Cavernous Malformations ◽  
Hispanic Families ◽  
Cavernous Malformations ◽  
Familial Form

scholarly journals Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: a susceptibility-weighted imaging study with 7-Tesla MRI

2017 ◽  
Vol 126 (2) ◽  
pp. 570-577 ◽  
Author(s):  
Philipp Dammann ◽  
Karsten Wrede ◽  
Yuan Zhu ◽  
Toshinori Matsushige ◽  
Stefan Maderwald ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Screening Method ◽  
7 Tesla ◽  
Susceptibility Weighted Imaging ◽  
Consecutive Series ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Venous Anomalies ◽  
Familial Disease ◽  
Familial Form

OBJECTIVE Multiple cerebral cavernous malformations (CCMs) are rare lesions that occur in sporadic or familial form. Depending on the disease form, the natural history and treatment of the lesions strongly vary. Molecular analysis of an underlying germline mutation (CCM1–3) is the most sensitive screening method to distinguish between sporadic and familial cases. However, based on the different pathomechanisms that are believed to be involved in either form, significant distinctions in the CCM-associated cerebral venous angioarchitecture should be detectable. This has not been systematically studied. METHODS A consecutive series of 28 patients with multiple CCMs (681 total) diagnosed on 1.5-T MRI underwent genetic screening for CCM1–3 mutations and high-resolution susceptibility-weighted imaging (SWI) of the cerebral venous angioarchitecture with 7-T MRI. Imaging data were analyzed to examine the CCM-associated venous angioarchitecture. Results were correlated with findings of molecular analysis for CCM1–3 mutations. RESULTS Two different SWI patterns (sporadic and familial) were found. The presence of associated developmental venous anomalies correlated with negative screening for germline mutations (11 sporadic) in all cases. All patients with confirmed familial disease showed normal underlying venous angioarchitecture. Additionally, a very unusual case of a probable somatic mutation is presented. CONCLUSIONS The SWI results of the venous angioarchitecture of multiple CCMs correlate with sporadic or familial disease. These results are consistent with the theory that venous anomalies are causative for the sporadic form of multiple CCMs.

scholarly journals Vascular Permeability in Cerebral Cavernous Malformations

2015 ◽  
Vol 35 (10) ◽  
pp. 1632-1639 ◽  
Author(s):  
Abdul G Mikati ◽  
Omaditya Khanna ◽  
Lingjiao Zhang ◽  
Romuald Girard ◽  
Robert Shenkar ◽  
...  
Keyword(s):  
Disease Activity ◽  
Vascular Permeability ◽  
Human Subjects ◽  
Endothelial Permeability ◽  
Perfusion Magnetic Resonance Imaging ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Familial Form

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

Cerebral Cavernous Malformations: Patient-Reported Outcome Validates Conservative Management

2017 ◽  
Vol 44 (5-6) ◽  
pp. 313-319 ◽  
Author(s):  
Vitor Chehuen Bicalho ◽  
Anke Bergmann ◽  
Flávio Domingues ◽  
João Thiago Frossard ◽  
Jorge Paes Barreto Marcondes de Souza
Keyword(s):  
Vascular Malformations ◽  
Patient Reported Outcome ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Sf 36 ◽  
Patient Reported

Background: Cerebral cavernous malformations (CCM) are clusters of dilated sinusoidal channels lined by a single layer of endothelium. In contradistinction to arteriovenous malformations, these lesions do not have smooth muscle or elastin in their lining and they are angiographically occult, and the MRI is the most sensitive test for CCM detection. CCM are one of the most prevalent vascular malformations of the central nervous system, affecting about 0.4-0.6% of the general population. The main complication of this malformation is the risk of bleeding, which may cause neurological deficits that affect the quality of life (QoL) in patients. When symtomatic, they may be surgically treated for relieving the mass effect and seizures refractory to drug uses, hemorrhage and drug-refractory epilepsy. Patient-reported outcome (PRO) may be a strategy that can be used to evaluate QoL of CCM population and was used in a sample of non-operated patients. Methods: An observational, cross-sectional analysis to evaluate the PRO using the SF-36 and EuroQol 5 dimensions (EQ-5D) questionnaires of QoL added to functional metrics using the Karnofsky Performance Status (KPS) in 49 patients not submitted to intervention and with long-term follow-up. Results: During the 364 person-years of follow-up, there was an average of individual follow-up of 7.42 years. The mean age was 46.8 years (18-84) - 57% of them were female, 71% had superficial lesions, and 65% had the familial form. Comparisons of SF-36 dimensions with KPS graded <100 had a worse score only in terms of the pain (p = 0.04), vitality (p = 0.001), and general state of health (p = 0.03) domains. The domain mental health was worse in patients without surgical indication (p = 0.032). The functional capacity domain had the highest overall grading in the group. The EQ-5D dimensions of mobility (p = 0.03) and pain/discomfort (p = 0.001) were the ones with lower score compared to KPS <100. Conclusion: The study is the first to evaluate, with validated tools, the PRO of non-operated CCM patients and has demonstrated in a selected group of patients that it was possible to achieve long-term clinical stability, thereby maintaining QoL and functional neurological outcome.

scholarly journals Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 704
Author(s):  
Giulia Riolo ◽  
Claudia Ricci ◽  
Stefania Battistini
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Cellular Level ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Protein Functions

Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.

scholarly journals Absence of mutations at SERPINI1 gene in a cohort of patients with Cerebral Cavernous Malformations

2021 ◽  
Author(s):  
Concetta Scimone ◽  
Rosalia D'Angelo ◽  
Simona Alibrandi ◽  
Fabiana Nicita ◽  
Luigi Donato ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Gene Expression Regulation ◽  
Mutational Analysis ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Nucleotide Polymorphisms ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Noncoding Exon ◽  
History Of

Cerebral cavernous malformations (CCM) are vascular lesions affecting brain microvessels. While molecular bases of the sporadic condition are not yet well elucidated, familial forms arise following mutations at three different loci KRIT1, CCM2 and PDCD10. However, no germline mutations are detected in a small percentage of families with hereditary history of CCM. In order to detect other possible candidate genes, we performed molecular analysis of SERPINI1 gene in a cohort of patients carrying no mutations in the three CCM loci, aiming to detect mutations likely associated to lesion development. Therefore, we performed molecular analysis of the SERPINI1 gene in a cohort of 18 unrelated patients affected by both familial and sporadic CCM showing no germline causative mutations. Mutational analysis resulted negative and only few single nucleotide polymorphisms were detected. However, the rs11284733 SNP was detected in a high percentage of patients affected by familial form of the disease. This SNP occurs within a noncoding exon retained in an alternative spliced SERPINI1 transcript, suggesting its possible role in gene expression regulation.

scholarly journals KRIT1 Gene in Patients with Cerebral Cavernous Malformations: Clinical Features and Molecular Characterization of Novel Variants

2021 ◽  
Author(s):  
Claudia Ricci ◽  
Alfonso Cerase ◽  
Giulia Riolo ◽  
Giuditta Manasse ◽  
Stefania Battistini
Keyword(s):  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Premature Stop Codon ◽  
De Novo Mutation ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Mutation Carriers ◽  
Familial Form ◽  
Sporadic Cases

AbstractCerebral cavernous malformations (CCMs) are vascular malformations that may result in headaches, seizures, focal neurological deficits, and hemorrhage. CCMs occur sporadically (80%) or in familial form (20%), with autosomal dominant inheritance. Among the three CCM-related genes, mutations in KRIT1 account for 53–65% of familial cases and more than 100 different mutations have been identified so far. In the present work, we describe the clinical, neuroradiological, and genetic findings of sixteen CCM Italian patients, 13 belonging to 4 unrelated families and 3 sporadic cases. Six distinct KRIT1 gene variants, two novel (c.1730+1_1730+3del, c.1664 C>T) and four previously described (c.966G>A, c.1255-1G>A c.1197_1200del, c.1255-1_1256del), were identified, including a possible de novo mutation. All the variants resulted in a premature stop codon. Cerebral 1.5 T magnetic resonance imaging showed multiple CCMs in all the mutation carriers for whom it was available, including sporadic cases. One patient had also cutaneous angiomas. Among the mutation carriers, symptomatic patients constituted 66% and a variable phenotypic expression was observed. Our data confirms phenotypic variability and incomplete penetrance of neurological symptoms in KRIT1-positive families, expands the mutational spectrum of this gene, and highlights how sporadic cases with multiple lesions need an approach similar to individuals with familial CCM.

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