Transgenic Mice Expressing Mutant Notch3 Develop Vascular Alterations Characteristic of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Mm, Ruchoux; Domenga, Valérie; Brulin, Peggy; Maciazek, Jacqueline; Limol, Sylvie; Tournier‐Lasserve, Elisabeth; Joutel, Anne

doi:10.1016/s0002-9440(10)63824-2

Cited by 198 publications

(204 citation statements)

References 32 publications

(27 reference statements)

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“…Endothelium-dependent vasodilation is impaired in resistance arteries (not conductive ones) in the forearm of patients 18 . Transgenic mice expressing mutant Notch 3 develop CADASIL typical vascular alterations 19 . These mice exhibit altered autoregulation of cerebral blood flow (CBF): the mutation appears to reduce the relaxation ability or to increase vascular resistance of resistance vessels 20 .…”

Section: Genetics and Pathogenesismentioning

confidence: 99%

CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic cause of ischemic strokes and a most important model for the study of subcortical vascular dementia. This unrelentlessly progressive disease affects many hundreds of families all over the world but is not well studied in Brazil. This manuscript reviews pathogenetic, clinical, radiological and therapeutic features of CADASIL. The causal mutations are now very well known, but the same can not be said about its intimate pathogenetic mechanisms. The variable clinical presentation should lead physicians to actively pursue the diagnosis in many settings and to more thouroughly investigate family history in first degree relatives. A rational approach to genetic testing is however needed. Treatment of CADASIL is still largely empiric. Highquality therapeutic studies involving medications and cognitive interventions are strongly needed in CADASIL. Key words: CADASIL, etiology, genetics, diagnosis, therapeutics.cADAsIL: patogênese, achados clínicos e radiológicos e tratamento resumo CADASIL é a causa genética mais freqüente de infartos cerebrais e constitui modelo importante de estudo de demências vasculares subcorticais. De natureza inexoravelmente progressiva, afeta milhares de pessoas em todo o mundo. Sua importância é pouco reconhecida entre nós, o que nos levou à presente revisão dos principais aspectos patogenéticos, clínicos, neuroradiológicos e terapêuticos da doença. As mutações causais são hoje bem conhecidas, mas os mecanismos patogenéticos íntimos ainda permanecem misteriosos. A apresentação clínica variável deve fazer com que os médicos considerem o diagnóstico em vários contextos clínicos e investiguem de forma mais extensa que o usual a história familial deparentes de primeiro grau. Além disso, uma abordagem racional é necessária para reduzir custos e aumentar a eficiência do diagnóstico genético. O tratamento atual de pacientes com CADASIL é basicamente empírico. Estudos clínicos sobre medicamentos e intervenções cognitivas de alto nível metodológico constituem uma necessidade urgente.

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Section: Genetics and Pathogenesismentioning

confidence: 99%

CADASIL: pathogenesis, clinical and radiological findings and treatment

André

2010

Arq. Neuro-Psiquiatr.

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“…In an attempt to clarify the mechanism of VSMC degeneration, Ruchoux et al (2003) developed a transgenic mouse that expresses the mutant R90C form of human Notch3 protein in VSMC and is associated with typical CADASIL lesions. This mouse expressing the mutant form of Notch3 at a very low level is more similar to the normal adult human tissues than to the previously used transfected cell lines (Karlström et al, 2002).…”

Section: Animal Models In Cadasilmentioning

confidence: 99%

“…These changes, evident in CADASIL patients, were attributed to loss of VSMC (Brulin et al, 2002). Since the survival of certain cell types depends on adhesion to the ECM and that destruction of appropriate cell-cell and cell-matrix contacts may cause cell death in vivo and in vitro (Frisch and Francis, 1994;McGill et al, 1997;Ding et al, 2000), it is possible that destruction of normal VSMC anchorages is a key event leading to degeneration of VSMC in CADASIL (Ruchoux et al, 2003).…”

Section: Animal Models In Cadasilmentioning

confidence: 99%

Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will sumarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

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“…Definitive diagnosis is confirmed in patients with clinical and radiological features by the finding of mutations in the notch-3 gene, located on chromosome 19p13.1 (4,5). At the molecular level, strongly stereotyped mutations in repetitive EGF-like domains in the extracellular portion of the trans-membrane notch-3 protein are observed (5,6). All these mutations result in the loss or gain of a cysteine residue, which suggests that the disease could result from abnormal disulphide bridge formation in the secondary or tertiary structure of the proteins.…”

Section: Discussionmentioning

confidence: 99%

Anesthetic Management and Postoperative Care of a Patient with CADASIL (Cerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and leukoencephalopathy) for Cesarean Section

Rasooli¹,

Moslemi²,

Tagavi³

2014

IJWHR

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Case descriptionWe describe the anesthetic management and postoperative care of a 36 years old pregnant woman with CADASIL disease who needed urgent cesarean section. According to her past medical history, she was already diagnosed as CADASIL syndrome 3 years ago. Her medical history included left hemi lateral paresis, accompanied by walking difficulties, urinary incontinence, psychiatric symptoms, apathy, diabetes mellitus, hypertension, and ovarian cyst. CADASIL diseases, was diagnosed after a hemi paretic attack when she was 32 years old. As a consequence of headache, was followed by neurologic symptoms. After admission to hospital, the clinical and neurological examination, MRI and CT-scan, and by genetic examinations, CADASIL disease was diagnosed. She got one dilatation and curettage due to a missed abortion pregnancy under sedation, 2 years ago at a primary care clinic. Now, her symptoms associated with CADASIL were intermittent headache and left hemi lateral paresis, and hypertension. She was taking methyldopa and aspirin (80 mg daily). Her diabetes was controlled by Insulin during pregnancy. She admitted to the Alzahra hospital due to hypertension one day ago. She received 5mg hydralazine and stopped aspirin. On preoperative evaluation, there were no abnormalities in laboratory tests and radiologic evaluations except slightly elevated U/A protein 1+. Her brain CT was checked two months ago revealed the confluent low densities at the subcortical and deep white matter of both cerebral hemispheres and several small old infarctions in both basal ganglia and thalami. But the neurologist who examined the patient after admission judged her still neurologically normal.Because of recent aspirin medication, we decided to conduct general anesthesia with informed consent. After premedication with ranitidine 50 mg and metoclopramide 10 mg IV, the patient was taken to the operating room. With standard monitoring (ECG, pulse oximetry, noninvasive blood pressure, and capnography) and preoxygenation, a rapid sequence induction with cricoid pressure using fentanyl, thiopental, and succinylcholine was carried out. For intubation used a cuffed 7.0 mm ETT. Neuromuscular block was achieved with atracurium, and anesthesia was maintained by controlled ventilation with an oxygen/N2O 50%/50% and isoflurane 1% mixture. With recommendations concerning the anaesthetic management of patients with CADASIL arteriopathy, we kept mean arterial blood pressure greater than 60 mm Hg and end-tidal carbon dioxide around 40 mm Hg so as to prevent any cerebral ischemic or vasospastic phenomenon. Patient's blood sugar within the perioperative was in the normal range. Moreover, the cerebral venous return was preserved by the patient received 8 ml/kg of ringer's solution in the left lateral position. The condition of neonate was assessed by apgar score at 1 st and 5 th after delivery who was 8 and 9 respectively. Mother received oxytocin 5 IU by continues infusion after delivery. Surgery and recovery were uneventful. The neurological examination ...

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Transgenic Mice Expressing Mutant Notch3 Develop Vascular Alterations Characteristic of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Cited by 198 publications

References 32 publications

CADASIL: pathogenesis, clinical and radiological findings and treatment

CADASIL: pathogenesis, clinical and radiological findings and treatment

Physiology and pathology of notch signalling system

Anesthetic Management and Postoperative Care of a Patient with CADASIL (Cerebral Arteriopathy, Autosomal Dominant, with Subcortical Infarcts and leukoencephalopathy) for Cesarean Section

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