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Biomedical subjects

E Tournier-Lasserve

Publications and source records attributed to E Tournier-Lasserve.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2000

[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): clinical features and neuroimaging].

Recently identified in a french family, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a generalised disease of small arteries, largely predominating in the brain. Its clinical manifestations start during mid-adulthood and include recurrent ischaemic subcortical events, attacks of migraine with aura, severe mood disorders, subcortical dementia, and, at magnetic resonance imaging, widespread leuko-encephalopathy. There is so far no specific treatment and the mean duration of the disease is 20 years. CADASIL is most frequently a familial disorder with an autosomal dominant mode of transmission. Its responsible gene, Notch 3, is located on Chromosome 19. By the identification of its gene, CADASIL, (which is now known to affect over 400 families worldwide) is a unique variety of cerebro-vascular disease, affecting mainly the subcortical white matter.

Dementia, Multi-Infarct↗
PubMed2000

[CADASIL: genetics and physiopathology].

CADASIL, an autosomal dominant adult onset arteriopathy causing stroke and dementia in humans, is underlaid by a non atherosclerotic non amyloid angiopathy involving mainly the media of small cerebral arteries; it is characterized by major lesions of vascular smooth muscle cells. Using a positional cloning approach, we mapped CADASIL locus on chromosome 19 and identified the mutated gene as being Notch3. This gene, previously unknown in humans, encodes for a large transmembrane receptor belonging to the Notch/lin12 gene family which are known to be involved in cell fate specification during development. Genetic analysis of more than 120 CADASIL unrelated families allowed us to show that these mutations are highly stereotyped and affect only the extra cellular domain of the protein. On the basis of these data, a molecular diagnostic test has been set up and is now widely required by clinicians involved in the diagnosis of vascular leukoencephalopathies. Using this test, we recently showed that CADASIL can also occur in patients who do not have any affected relative due to the existence of notch3 de novo mutations. As a first step to investigate the molecular and cellular mechanisms leading from Notch3 mutations to CADASIL phenotype, we analyzed by in-situ hybridization and immunohistochemistry the pattern of expression of this gene. Notch3 expression is highly restricted to the vascular smooth muscle cell in normal human adults. In CADASIL tissues there is a dramatic accumulation of the extracellular domain of the protein which suggests that one of the main mechanisms of CADASIL involves anomalies in the proteolytical cleavage and clearance of this protein. These data provide important clues to the mechanisms of this condition and current work should lead in the next future to a complete understanding of CADASIL and set up the basis of a rational therapeutical approach of this condition.

Dementia, Multi-Infarct↗
PubMed1999

High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.

OBJECTIVE: To characterize the nature of CACNA1A mutations in episodic ataxia type 2 (EA2), to search for mutations in sporadic cases, and to delineate better the clinical spectrum. BACKGROUND: EA2 is an autosomal dominant disorder characterized by recurrent acetazolamide-responsive attacks of cerebellar ataxia. The mutated gene, CACNA1A, located on chromosome 19, encodes the alpha1A subunit of a voltage-dependent calcium channel. So far, only three CACNA1A mutations have been identified-in two EA2 families and in one sporadic case. These three mutations disrupted the reading frame and led to truncated proteins. Interestingly, distinct types of CACNA1A mutations have been identified in familial hemiplegic migraine (missense mutations) and spinocerebellar ataxia type 6 (SCA-6) progressive cerebellar ataxia (expanded CAG repeats). However, except for SCA-6, these genotype-phenotype correlations relied on the analysis of very few families. METHODS: To characterize CACNA1A mutations, eight familial and seven sporadic EA2 patients were selected. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. In addition, the length of the CAG repeat has been determined in all patients. RESULTS: Seven new mutations were detected in four multiple case families and three sporadic cases. Six of them lead most likely to truncated or aberrant proteins. CAG repeat sizes were in the normal range. CONCLUSION: These data clearly establish the specificity of EA2 mutations compared with SCA-6 and familial hemiplegic migraine. Detailed clinical analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia or severe, permanent, and isolated cerebellar ataxia).

Adolescent↗
PubMed1999

Poly(ADP-ribose) polymerase alleles in French Caucasians are associated neither with lupus nor with primary antiphospholipid syndrome. GRAID Research Group. Group for Research on Auto-Immune Disorders.

OBJECTIVE: To investigate the putative involvement of poly(ADP-ribose) polymerase (PARP) alleles in systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). METHODS: This study of French Caucasians included 171 unrelated patients with SLE, 88 unrelated patients with primary APS, and 193 ethnically matched healthy controls. The SLE group comprised 89 patients with sporadic SLE and 82 patients with familial SLE. Patients' and controls' DNA were genotyped for the various alleles of a polymorphic CA dinucleotide repeat located within the promoter region of PARP. RESULTS: No statistically significant difference was observed for the distribution of PARP alleles between the healthy control group and each patient group or the pooled SLE patient group. CONCLUSION: The study findings strongly suggest that these alleles do not influence susceptibility to SLE or primary APS in French Caucasians.

Alleles↗
PubMed1999

An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families.

Cerebral cavernomas (CCMs) are vascular malformations that may be inherited as an autosomal dominant condition for which a gene, CCM1, was mapped to chromosome 7. Poorly defined cutaneous malformations were sometimes described in association with CCMs. During a national survey, 57 French CCM families were studied. Co-occurrence of CCMs and a distinctive cutaneous vascular malformation was observed in 4 families. Ten individuals belonging to these families showed similar hyperkeratotic cutaneous capillary venous malformations (HCCVMs). In 3 families, the histology showed orthokeratosis and hyperkeratosis as well as dilated capillaries in the dermis extending to the hypodermis and confirmed the diagnosis of HCCVM. Genetic analysis strongly supports linkage of these families to the CCM1 locus on chromosome 7. The HCCVM seems to be a peculiar cutaneous vascular malformation associated with CCMs. These data strongly suggest that HCCVMs and CCMs in these families are due to the same genetic abnormality.

Adult↗
PubMed1999

Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.

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.

Amino Acid Sequence↗
PubMed1999

Recurrent episodes of coma: an unusual phenotype of familial hemiplegic migraine with linkage to chromosome 1.

Over a period of ten years, a boy had several episodes of coma, lasting three to five days. Each episode was preceded by hemiparesis or paresthesias, aphasia, headaches and behavioural changes, with subsequent loss of consciousness. Partial seizures occurred during the first episode. A history of migraine or hemiplegic migraine was found in several members of the family. Linkage to chromosome 1q21-23, where a gene for familial hemiplegic migraine has been mapped, was shown in this family.

Child↗
PubMed1999

Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.

Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the alpha1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.

Calcium Channels↗