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Biomedical subjects

E Tournier-Lasserve

Publications and source records attributed to E Tournier-Lasserve.

At least 19 recordsLinked to original sources
PubMed2002

Krit1/cerebral cavernous malformation 1 mRNA is preferentially expressed in neurons and epithelial cells in embryo and adult.

Cavernous malformations are capillaro-venous lesions mostly located within the central nervous system (CCM/OMIM#116860) and occasionally within the skin and/or retina. They occur as a sporadic or hereditary condition. Three CCM loci have been mapped, and the sole gene identified so far, CCM1, has been shown to encode KRIT1, a protein of unknown function. In an attempt to get some insight on the relationship between KRIT1 mutations and CCM lesions, we investigated Krit1 mRNA expression during mouse development from E7.5 to E20.5 and in adult tissues, of both mouse and human origin. A ubiquitous Krit1 mRNA expression was detected from E7.5 up to E9.5. Then, it became progressively restricted from E10.5 to E12.5, to become detectable later essentially in the nervous system and various epithelia. Strong labelling was observed in neurons in the brain, cerebellum, spinal cord, retina and dorsal root ganglia. In epithelia, Krit1 mRNA expression was detected in differentiating epidermal, digestive, respiratory, uterine and urinary epithelia. A similar pattern of expression persisted in mouse and man adult nervous system and epithelia. Unexpectedly, in vascular tissues, expression of Krit1 was detected only in large blood vessels of the embryo.

Adult↗
PubMed2002

Anticardiolipin antibodies in patients with multiple sclerosis do not represent a subgroup of patients according to clinical, familial, and biological characteristics.

BACKGROUND: In multiple sclerosis (MS), case control studies have shown that anticardiolipin antibodies (aCL Ab) are more frequent than in the general population and that aCL Ab positivity may be associated with specific clinical characteristics. OBJECTIVES: To determine whether patients with MS who are positive for aCL Ab have specific characteristics. METHODS: 285 consecutive patients with MS were tested for aCL Ab positivity. Patients also underwent complete autoimmune screening and were systematically evaluated for clinical characteristics and individual or family history of autoimmune disease. RESULTS: aCL Ab positivity was found in 42 patients (15%). The main isotype was aCL IgM (32 patients, 11%). Demographics and clinical characteristics including sex, age at onset, course of the disease, expanded disability status scale score, and progression index were not different between aCL Ab positive and aCL Ab negative patients. Clinical systems involved at onset or during the course of the disease were not different from what is usually observed in MS. aCL Ab positivity was not associated with an increased frequency of autoimmune disease and was not predictive of a family history of autoimmune disease. Patients positive for aCL IgM were more frequently positive for the presence of non-organ specific antibodies (53% v 39%, respectively, p = 0.02). CONCLUSIONS: These results do not support the hypothesis that patients with MS with aCL Ab constitute a subgroup of MS according to demographic clinical and familial characteristics. The greater frequency of other antibodies in aCL Ab positive patients suggests that they only reflect a more general autoimmune activation in MS.

Adult↗
PubMed2002

[Molecular basis and physiopathogenic mechanisms of CADASIL: a model of small vessel diseases of the brain].

Diseases of the small cerebral arteries account for approximately 20% of the ischaemic strokes. Their diagnosis is difficult and their pathogenic mechanisms are yet unclear. A certain proportion of these diseases is familial. CADASIL is a recently identified small-artery disease of the brain, which occurs both as an autosomal dominant and a sporadic condition caused by mutations in the Notch3 gene. Since the acronym CADASIL was coined to designate this disorder in 1993, an exponentially growing number of patients has been identified all over the world. Notch3 belongs to the highly conserved Notch genes family which encode transmembrane receptors involved in cell fate specification during development. The role of Notch3 is so far unknown. We recently established that in normal adult tissues expression of Notch3 is essentially restricted to vessel and vascular smooth muscle cells (VSMC). CADASIL patients carry highly stereotyped mutations leading to an odd number of cysteine residues within the extracellular domain. Mutations are associated with an impaired clearance of the Notch3 protein leading to its abnormal accumulation at the membrane of VSMC. These data establish that VSMC is the primary target of the pathogenic process. In addition they give support to the role of the Notch3 pathway in vascular homeostasis. Furthermore, they open new perspectives in the field of small-artery diseases of the brain and should help to further dissect their genetic etiologies and understand their pathogenic mechanisms.

Cell Membrane↗
PubMed2001

Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature. We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients). In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.

Adult↗
PubMed2001

The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.

BACKGROUND: Familial hemiplegic migraine, an autosomal dominant disorder characterized by attacks of transient hemiparesis followed by a migraine headache, is classically divided into pure familial hemiplegic migraine (affecting 80 percent of families) and familial hemiplegic migraine with permanent cerebellar signs (affecting 20 percent of families). Mutations in CACNA1A, which encodes a neuronal calcium channel, are present in 50 percent of families with hemiplegic migraine, including all those with cerebellar signs. We studied the various clinical manifestations associated with mutations in CACNA1A in families with hemiplegic migraine with and without cerebellar signs. METHODS: CACNA1A was analyzed and nine mutations were detected in 15 of 16 probands of families affected by hemiplegic migraine and cerebellar signs, in 2 of 3 subjects with sporadic hemiplegic migraine and cerebellar signs, and in 4 of 12 probands of families affected by pure hemiplegic migraine. Genotyping of probands and relatives identified a total of 117 subjects with mutations whose clinical manifestations were assessed in detail. RESULTS: Eighty-nine percent of the subjects with mutations had attacks of hemiplegic migraine. One third had severe attacks with coma, prolonged hemiplegia, or both, with full recovery. All nine mutations, including five newly identified ones, were missense mutations. Six mutations were associated with hemiplegic migraine and cerebellar signs, and 83 percent of the subjects with these six mutations had nystagmus, ataxia, or both. Three mutations were associated with pure hemiplegic migraine. CONCLUSIONS: Hemiplegic migraine in subjects with mutations in CACNA1A has a broad clinical spectrum. This clinical variability is partially associated with the various types of mutations.

Age of Onset↗
PubMed2001

Missense CACNA1A mutation causing episodic ataxia type 2.

OBJECTIVES: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. BACKGROUND: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. METHODS: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. RESULTS: A CACNA1A missense mutation, Glu 1757 Lys, was identified. It was absent in 200 control chromosomes. It is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. CONCLUSIONS: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.

Calcium Channels↗
PubMed2001

A dinucleotide repeat polymorphism at the poly(ADP-ribose) polymerase gene is not associated with predisposition to type 1 diabetes in French Caucasians.

The poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that detects and binds DNA strand breaks. Excessive PARP activation leads to the death of mice islet beta-cells by depleting cellular energy reserves. On the other hand, PARP-mutant mice are resistant to streptozotocine-induced diabetes, and in the non-obese diabetic (NOD) mouse model, treatment with nicotinamide, a PARP inhibitor, protects islet cells against cytotoxic actions in vitro and results in a decreased incidence of type 1 diabetes. PARP gene in human is located within a recently identified type 1 diabetes-susceptibility region on chromosome 1q41-42, and contains a polymorphic CA dinucleotide repeat in the promoter region. To consider the putative involvement of PARP polymorphism in predisposition to type 1 diabetes, we performed genotyping for the various alleles of the CA dinucleotide repeat in 158 unrelated French Caucasian patients with type 1 diabetes and 193 ethnically-matched healthy controls. We found no significant difference of PARP alleles distribution between patients and controls, even after stratification of the patients according to HLA class II genotype or to age at disease onset. Our results suggest that this PARP polymorphism does not influence susceptibility to type 1 diabetes in French Caucasians.

Adolescent↗
PubMed2001

Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.

Acetazolamide↗
PubMed2001

Familial lupus erythematosus. Clinical and immunologic features of 125 multiplex families.

Evidence for a genetic susceptibility to systemic lupus erythematosus (SLE) in humans is based on the high concordance rate observed in identical twins and on the relatively high incidence of familial cases. Although recent genetic studies have lead to significant advances in the identification of new susceptibility genes in SLE, no large clinico-pathologic study of familial SLE has been reported to date. In the present study, we describe the main clinical and immunologic features of 125 lupus multiplex families including at least 2 cases of SLE and/or discoid lupus erythematosus (DLE), recruited through a French national survey starting in July 1997. Medical records of all affected members were reviewed by the same investigator, all available family members were interviewed using the same standardized procedure, and blood was drawn for autoantibodies typing. Clinical and immunologic features of 90 probands from multiplex SLE families were compared with those of 100 sporadic SLE patients sharing the same French Caucasian origin. The 125 lupus multiplex families included 282 affected members (2.3 patients per family); of the 125 families, 96 were of French Caucasian origin. One hundred multiplex families included 2 affected relatives, while 25 included 3 or more affected individuals. The relationship between affected members was sibs (45%), parent-offspring (31%), and second-degree (24%). An autosomal dominant mode of inheritance was strongly suggested in 1 extended pedigree with 6 clinically affected members, and a recessive pattern was suspected in 5 other families. No obvious mode of inheritance could be suspected in most of the remainder. Among French Caucasians, sex ratio, mean age at onset, and clinical and biologic SLE-related manifestations were not significantly different in multiplex compared with sporadic SLE cases. The analysis of these 125 multiplex families suggests a genetic heterogeneity that should be considered for ongoing genomic screening.

Age of Onset↗
PubMed2000

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy.

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.

Adult↗
PubMed2000

Autoimmune diseases in families of French patients with multiple sclerosis.

Multiple sclerosis (MS) is associated with autoimmune disorders (AIDs) in individual patients, and limited data suggest a possible familial association of MS and AIDs; however, no systematic study has been conducted on the occurrence of AIDs in the families of MS patients. Using a standardized interview focused on AIDs, we obtained the family histories of 357 consecutive patients from our MS clinic. Adequate information was obtained on 1971 first-degree relatives. Fifty-five patients (15.4%) had first-degree relatives with MS (n=22, 6.2%) another AID (n = 30, 8.4%), or both (n = 3, 0.8%). In 16 families (4.5%), at least 3 first-degree relatives had MS or another AID. MS, Grave's disease, rheumatoid arthritis, vitiligo, type 1 insulin-dependent diabetes mellitus, and uveitis, were the most common AIDs in these families. Such multiplex families (families with MS plus AID) are appropriate for identifying susceptibility genes that may be common to MS and other AIDs.

Adult↗
PubMed2000

Familial form of intracranial cavernous angioma: MR imaging findings in 51 families. French Society of Neurosurgery.

PURPOSE: To analyze the magnetic resonance (MR) imaging features of familial cerebral cavernous angioma in non-Hispanic families. MATERIALS AND METHODS: Between November 1996 and June 1997, 51 non-Hispanic families with familial cavernous angioma were identified. Cerebral MR images in 83 symptomatic subjects and 73 asymptomatic subjects were reviewed. Spin-echo (SE) and gradient-echo (GRE) MR imaging features of cavernous angioma were recorded and, in 91 subjects with both SE and GRE images, lesions were graded as type 1, 2, 3, or 4, according to a published classification scheme. MR imaging features were compared between symptomatic and asymptomatic subjects, and sensitivities of SE and GRE images were determined. RESULTS: Multiple lesions were more common than single lesions in both symptomatic and asymptomatic subjects, with no difference in mean number of lesions between groups. More lesions were detected on GRE images than on SE images. Type 1 and type 2 lesions were more numerous in symptomatic than in asymptomatic subjects. The numbers of types 2, 3, and 4 lesions increased with age in both groups. CONCLUSION: The familial form of cavernous angioma is characterized by multiple lesions and by a correlation between lesion number and subject age. The clinical manifestation may be more closely related to the type of lesion than to the number of lesions. GRE MR images are more sensitive than SE images for demonstration of cavernous angioma.

Adolescent↗
PubMed2000

The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients.

Mutations in Notch3 cause CADASIL (cerebral autosomal dominant adult onset arteriopathy), which leads to stroke and dementia in humans. CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits. Patients carry highly stereotyped mutations that lead to an odd number of cysteine residues within EGF-like repeats of the Notch3 receptor extracellular domain. Such mutations may alter the processing or the trafficking of this receptor, or may favor its oligomerization. In this study, we examined the Notch3 expression pattern in normal tissues and investigated the consequences of mutations on Notch3 expression in transfected cells and CADASIL brains. In normal tissues, Notch3 expression is restricted to vascular smooth muscle cells. Notch3 undergoes a proteolytic cleavage leading to a 210-kDa extracellular fragment and a 97-kDa intracellular fragment. In CADASIL brains, we found evidence of a dramatic and selective accumulation of the 210-kDa Notch3 cleavage product. Notch3 accumulates at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not within the granular osmiophilic material. These results strongly suggest that CADASIL mutations specifically impair the clearance of the Notch3 ectodomain, but not the cytosolic domain, from the cell surface.

Aged↗
PubMed2000

De novo mutation in the Notch3 gene causing CADASIL.

CADASIL, an autosomal dominant arteriopathy responsible for stroke and dementia, is caused by strongly stereotyped mutations in the Notch3 gene. We report a patient with a condition strongly suggestive of CADASIL (migraine, stroke, and white matter abnormalities), except that this patient did not have any first-degree relatives with similar symptoms. This patient carried a heterozygous Arg182Cys mutation in the Notch3 gene; this mutation was absent in his two biological parents. These data demonstrate the occurrence of a de novo noninherited mutation in the Notch3 gene, which indicates that CADASIL should not be rejected in the absence of a family history. Therefore, our finding suggests that CADASIL may be more frequent than anticipated.

Brain↗