Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly ...stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22α promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation. Transgenic mice showed no evidence of prominent brain parenchyma damage but demonstrated the two hallmarks of the CADASIL angiopathy, GOM deposits and Notch3 accumulation, within both the cerebral and peripheral arteries. Of interest, arteries of the tail were more severely affected with prominent signs of VSMC degeneration. Time-course analysis of vessel changes revealed that disruption of normal VSMC anchorage to adjacent extracellular matrix and cells, VSMC cytoskeleton changes as well as starting signs of VSMC degeneration, which were detected around 10 months of age, preceded Notch3 and GOM accumulation appearance, which were observed only by 14 to 16 months of age. In conclusion, we have generated transgenic mice that recapitulate the characteristic vascular lesions observed in CADASIL. Our results indicate that Notch3 or GOM accumulation are unlikely to be the prerequisites for the induction of VSMC degeneration and suggest that degeneration of VSMCs may rather be triggered by the disruption of their normal anchorage, based on the important role of adhesion for cell survival.
We recently showed that the severity of MRI signal abnormalities increases with age in CADASIL, an arteriopathy due to mutations of notch 3 gene on chromosome 19. Previous results also suggest that ...the various hemispheric subcortical areas have a different vulnerability to ischemia in this disease. The distribution of the lesions at the brain stem level has not yet been reported.
We reviewed the MRIs of 68 affected patients having signal abnormalities in the hemispheric white matter to assess the distribution and clinical consequences of brain stem signal abnormalities in CADASIL. We found hypersignals on T2-weighted images in the brain stem in 45% of the subjects. The pons was more frequently involved (100%) than the mesencephalon (69%) and the medulla (35%). Hyposignals on T1-weighted images, at the brain stem level, were observed only in two thirds of these subjects. The lack of signal abnormalities reaching the brain stem surface and the absence of cerebellar lesions were noteworthy.
Brain stem signal abnormalities observed in CADASIL are found in regions irrigated only by perforating arteries. These results support parallel observations made for CADASIL-associated signal abnormalities in the cerebral hemispheres and emphasize the importance of the angioarchitecture of the cerebral vasculature to explain why a condition characterized by a systemic vessel wall pathology is manifested only as a brain disease.
Genetic syndromes that mimic congenital infections must be recognized because of the associated risk of recurrence. We describe a male infant who was born with the association of intra-uterine growth ...retardation, microcephaly, intracranial calcifications, white matter abnormalities, microphtalmy, bilateral cataract, and hearing loss. Congenital cytomegalovirus (CMV) infection was suspected, but serologic CMV markers were not decisive (IgG+/IgM-). His half-sister (same father) presented a similar phenotype. Therefore, the diagnosis of congenital CMV infection was questioned and a genetic hypothesis was suggested. In 1983, Baraitser et al. first described two brothers with microcephaly and intracranial calcifications and negative TORCH analysis. Later, a number of authors reported children in whom detailed investigation failed to objectively confirm an intra-uterine infective agent. Clinical features include severe postnatal microcephaly, seizures, and pronounced developmental arrest. These cases have been considered to define a distinct autosomal recessive disorder first named pseudo-Torch syndrome. The family described herein is different from the cases previously described with a suspected autosomal dominant inheritance, severe ophtalmological abnormalities, and unusual brain imaging.
Several homologs of theDrosophila
Notch receptor and its ligands, Delta/Serrate, have been cloned in man. Three human disorders including a neoplasia (a T-cell acute lymphoblastic leukemia/lymphoma), ...a late onset neurological disease (CADASIL) and a developmental disorder (the Alagille syndrome) are associated with mutations in, respectively, theNotch1, Notch3
andJagged1
genes, pointing out the broad spectrum of Notch activity in humans. We report herein on what has been learned on the role of these humanNotch
genes and the mechanisms leading from mutations in those genes to the observed phenotypes.
New Players in the Genetics of Stroke Tournier-Lasserve, Elisabeth
The New England journal of medicine,
11/2002, Letnik:
347, Številka:
21
Journal Article
Recenzirano
Stroke is the second leading cause of death and the most common cause of disability in the world. Its incidence is rising with increasing life expectancy. To relieve the heavy burden of stroke, we ...need to understand the mechanisms that will form the basis of improved prevention and treatment. Ischemic or hemorrhagic stroke is the outcome of a number of different pathophysiological mechanisms, which include cardioembolism, prothrombotic states, and disease of large and small cerebral vessels. Epidemiologic studies involving twins, siblings, or families have found evidence of a genetic influence on stroke. From the clinical point of view, it is . . .
OBJECTIVES To characterise clinically a large French family affected with cerebral cavernomas and to check for linkage of this condition to chromosome 7. METHODS A family, originating from Normandy ...and in which five members had undergone surgery for cavernomas, was extended. All members older than 18 were studied clinically and by neuroimaging. Genetic linkage analysis was conducted using 11 polymorphic microsatellite markers located between D7S502 and D7S479. RESULTS The family included three generations. Among the 25 members investigated, 11 had an abnormal cerebral MRI, eight of them being symptomatic, and 12 were asymptomatic with a normal MRI. The status of the two remaining members could not be established on the basis of clinical and MRI data. The family reported shares some striking features with other previously linked families—namely, a high clinical penetrance and the presence of multiple lesions within most of the affected members. A lod score of 4.04 was obtained with marker D7S657 with no recombinant. Significant lod scores were also obtained with D7S524 (Zmax=3.32 at θ=0.00) and D7S630 (Zmax=3.44 at θ=0.00). These results establish linkage of the condition found in this family to chromosome 7. Haplotype analysis strongly suggests that the gene is telomeric to D7S802 and centromeric to D7S479. CONCLUSIONS These data confirm linkage of cerebral cavernous malformations to chromosome 7 in a non-Hispanic family.
Cavernous angiomas are vascular malformations mostly located in the central nervous system and characterized by enlarged capillary cavities without intervening brain parenchyma. Clinical symptoms ...include seizures, haemorrhage and focal neurological deficits. Cavernous angiomas prevalence is close to 0.5% in the general population. They may be inherited as an autosomal dominant condition in as much as 50% of cases. Cerebral cavernous malformations (CCM) loci were previously identified on 7q, 7p and 3q (refs 4,5). A strong founder effect was observed in the Hispano-American population, all families being linked to CCM1 on 7q (refs 4,7). CCM1 locus assignment was refined to a 4-cM interval bracketed by D7S2410 and D7S689 (ref. 8). Here we report a physical and transcriptional map of this interval and that CCM1, a gene whose protein product, KRIT1, interacts with RAP1A (also known as KREV1; ref. 9), a member of the RAS family of GTPases, is mutated in CCM1 families. Our data suggest the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis.
Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being ...characterized by the presence of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers. Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom‐free. Mean age at clinical onset was 29.7 years (range, 2–72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (±7.2) and on gradient echo sequences 19.8 (±33.2). Twenty‐six mutation carriers harbored only one lesion on T2‐weighted MRI, including 4 mutation carriers, aged from 18 to 55 yr‐old, who presented only one CCM lesion both on T2‐weighted and on highly sensitive gradient echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr‐old, did not have any detectable lesion both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation carriers aged 50 or more are symptom‐free. The presence of only one lesion, even when using gradient echo MRI sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be overlooked in some mutation carriers presenting as sporadic cases with a unique lesion. Ann Neurol 2004
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of ...presentation. The defective gene in CADASIL is
Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the NotchS domains involved in CADASIL, we undertook mutations analysis in this gene in a group of CADASIL patients.
50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire
Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis.
Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients. Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to loss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls.
Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, an easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of NotchS, due to abnormal disulphide bridging with another NotchS molecule or with another protein, may be involved in the pathogenesis of this disorder.
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