Identification of LDLR mutation in cerebral venous sinus thrombosis co-existing with dural arteriovenous fistulas: a case report.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is typically associated with a prothrombotic state of the blood, with its causative factors varying widely. Prior research has not reported the simultaneous occurrence of CVST and dural arteriovenous fistulas (DAVFs) as potentially resulting from genetic mutations. In this case report, we introduce a unique occurrence wherein a patient with a heterozygous mutation of the low-density lipoprotein receptor (LDLR) gene presented with CVST in conjunction with DAVFs. CASE: Presentation: A male patient, aged 51, sought treatment at our facility due to a consistent decline in cognitive functions accompanied by recurrent headaches. Comprehensive evaluations were administered, including neurological examinations, laboratory tests, magnetic resonance imaging, digital subtraction angiography, and whole exome sequencing. Digital subtraction angiography identified DAVFs in the patient's right sigmoid sinus and an occlusion within the left transverse sinus. The whole exome sequencing of blood samples pinpointed a heterozygous mutation in the LDLR gene (NM_000527:exon12:c.C1747T:p.H583Y). Following the confirmed diagnosis of CVST and DAVFs, the patient underwent anticoagulant therapy combined with endovascular procedures - these comprised embolization of the arteriovenous fistula in the right sigmoid sinus and balloon dilation with stent implantation in the left transverse sinus. A six-month follow-up indicated a significant abatement in the patient's symptoms. CONCLUSIONS: This report marks the first documented case of an LDLR gene mutation that could be associated with the onset of CVST and DAVFs. The mutation in the LDLR gene might foster a prothrombotic environment, facilitating the gradual emergence of CVST and the subsequent genesis of DAVFs.

Angioarchitecture and genetic variants of spinal cord cavernous malformations and associated developmental venous anomalies: a case report.

Cavernous malformations (CM) have long been considered congenital of central nervous system, while the mechanism of CMs detailed development process associated with genetic factors remains unclear. We reported an uncommon case which suffered spinal cord cavernous malformations. In this work, representative samples were obtained, and the sequenced results were described for the first time. A 9-year-old boy was found oblique shoulder with slightly weakness of left limbs; MRI indicated spinal cord cavernous malformations (CMs) located at the C4-C6 vertebral level. On genetic analysis, a shared mutation of PIK3CA (p.H1047R) in CMs and associated developmental venous anomalies (DVAs) was detected, with a different abundance (2% and 7%, respectively), and a somatic mutation of MAP3K3 (p.I441M) was detected in the CM tissue samples. This case provides better knowledge of the formation history and genetic triggers of the DVA-associated CMs. This evidence allows us to speculate the developmental history of the CM lesion: The DVA with PIK3CA mutation might be genetic precursor, and then the associated CM could be derived from terminal cell population of the DVA by acquiring a somatic mutation in MAP3K3.

Cerebrovascular Anomalies: Perspectives From Immunology and Cerebrospinal Fluid Flow.

Appropriate vascular function is essential for the maintenance of central nervous system homeostasis and is achieved through virtue of the blood-brain barrier; a specialized structure consisting of endothelial, mural, and astrocytic interactions. While appropriate blood-brain barrier function is typically achieved, the central nervous system vasculature is not infallible and cerebrovascular anomalies, a collective terminology for diverse vascular lesions, are present in meningeal and cerebral vasculature supplying and draining the brain. These conditions, including aneurysmal formation and rupture, arteriovenous malformations, dural arteriovenous fistulas, and cerebral cavernous malformations, and their associated neurological sequelae, are typically managed with neurosurgical or pharmacological approaches. However, increasing evidence implicates interacting roles for inflammatory responses and disrupted central nervous system fluid flow with respect to vascular perturbations. Here, we discuss cerebrovascular anomalies from an immunologic angle and fluid flow perspective. We describe immune contributions, both common and distinct, to the formation and progression of diverse cerebrovascular anomalies. Next, we summarize how cerebrovascular anomalies precipitate diverse neurological sequelae, including seizures, hydrocephalus, and cognitive effects and possible contributions through the recently identified lymphatic and glymphatic systems. Finally, we speculate on and provide testable hypotheses for novel nonsurgical therapeutic approaches for alleviating neurological impairments arising from cerebrovascular anomalies, with a particular emphasis on the normalization of fluid flow and alleviation of inflammation through manipulations of the lymphatic and glymphatic central nervous system clearance pathways.

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

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.

Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier.

Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler syndrome by inactivating Flvcr2 in mice. We showed that Flvcr2 was necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood-brain barrier. Endothelial cells lacking Flvcr2 had altered expression of angiogenic factors, failed to adopt tip cell properties, and displayed reduced sprouting, leading to vascular malformations similar to those seen in humans with Fowler syndrome. Brain hypovascularization was associated with hypoxia and tissue infarction, ultimately causing hydrocephalus and death of mutant animals. Strikingly, despite severe vascular anomalies and brain tissue infarction, the blood-brain barrier was maintained in Flvcr2 mutant mice. Our Fowler syndrome model therefore defined the pathobiology of this disease and provided new insights into brain angiogenesis by showing uncoupling of vessel morphogenesis and blood-brain barrier formation.

Internal Carotid Artery Aplasia in a Patient With Nail-Patella Syndrome.

Nail-patella syndrome (NPS) is a rare disorder characterized by abnormal development of ectodermal and mesodermal tissues. Classically, NPS presents as a triad of nail dysplasia, dysplastic patellae, and bony exostoses of the ilia known as "iliac horns." Apart from dermatological and skeletal abnormalities, patients may also have involvement of ophthalmologic and renal systems. The underlying molecular etiology in NPS is the mutation of LMX1B homeobox gene which results in loss of function of its protein also called LMX1B, a DNA-binding protein belonging to the larger LIM-homeodomain transcription factor family. Normal LMX1B gene and protein function are essential for dorsalization of the vertebrate limb bud, development of anterior eye structures, skull formation, and differentiation and migration of neurons in the central nervous system. We report a case of confirmed NPS presenting with congenital aplasia of the internal carotid artery and believe this is the first report of cerebrovascular developmental abnormality associated with NPS.

Fetal and neonatal neurogenetics.

Disorders of the developing nervous system may be of genetic origin, comprising congenital malformations of spine and brain as well as metabolic or vascular disorders that affect normal brain development. Acquired causes include congenital infections, hypoxic-ischemic or traumatic brain injury, and a number of rare neoplasms. This chapter focuses on the clinical presentation and workup of neurogenetic disorders presenting in the fetal or neonatal period. After a summary of the most frequent clinical presentations, clues from history taking and clinical examination are illustrated with short case reports. This is followed by a discussion of the different tools available for the workup of neurogenetic disorders, including the various genetic techniques with their advantages and disadvantages. The implications of a molecular genetic diagnosis for the patient and family are addressed in the section on counseling. The chapter concludes with a proposed workflow that may help the clinician when confronted with a potential neurogenetic disorder in the fetal or neonatal period.

Polymorphism in dural arteriovenous fistula: matrix metalloproteinase-2-1306 C/T as a potential risk factor for sinus thrombosis.

Essentials Sinus thrombosis may play a crucial role in development of dural arteriovenous fistula (DAVF). Little is known about the association between gene polymorphism and the development of DAVF. MMP-2-1306 C/T showed a higher prevalence rate in DAVF cases with sinus thrombosis. MMP-2-1306C/T polymorphism is likely a potential risk factor for sinus thrombosis in DAVF. SUMMARY: Background Dural arteriovenous fistula (DAVF) is a rare but important cerebrovascular disorder in adults. Little is known about the molecular genetic pathogenesis underlying DAVF development. Objectives To investigate the associations of gene polymorphisms and DAVF. Materials and Methods By the use of real-time PCR genotyping, seven single-nucleotide polymorphisms (SNPs) of angiogenesis-related genes were analyzed in 72 DAVF patients. Pertinent clinical and imaging data were subgrouped on the basis of location (cavernous sinus versus lateral sinus), lesions (single versus multiple), cerebral venous reflux (CVR) grading (Borden I versus Borden II/III), and sinus thrombosis (with versus without). Results We found that individuals carrying the polymorphic allele of matrix metalloproteinase (MMP)-2-1306 C/T (rs243865) had a significantly increased risk of sinus thrombosis in DAVF (odds ratio 6.2; 95% confidence interval 1.7-22.9). There was a weak difference in associations of tissue inhibitor of metalloproteinase (TIMP)-2 (rs2277698) gene polymorphism and DAVF patients subgrouped by CVR grading. Conclusions These preliminary results indicate that MMP-2-1306 C/T, but not MMP-9, TIMP-1, TIMP-2, and vascular endothelial growth factor A SNP variants, is a risk factor for the development of sinus thrombosis in DAVF patients.

Diagnóstico molecular de cavernomatosis cerebral / Molecular diagnosis in cerebral cavernous malformations

Introducción: Las malformaciones cavernosas cerebrales (CCM; OMIM 116860) son engrosamientos cavernosos vasculares sin intervención del parénquima cerebral con una prevalencia estimada en la población general del 0,1-0,5%. La cavernomatosis cerebral presenta un patrón de herencia autosómico dominante con penetrancia clínica y radiológica incompleta. Tres genes se han asociado al desarrollo de lesiones: CCM1/KRIT1, CCM2/MGC4607 y CCM3/PDCD10. Desarrollo: La mutación responsable no es detectada en un alto porcentaje de casos, por lo que nuevos enfoques son necesarios para su detección. En esta revisión se analizan las técnicas actualmente utilizadas y las posibles mutaciones o variantes que pueden ser detectadas en un laboratorio de genética molecular o biología molecular. Asimismo, se analizan alternativas que pueden ser abarcadas para la detección de mutaciones en aquellos pacientes en los que los estudios hayan resultado negativos. Conclusiones: El diagnóstico molecular de la cavernomatosis cerebral debe incluir al menos la detección del número de copias y la secuenciación de los genes CCM. Finalmente, ofrecer un adecuado consejo genético es crucial para proporcionar información y apoyo a los pacientes y familias que padecen la enfermedad (AU)

Introduction: Cerebral cavernous malformations (CCMs; OMIM 116860) are enlarged vascular cavities without intervening brain parenchyma whose estimated prevalence in the general population is between 0.1% and 0.5%. Familial CCM is an autosomal dominant disease with incomplete clinical and radiological penetrance. Three genes have been linked to development of the lesions: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. Development: : The aetiological mutation is not detected in a large percentage of cases and new approaches are therefore needed. The aim of this review is to analyse current molecular techniques and the possible mutations or variations which can be detected in a molecular genetics or molecular biology laboratory. Likewise, we will analyse other alternatives that may help detect mutations in those patients showing negative results. Conclusions: A molecular diagnosis of cerebral cavernous malformations should provide at least the copy number variation and sequencing of CCM genes. In addition, appropriate genetic counselling is a crucial source of information and support for patients and their relatives (AU)

Identification of a Novel Deletion Mutation (c.1780delG) and a Novel Splice-Site Mutation (c.1412-1G>A) in the CCM1/KRIT1 Gene Associated with Familial Cerebral Cavernous Malformation in the Chinese Population.

Cerebral cavernous malformation (CCM) is a congenital vascular anomaly predominantly located within the central nervous system. Its familial forms (familial cerebral cavernous malformation (FCCM)), inherited in an autosomal dominant manner with incomplete penetrance, are attributed to mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes. To date, little is known about the genetic alterations leading to FCCM in the Chinese population. We aimed to investigate the genetic defect of FCCM by DNA sequencing in Chinese families. This study enrolled five Chinese families with FCCM. All index cases underwent surgical treatment and were diagnosed with CCM by pathology; their relatives were diagnosed based on radiological and/or pathological evidence. Genomic DNA was extracted from peripheral blood and amplified using polymerase chain reaction (PCR) for DNA sequencing. The five families comprised a total of 21 affected individuals: 12 of these were symptomatic, and 9 were asymptomatic. Sequence analyses in the index patients disclosed three heterozygous loss-of-function mutations in the CCM1/KRIT1 gene in three families, respectively: a novel deletion mutation (c.1780delG; p.Ala594HisfsX67) in exon 16, a novel splice-site mutation (c.1412-1G>A) in the splice acceptor site in intron 13, and a previously described 4-bp deletion (c.1197_1200delCAAA; p.Gln401ThrfsX10) in exon 12. All of these mutations are predicted to cause a premature termination codon to generate a truncated Krev interaction trapped 1 (Krit1) protein. These mutations segregated in affected relatives. Our findings provided new CCM1 gene mutation profiles, which help to elucidate the pathogenesis of FCCM and will be of great significance in genetic counseling.

ARL6IP6, a susceptibility locus for ischemic stroke, is mutated in a patient with syndromic Cutis Marmorata Telangiectatica Congenita.

Cutis Marmorata Telangiectatica Congenita (CMTC) is a congenital localized or generalized vascular anomaly, usually sporadic in occurrence. It can be associated with other cutaneous or systemic manifestations. About 300 cases have been reported. The molecular etiology remains largely unknown. The main purpose of this study is to delineate the molecular basis for a syndromic CMTC phenotype in a consanguineous Saudi family. Clinical phenotyping including detailed neurological imaging, followed by autozygosity mapping and trio whole exome sequencing (WES) are also studied. We have identified a homozygous truncating mutation in ARL6IP6 as the likely cause of a syndromic form of CMTC associated with major dysmorphism, developmental delay, transient ischemic attacks and cerebral vascular malformations. This gene was previously implicated by genome wide association study (GWAS) as a susceptibility locus to ischemic stroke in young adults. We identify ARL6IP6 as a novel candidate gene for a syndromic form of CMTC. This suggests that ischemic stroke or transient ischemic attacks (TIA) may represent, at least in some cases, the mild end of a phenotypic spectrum that has at its severe end autosomal recessive CMTC. This finding contributes to a growing appreciation of the continuum of Mendelian and common complex diseases.

Langer-Giedion syndrome associated with congenital dural arterio-venous fistula.

Langer-Giedion syndrome (LGS) is a rare disease caused by deletion of chromosome 8q23.3-q24.11. Clinical manifestations include among others multiple exostoses, short stature, intellectual disability, and typical facial dysmorphism. Dural arterio-venous shunts (DAVS) in the pediatric age are rare lesions, which have been classified into three types: dural sinus malformations (DSM), infantile type DAVS (IDAVS), and adult type DAVS (ADAVS). We report a case of a patient with a known LGS who was diagnosed with complex intracranial dural AV fistula at the age of 20. An association between LGS and intracranial dural AV fistulas has to our knowledge never been reported before.

De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation.

BACKGROUND AND PURPOSE: In humans, activin receptor-like kinase 1 (Alk1) deficiency causes arteriovenous malformations (AVMs) in multiple organs, including the brain. Focal Alk1 pan-cellular deletion plus vascular endothelial growth factor stimulation induces brain AVMs in the adult mouse. We hypothesized that deletion of Alk1 in endothelial cell (EC) alone plus focal vascular endothelial growth factor stimulation is sufficient to induce brain AVM in the adult mouse. METHODS: Focal angiogenesis was induced in the brain of 8-week-old Pdgfb-iCreER;Alk1(2f/2f) mice by injection of adeno-associated viral vectors expressing vascular endothelial growth factor. Two weeks later, EC-Alk1 deletion was induced by tamoxifen treatment. Vascular morphology was analyzed, and EC proliferation and dysplasia index (number of vessels with diameter>15 µm per 200 vessels) were quantified 10 days after tamoxifen administration. RESULTS: Tangles of enlarged vessels resembling AVMs were present in the brain angiogenic region of tamoxifen-treated Pdgfb-iCreER;Alk1(2f/2f) mice. Induced brain AVMs were marked by increased dysplasia index (P<0.001) and EC proliferation clustered within the dysplastic vessels. AVMs were also detected around the ear tag-wound and in other organs. CONCLUSIONS: Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo brain AVM.

[Trilateral retinoblastoma. Correlation between the genetic anomalies of the RB1 gene and the presence of pineal gland cysts]. / Retinoblastoma trilateral. Correlación de las alteraciones genéticas del gen RB1 y la presencia de quistes de la glándula pineal.

OBJETIVE: To determine the correlation between the presence of genetic anomalies identified in the RB1 gene and the development of trilateral retinoblastoma. METHOD: No patients with primitive neuroectodermal tumour (PNET) were identified out of a total of 206 patients, but there were 17 cases of pineal cysts, of which 11 had a genetic study. RESULTS: Of the 11 patients who had a genetic study performed, the anomaly in the germinal line was identified in 8 cases, which was equivalent to 100% of the bilateral retinoblastomas, and 25% of the unilateral ones. It is more common to find a germinal mutation in patients with bilateral disease (P=.024). There are no significant differences in the type of anomaly identified, although the nonsense-frameshift type is more frequent in cases with bilateral involvement. Identification of the genetic anomaly is more frequent in patients who have pineal cysts (Fisher test; P=.490). Nine of the 17 patients received systemic chemotherapy (52.29% of the cases), which could be able to prevent the development of PNET. Although a certain trend was observed in all the mentioned parameters, there was a relationship between, the presence of pineal cysts and bilateral disease (Pearson Chi X2: P=.191), a known family history (Fisher test; P=.114) and age of early diagnosis (Fisher test; P=.114). There were no significant differences in the mutation type identified. CONCLUSIONS: Considering pineal cysts as a pre-malignant form of pinealoblastoma, we found a relationship between the germinal line mutation of the RB1 gene and the cases with bilateral or unilateral retinoblastoma.

Familial intracranial dural arteriovenous fistulas.

BACKGROUND AND IMPORTANCE: Intracranial dural arteriovenous fistulas (DAVFs) are acquired abnormal communications between dural arteries and veins. Risk factors for development include sinus thrombosis and hypercoagulability, such as occurs in heritable thrombophilias. While there have been reports of other types of vascular anomalies (such as cavernous and arteriovenous malformations) occurring in families, to our knowledge there have been no reports of familial intracranial DAVFs. We describe the first 2 cases of intracranial DAVFs occurring in first-degree relatives. CLINICAL PRESENTATION: A 66-year-old woman presented with an 18-month history of bilateral pulsatile tinnitus. Neurological examination was significant for a prominent pulsatile bruit over the left mastoid region. Laboratory studies demonstrated heterozygosity for Prothrombin G20210A mutation. Imaging disclosed a large left Type I Borden DAVF involving the distal transverse-sigmoid sinus junction. She underwent uncomplicated stereotactic radiosurgery to the fistula that led to complete resolution of her tinnitus and the fistula. A 73-year-old woman, the sister of the previous patient, presented with a 24-month history of pulsatile tinnitus affecting the left ear. Laboratory studies demonstrated heterozygosity for the Prothrombin G20210A mutation. Imaging revealed a left Type I Borden DAVF involving the left transverse and sigmoid sinuses. The patient's symptoms resolved spontaneously without treatment. Repeat imaging revealed interval involution of the fistula. CONCLUSION: We describe 2 sisters who were heterozygous for Prothrombin G20210A mutation and found to have DAVFs. Clinicians should be aware of the potential for these fistulas to congregate in first-degree relatives via heritable thrombophilias such as the Prothrombin G20210A mutation.

Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth.

Cardiovascular growth must balance stabilizing signals required to maintain endothelial connections and network integrity with destabilizing signals that enable individual endothelial cells to migrate and proliferate. The cerebral cavernous malformation (CCM) signaling pathway utilizes the adaptor protein CCM2 to strengthen endothelial cell junctions and stabilize vessels. Here we identify a CCM2 paralog, CCM2L, that is expressed selectively in endothelial cells during periods of active cardiovascular growth. CCM2L competitively blocks CCM2-mediated stabilizing signals biochemically, in cultured endothelial cells, and in developing mice. Loss of CCM2L reduces endocardial growth factor expression and impairs tumor growth and wound healing. Our studies identify CCM2L as a molecular mechanism by which endothelial cells coordinately regulate vessel stability and growth during cardiovascular development, as well as postnatal vessel growth.

Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management.

Cerebral cavernous (or capillary-venous) malformations (CCM) have a prevalence of about 0.1-0.5% in the general population. Genes mutated in CCM encode proteins that modulate junction formation between vascular endothelial cells. Mutations lead to the development of abnormal vascular structures.In this article, we review the clinical features, molecular and genetic basis of the disease, and management.