Spanish families with cavernous angiomas do not share the Hispano-American CCM1 haplotype.
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Brain Neoplasms↗
Biomedical subjects
E Tournier-Lasserve
Publications and source records attributed to E Tournier-Lasserve.
Brain stem MRI signal abnormalities in CADASIL.
BACKGROUND: 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. CASE DESCRIPTIONS: 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. CONCLUSIONS: 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.
Brain Stem↗
Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Société Française de Neurochirurgie.
BACKGROUND: Cavernous angiomas, which are vascular malformations mostly located in the central nervous system, may be inherited as an autosomal dominant disorder known as familial cerebral cavernoma (FCC). FCC has been studied in Hispanoamerican families, in which a strong founder effect was shown. We studied the families of 57 non-Hispanic patients with cavernous angiomas. METHODS: All 28 neurosurgery centres in France collaborated in the study. Inclusion criteria were: families of index patients known to have at least one clinically affected relative, and families of index patients with multiple cavernous angiomas who initially presented as sporadic cases. Clinical and cerebral magnetic resonance imaging (MRI) investigations were done in all patients and in other at-risk individuals who consented to take part. FINDINGS: On MRI, 16 of 22 sporadic index patients had relatives with cavernous angiomas. 51 multiple-case families, including 100 patients with symptoms and 164 symptom-free individuals had MRI lesions. Most FCC patients had multiple lesions and there was a strong correlation between number of lesions and age (p<0.01). The sensitivity of gradient-echo sequences was higher than that of standard MRI for detection of small cavernous angiomas. Pattern of inheritance was autosomal dominant, with incomplete clinical penetrance. The occurrence of de-novo mutations was strongly suggested in some families. INTERPRETATION: Neuroimaging penetrance of FCC is much higher than clinical penetrance. 75% of sporadic cases with multiple lesions are in fact familial cases. The proportion of patients developing clinical symptoms is higher in the hereditary form than in the sporadic form of the disorder.
Adolescent↗
Notch signalling pathway and human diseases.
Several homologs of the Drosophila 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, the Notch1, Notch3 and Jagged1 genes, pointing out the broad spectrum of Notch activity in humans. We report herein on what has been learned on the role of these human Notch genes and the mechanisms leading from mutations in those genes to the observed phenotypes.
Alagille Syndrome↗
Differential diagnosis of a vascular leukoencephalopathy within a CADASIL family: use of skin biopsy electron microscopy study and direct genotypic screening.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations of Notch3 gene on chromosome 19. Ultrastructural analysis of skin vessels discloses typical granular osmiophilic material (GOM) within the vascular smooth muscle basal lamina. We describe a CADASIL family in which two members suffering from a vascular leukoencephalopathy were shown to be CADASIL phenocopies: clinical and magnetic resonance imaging (MRI) findings in these two patients were similar to those observed in their affected relatives. However, the skin biopsy performed on one of them did not reveal any GOM in the vascular smooth muscle cells, and the Notch3 mutation present in this family was shown to be absent in these two individuals. We emphasize the role of a direct DNA test for gene mutation to make a differential diagnosis between CADASIL and other forms of vascular leukoencephalopathy.
Adult↗
[Immunogenetic bases of systemic lupus erythematosus in humans].
INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown pathogenesis. Familial studies and concordance rates among affected twins suggest that human SLE has a strong genetic basis. CURRENT KNOWLEDGE AND KEY POINTS: Recent studies have emphasized that SLE, like other autoimmune diseases, is a complex genetic trait with contributions of both major histocompatibility complex (MHC) associated genes and multiple non-MHC genes. Recent significant advances have been made in the genetic analysis of complex traits, which allow the identification of new candidate genes in SLE. Among the genes reviewed in this article, some polymorphisms of Fc gamma receptor genes and other genes or loci localized on the long arm of the human chromosome 1 appear to be very promising. FUTURE PROSPECTS AND PROJECTS: The identification of new susceptibility genes in SLE will certainly provide important insights into the breakdown of self-tolerance mechanisms leading to autoimmune diseases. To achieve this objective, the recruitment of a large number of genetic traits of multiplex families presenting with SLE is therefore essential. More than 125 multiplex families have been collected to date in France.
Animals↗
SPECT study of a German CADASIL family: a phenotype with migraine and progressive dementia only.
OBJECTIVE: We describe the clinical, molecular, genetic, MRI, and SPECT features of a German family with autosomal dominant migraine and dementia, mapping to the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) locus. We studied the correlation of cerebral blood flow, MRI, and cognitive function. BACKGROUND: CADASIL is a small-vessel disease of the brain mapped to chromosome 19p13.1. Mutations of the Notch3 gene cause this disorder. Most phenotypes are characterized by transient ischemic attacks (TIAs) and lacunar strokes leading to dementia. Migraine is frequent. A single photon emission computed tomographic (SPECT) study of this disorder has not yet been published. METHODS: We studied 13 individuals clinically and performed neuroimaging studies with MRI and SPECT. RESULTS: Genetic analysis strongly supported linkage to the CADASIL locus, and the disease haplotype was found in six individuals. Analysis by single-strand confirmation polymorphism did not identify Notch3 mutations. All affected individuals had MRI white matter hyperintensities and four individuals had additional basal ganglial signal abnormalities. Four affected individuals had migraine, two of whom had slowly progressive dementia. TIAs, stroke, and focal neurologic signs were absent. Cerebral blood flow reduction in SPECT studies of affected individuals matched with MRI signal abnormalities. Cognitive impairment was linked to signal abnormalities and hypoperfusion in the basal ganglia. Demented patients had a pattern of frontal, temporal, and basal ganglial hypoperfusion. CONCLUSIONS: We describe a CADASIL phenotype that is characterized by the absence of focal neurologic symptoms and present the first SPECT study of this disorder.
Adolescent↗
Patterns of MRI lesions in CADASIL.
OBJECTIVE: To investigate the location and severity of MRI signal abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: One hallmark of this arteriopathy due to mutations of Notch 3 gene is the presence of MRI signal abnormalities in both symptomatic and asymptomatic patients. METHODS: MRIs of 75 patients (43 with symptoms) were reviewed by a neuroradiologist masked to their clinical status. After assessing the presence of MRI lesions on T1- and T2-weighted images (T1-WI, T2-WI) in different subcortical regions, the severity of hyperintensities on T2-WI was scored using a global rating scale and a regional semiquantitative scale in the periventricular white matter (PV), deep white matter (WM), basal ganglia (BG), and infratentorial areas (IT). RESULTS: Sixty-eight patients (90%) had hyperintensities on T2-WI located in the white matter, more frequent in PV (96%) and WM (85%) than in the superficial white matter (25%). Hyperintensities also occurred in BG (60%) and brainstem (45%). Forty-seven patients (62%) presented with hypointensities on T1-WI. In one-third of the affected individuals, white matter hyperintensities occurred in the absence of small deep infarcts on T1-WI. The frequency and severity scores calculated for PV, WM, BG, or IT hyperintensities increase dramatically with age. These scores were higher in symptomatic compared with asymptomatic gene carriers. Dementia, Rankin score > 1, or both occurred only in the presence of diffuse white matter signal abnormalities. CONCLUSION: Our results suggest that different subcortical areas have different vulnerabilities to ischemia in CADASIL. The age effect we observed may show an accumulation of lesions with aging during the course of the disease. A prospective study is needed to investigate if the rating of MRI lesions is of prognostic value in CADASIL.
Adult↗
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
BACKGROUND: 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 Notch3 domains involved in CADASIL., we undertook mutations analysis in this gene in a group of CADASIL patients. METHODS: 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. FINDINGS: 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. INTERPRETATION: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.
Case-Control Studies↗
Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.
Adult↗
Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity.
Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped an FHM gene on the short arm of chromosome 19. Mutations in this gene, recently shown to be the alpha1 subunit of a P/Q-type voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of unselected FHM families and in all families where migraine attacks are associated with permanent cerebellar ataxia. As a first step toward the identification of other FHM genes, we conducted a genetic linkage analysis in one large French pedigree and showed significant linkage to two microsatellite markers D1S2635 (Zmax: 3.33 at theta = 0.05) and D1S2705 (Zmax: 3.64 at theta = 0.05), establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21-q23. Analysis of six additional FHM families favored linkage to this locus in two of them; linkage was excluded in the last four families, indicating further heterogeneity. Chromosome 1-linked families differ from the ones linked to chromosome 19, because penetrance in those families is much lower, and in some of their members, epileptic seizures occur during severe migraine attacks.
Chromosome Mapping↗
Familial cavernous malformations in a large French kindred: mapping of the gene to the CCM1 locus on chromosome 7q.
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 0=0.00) and D7S630 (Zmax=3.44 at 0=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.
Adolescent↗
Lack of association between thrombosis in primary antiphospholipid syndrome and the recently described thrombophilic 3'-untranslated prothrombin gene polymorphism.
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Adult↗
[CADASIS. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalophathy].
CADASIL is an inherited arterial disease of the brain with an autosomal dominant pattern of transmission. The mapping of the affected gene in 1993 allowed us to describe the natural history of the disease. In some patients, the disease starts with attacks of migraine with aura at a mean age of 30 years. The most frequent clinical manifestations are subcortical transient ischemic attacks or completed strokes usually occurring between 40 and 50 years of age which are sometimes associated with severe mood disturbances. The disease leads about two decades later to death after a variable period of subcortical dementia associated with pseudobulbar palsy and urinary incontinence. In one given family, the severity of the clinical presentation varies among the affected subjects. MRI is always abnormal in symptomatic subjects. It shows more or less confluent hypersignals on T2-weighted images in white-matter and basal ganglia and hyposignals on T1-weighted images in the same regions corresponding to small infarcts. These signal abnormalities are even observed a long time before the onset of clinical manifestations as they are present in totally asymptomatic young family members. Histologic studies show a widespread palor of white-matter and multiple small infarcts in the white-matter and basal ganglia underlaid by a small artery disease of the brain. Electron microscopy studies show that the media of the white-matter and leptomeningeal small arteries is thickened by a granular, eosinophilic and non-amyloid material of undetermined origin close to the smooth muscle cells. These ultrastructural wall abnormalities have been observed in other arteries, particularly in muscular and skin arteries. Mutations of Notch3 gene located on chromosome 19 are responsible for the disease. The diagnosis should be discussed in subjects with a history of unexplained subcortical ischemic strokes, attacks of migraine with aura, mood disorders of subcortical dementia whenever associated with MRI signal abnormalities in white-matter and basal ganglia.
Brain↗
A human homolog of bacterial acetolactate synthase genes maps within the CADASIL critical region.
CADASIL, a recently identified autosomal dominant condition characterized by the recurrence of subcortical infarcts leading to dementia, was previously mapped to chromosome 19p13.1 within a 2-cM interval, D19S226-D19S199. No recombination event was observed with D19S841, a highly polymorphic microsatellite marker isolated from a cosmid mapped to this region. We recently identified within this cosmid a conserved sequence that we used to screen a fetal brain cDNA library and isolated an ubiquitous and abundantly transcribed gene. We did not detect any mutation of this gene in CADASIL patients, suggesting that it is not implicated in this disorder. Interestingly, this gene encodes a putative protein homologous to several thiamine pyrophosphate-binding proteins previously identified in bacteria, yeast, and plants. The proteins with the highest degree of similarity were the acetolactate synthase enzymes which, in prokaryotes, are involved in the branched chain amino acid biosynthetic pathway, raising fascinating questions on the yet unknown function of this gene in mammals.
Acetolactate Synthase↗
An additional monogenic disorder that masquerades as multiple sclerosis.
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Brain↗
Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.
Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
Adult↗
TCR alpha beta gene usage for myelin basic protein recognition in healthy monozygous twins.
The pathogenic role of myelin basic protein (MBP)-specific T lymphocytes in multiple sclerosis (MS) has been suggested by the encephalitogenicity of MBP-specific T cells in experimental allergic encephalomyelitis (EAE). In humans, extensive analysis of TCRs involved in MBP recognition has led to conflicting results, varying from an intra- and/or interindividual restriction to high diversity in TCRAV/TCRBV gene usage. We previously established MBP-specific T cell lines (TCLs) from healthy monozygous twins and characterized their fine epitope specificity. In this study, we report on the TCR alpha beta gene usage of 52 of these MBP TCLs that are specific for epitopes recognized by both co-twins within the same pair. High overall diversity in the TCR alpha and TCR beta genes used for recognition of this self-Ag, MBP, was observed. Variable genes belonging to 19 different TCRAV and 16 different TCRBV subfamilies are expressed by the 52 TCLs herein studied. In co-twins, TCLs utilized genes belonging to common TCRAV and/or TCRBV gene subfamilies in 7 of 13 instances of shared epitope recognition. Statistical analysis of intrapair concordance for TCR gene usage for the recognition of a given peptide did not show any significant deviation from values that would be anticipated in the absence of genetic background effect.
Amino Acid Sequence↗