Genetic testing for cerebral cavernous malformations

Abstract Cavernous cerebral malformations (CCM) are vascular malformations of the brain and spinal cord. CCM affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhage and focal neurological deficit. CCM may be familial or sporadic. Familial forms have autosomal dominant inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

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Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

Journal of Experimental Medicine ◽

10.1084/jem.20110571 ◽

2011 ◽

Vol 208 (9) ◽

pp. 1835-1847 ◽

Cited By ~ 78

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.

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Genetic testing for aortic valve stenosis

The EuroBiotech Journal ◽

10.2478/ebtj-2018-0040 ◽

2018 ◽

Vol 2 (s1) ◽

pp. 61-63

Author(s):

Yeltay Rakhmanov ◽

Paolo Enrico Maltese ◽

Alessandra Zulian ◽

Stefano Paolacci ◽

Tommaso Beccari ◽

...

Keyword(s):

Risk Assessment ◽

Clinical Trials ◽

Differential Diagnosis ◽

Aortic Valve ◽

Aortic Valve Stenosis ◽

Autosomal Dominant ◽

Left Ventricular ◽

Dominant Inheritance ◽

Gene Test ◽

Left Ventricular Outflow

Abstract Aortic valve stenosis (AVS) is a congenital aortic defect in which the aortic lumen narrows due to thickening or calcification of the aortic valve without obstructing left ventricular outflow. Depending on the site of obstruction, AVS is classified as valvular, sub-valvular or supra-valvular. The prevalence of AVS is about 3% and increases with age. One in eight persons over the age of 75 years has moderate or severe AVS. AVS has autosomal dominant inheritance. It can be associated with mutations in the following genes: NOTCH1, SMAD6, SMAD4, and ELN. This Utility Gene Test was developed on the basis of the analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials, when available.

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

10.21203/rs.3.rs-1167740/v1 ◽

2021 ◽

Author(s):

Carol J Gallione ◽

Matthew R Detter ◽

Henrietta M Christmas ◽

Cornelia Lee ◽

Douglas A Marchuk

Keyword(s):

Vascular Malformations ◽

Cerebral Cavernous Malformations ◽

Autosomal Dominant Trait ◽

Cavernous Malformations ◽

North American Continent ◽

The North ◽

Genealogical Data ◽

The Brain ◽

Recombination Junction ◽

Pair Level

Abstract 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.

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Genetic testing for Ebstein anomaly

The EuroBiotech Journal ◽

10.2478/ebtj-2018-0038 ◽

2018 ◽

Vol 2 (s1) ◽

pp. 55-57

Author(s):

Yeltay Rakhmanov ◽

Paolo Enrico Maltese ◽

Alice Bruson ◽

Tommaso Beccari ◽

Munis Dundar ◽

...

Keyword(s):

Risk Assessment ◽

Congenital Heart ◽

Autosomal Dominant ◽

Heart Defects ◽

The Other ◽

Dominant Inheritance ◽

Ebstein Anomaly ◽

Live Births ◽

Downward Displacement ◽

Gene Test

Abstract Ebstein anomaly (EA) is a rare congenital tricuspid valve malformation, characterized by downward displacement of the septal leaflet and an atrialized right ventricle. About 80% of cases of EA are non-syndromic; in the other 20%, the anomaly is associated with a chromosomal or Mendelian syndrome. The prevalence of EA is estimated at about 1 per 20,000 live births, and accounts for less than 1% of all congenital heart defects. EA has autosomal dominant inheritance. Likely causative genes are: NKX2-5, MYH7 and TPM1. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, potential risk assessment and access to clinical trials.

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Management of Cerebral Cavernous Malformations: From Diagnosis to Treatment

The Scientific World JOURNAL ◽

10.1155/2015/808314 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 32

Author(s):

Nikolaos Mouchtouris ◽

Nohra Chalouhi ◽

Ameet Chitale ◽

Robert M. Starke ◽

Stavropoula I. Tjoumakaris ◽

...

Keyword(s):

Clinical Presentation ◽

Vascular Malformations ◽

Imaging Techniques ◽

Neurological Deficits ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Microsurgical Resection ◽

Different Characteristics ◽

The Brain ◽

Methods Of Treatment

Cerebral cavernous malformations are the most common vascular malformations and can be found in many locations in the brain. If left untreated, cavernomas may lead to intracerebral hemorrhage, seizures, focal neurological deficits, or headaches. As they are angiographically occult, their diagnosis relies on various MR imaging techniques, which detect different characteristics of the lesions as well as aiding in planning the surgical treatment. The clinical presentation and the location of the lesion are the most important factors involved in determining the optimal course of treatment of cavernomas. We concisely review the literature and discuss the advantages and limitations of each of the three available methods of treatment—microsurgical resection, stereotactic radiosurgery, and conservative management—depending on the lesion characteristics.

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Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures

Scientific Reports ◽

10.1038/s41598-019-54845-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Santhilal Subhash ◽

Norman Kalmbach ◽

Florian Wegner ◽

Susanne Petri ◽

Torsten Glomb ◽

...

Keyword(s):

Noncoding Rna ◽

Vascular Malformations ◽

Cerebrovascular Disorders ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

Low Flow ◽

Pcr Analysis ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Non Coding Rnas

AbstractCerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.

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Aeromedical Implications of Cerebral Cavernomas

Aerospace Medicine and Human Performance ◽

10.3357/amhp.5747.2021 ◽

2021 ◽

Vol 92 (2) ◽

pp. 120-123

Author(s):

Tania Jagathesan ◽

Michael OBrien

Keyword(s):

Clinical Presentation ◽

Clinical Symptoms ◽

Civil Aviation ◽

Complication Rates ◽

Cerebral Cavernous Malformations ◽

Cavernous Malformations ◽

Medical Certification ◽

The Uk ◽

Age Range ◽

The Brain

BACKGROUND: Cavernomas, cavernous angiomas, or cerebral cavernous malformations are clusters of endothelium-lined blood vessels usually found in the brain. With the increasing use of radiological imaging, these are being detected incidentally in asymptomatic aircrew. The UK Civil Aviation Authority (CAA) experience of cavernomas is described and the aeromedical concerns, that is, the risk of epilepsy, hemorrhage, and the development of a neurological deficit, are considered.METHODS: A search of the CAA database between 1990 and 2020 was performed for the term cavernoma. The gender, age at diagnosis, class of certification held, clinical presentation, location, and size of the lesion were noted. A PubMed literature review for papers with complications of cavernoma was performed.RESULTS: Six cases of cavernoma have been declared to the CAA: five professional pilots and one private pilot. Five were men and one was a woman. The age range was between 38 and 60 yr, with a mean of 48 yr. Two cases presented with clinical symptoms and four were asymptomatic. Complication rates for seizure and hemorrhage were extracted from the published literature together with the significance of other factors such as cavernoma size, family history, multiplicity, and the development of new lesions.DISCUSSION: A policy for the medical certification of aircrew with cavernomas that have presented with clinical symptoms and those that are detected incidentally is proposed.Jagathesan T, OBrien M. Aeromedical implications of cerebral cavernomas. Aerosp Med Hum Perform. 2021; 92(2):120123.

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Mural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314586 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2171-2186

Author(s):

Kang Wang ◽

Haifeng Zhang ◽

Yun He ◽

Quan Jiang ◽

Yoshiaki Tanaka ◽

...

Keyword(s):

Endothelial Cell ◽

Adhesion Formation ◽

Single Layer ◽

Cerebral Cavernous Malformations ◽

Mural Cell ◽

Cavernous Malformations ◽

Mural Cells ◽

Brain Pericytes ◽

The Brain ◽

Specific Deletion

Objective: Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in brain mural cell in CCM pathogenesis. Approach and Results: SM22α -Cre was used to drive a specific deletion of Ccm3 in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific CCM3 deletion models. Mechanistically, CCM3 loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-β1 (integrin β1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes. Conclusions: Our data demonstrate for the first time that deletion of a CCM gene in the brain mural cell induces CCM pathogenesis.

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Regional parenchymal enhancement with mixed cavernous/venous malformations of the brain

Journal of Neurosurgery ◽

10.3171/jns.1997.86.1.0154 ◽

1997 ◽

Vol 86 (1) ◽

pp. 154-158 ◽

Cited By ~ 30

Author(s):

Christopher H. Comey ◽

Douglas Kondziolka ◽

Howard Yonas

Keyword(s):

Clinical Symptoms ◽

Vascular Malformations ◽

Venous Hypertension ◽

Venous Malformations ◽

True Nature ◽

Cavernous Malformations ◽

Content Type ◽

Growth Factor Release ◽

The Brain ◽

Parenchymal Enhancement

✓ With improvements in imaging technology, the detection of both cavernous malformations and venous malformations has increased markedly in recent years. Although much has been learned about the association of cavernous and venous malformations, important questions regarding the true nature of such a relationship remain unanswered. It has been proposed that certain venous malformations produce local venous hypertension with resultant microhemorrhage, growth factor release, and creation of cavernous malformations. The authors report on two patients with cerebellopontine venous malformations associated with cavernous malformations. Both patients demonstrated persistent regional parenchymal enhancement associated with the vascular malformations. In addition, both patients had significant clinical symptoms referable to the region of affected brain. This previously undescribed finding may represent an imaging correlate to the complex interaction among venous malformations, venous hypertension, and cavernous malformations.

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Are cavernous sinus hemangiomas and cavernous malformations different entities?

Neurosurgical FOCUS ◽

10.3171/foc.2006.21.1.7 ◽

2006 ◽

Vol 21 (1) ◽

pp. 1-5 ◽

Cited By ~ 42

Author(s):

L. Fernando Gonzalez ◽

Gregory P. Lekovic ◽

Jennifer Eschbacher ◽

Stephen Coons ◽

Randall W. Porter ◽

...

Keyword(s):

Cavernous Sinus ◽

Cavernous Malformation ◽

Vascular Malformations ◽

Response To Treatment ◽

Vascular Tumors ◽

Cerebral Cavernous Malformations ◽

Imaging Studies ◽

Cavernous Malformations ◽

Cavernous Hemangiomas

✓Cavernous hemangiomas that occur within the cavernous sinus (CS) are different from cerebral cavernous malformations (CMs) clinically, on imaging studies, and in their response to treatment. Moreover, CMs are true vascular malformations, whereas hemangiomas are benign vascular tumors. Because of these differences, the authors suggest that these two entities be analyzed and grouped separately. Unfortunately, despite these differences, much confusion exists in the literature as to the nature, behavior, and classification of these two distinct lesions. This confusion is exacerbated by subtle histological differences and the inconsistent use of nomenclature. The authors use the term “cavernous malformation” to refer to intraaxial lesions only; they prefer to use the term “cavernous sinus hemangioma” to refer to extraaxial, intradural hemangiomas of the CS.

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