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E Mignot

Publications and source records attributed to E Mignot.

At least 91 records · Page 5Linked to original sources
PubMed1998

Microsatellite single nucleotide polymorphisms in the HLA-DQ region.

Sequencing studies were performed in three previously described microsatellite and minisatellite markers located within the HLA-DQ region, DQCAR, DQCARII and G51152. Multiple nucleotide substitutions that did not change size polymorphisms were observed in all three markers. In all loci, the number of core repeats did not correlate with neighboring DQ allele sequence motifs while single nucleotide changes within or flanking the microsatellite sequence did. This result indicates higher mutation rates for microsatellite expansions/contractions than for nucleotide substitutions in these loci. Further analysis indicated an almost complete phylogenetic correspondence between DQCAR single nucleotide polymorphisms (SNPs) and DQB1 sequences on one side (1.0-1.5 kb apart) and a complete relationship between DQCARII and DQA1 sequences on the other (4.5 kb apart). In contrast, G51152 sequences did not correspond perfectly with DQB1 allelic sequences, thus suggesting the existence of several ancestral crossovers between this marker and DQB1 (20-25 kb). Sequencing microsatellites might be useful in disease mapping studies by increasing marker informativeness and by helping in the interpretation of association study results. It is also proposed that SNPs within the flanking region of CA repeats could be used to develop biallelic markers from already available mapped microsatellite markers.

Alleles↗
PubMed1998

Genetic and familial aspects of narcolepsy.

Narcolepsy-cataplexy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal REM sleep. The development of human narcolepsy involves environmental factors acting on a specific genetic background. The importance of environmental factors is evidenced by the reported 25 to 31% of monozygotic twins who are concordant for narcolepsy. One of the predisposing genetic factors is located in the MHC DQ region. More than 85% of all narcoleptic patients with definite cataplexy share a specific HLA allele, HLA DQB1*0602 (most often in combination with HLA DR2), compared with 12 to 38% of the general population, as evaluated in various ethnic groups. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1 to 2% of the first-degree relatives of narcolepsy patients manifest the disorder, compared with 0.02 to 0.18% in the general population. Studies using a canine model of narcolepsy illustrate the importance of non-MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait, canarc-1. In spite of an association with immune-related polymorphisms, narcolepsy does not appear to be a classic autoimmune disease. Other pathophysiologic models involving the microglia and the release of specific cytokines in the CNS may be involved and are being explored. This approach, together with positional cloning studies in humans and canines, should reveal the cause of narcolepsy and open new therapeutic avenues.

Animals↗
PubMed1998

Investigations into the neurologic basis of narcolepsy.

The understanding of narcolepsy has been enhanced by neurophysiologic investigations in humans and by pharmacologic and biochemical studies using the canine model of narcolepsy. Repetitive microsleeps have a more deleterious effect on performance than several short complete naps during the day. Under normal living conditions, the nocturnal sleep of narcoleptic patients is disrupted, and the spectral analysis of central EEG leads shows less delta power density per epoch than it does in age-matched controls, who have an absence or decrease of the usual decay in delta power across the night. Cataplexy is associated with a drop in H-reflex, even during partial cataplectic attacks. Monitoring of heart rate and intra-arterial blood pressure during cataplexy in humans shows a decrease in heart rate and an increase in blood pressure with onset of cataplexy, but the change in heart rate is secondary to the change in blood pressure. Investigations of narcoleptic Doberman pinschers have implicated several neurotransmitters in the brainstem and amygdala. In vivo dialysis and in situ injections of carbachol indicate that the pontine reticular formation is not the only muscarinic cholinergic region involved, but data support the existence of a multisynaptic descending pathway involved in the muscle atonia of cataplexy. Carbachol injections into the basal forebrain induce status cataplecticus. Experimental findings suggest a hypersensitivity of the overall muscarinic cholinergic system and that this hypersensitive cholinergic system is linked to the limbic system. An increase in the postsynaptic D2 dopaminergic receptor is observed in the amygdala of narcoleptic dogs compared with controls, with impairment of dopamine release. The associated findings suggest that an abnormal cholinergic-dopaminergic interaction could underlie the pathophysiology of narcolepsy.

Animals↗
PubMed1997

Central administration of vitamin B12 aggravates cataplexy in canine narcolepsy.

Experimental evidence in canine narcolepsy suggests that central cholinergic systems are critically involved in the regulation of cataplexy, an abnormal manifestation of REM sleep atonia. In the current study, we found that intracerebroventricular perfusion of methyl-B12, (10(-5)-10(-2) M), significantly aggravated cataplexy and enhanced REM sleep in narcoleptic dogs. Choline, a direct precursor of acetylcholine, was also found to aggravate cataplexy, while cyano-B12, a vitamin B12 analog without methyl donating abilities, had no effect on cataplexy. Since both methyl-B12 and choline are reported to enhance acetylcholine synthesis, enhancement of the biosynthesis of acetylcholine may be involved in the effects observed in canine narcolepsy. Our results suggest that central administration of methyl-B12 has the potential to modulate both normal and pathological REM sleep.

Analysis of Variance↗
PubMed1997

Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy.

The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.

Animals↗
PubMed1997

Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog.

Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.

Animals↗
PubMed1997

HLA class II haplotype and sequence analysis support a role for DQ in narcolepsy.

A systematic haplotype and sequencing analysis of the HLA-DR and -DQ region in patients with narcolepsy was performed. Five new (CA)n microsatellite markers were generated and positioned on the physical map across the HLA-DQB1-DQA1-DRB1 interval. Haplotypes for these new markers and the three HLA loci were established using somatic cell hybrids generated from patients. A four-marker haplotype surrounding the DQB1(*)0602 gene was found in all narcolepsy patients, and was identical to haplotypes observed on random chromosomes harboring the DQB1(*)0602 allele. Eighty-six kilobases of contiguous genomic sequence across the region did not reveal new genes, and analysis of this sequence for single nucleotide polymorphisms did not reveal sequence variation among DQB1(*)0602 chromosomes. These results are consistent with other studies, suggesting that the HLA-DQ genes themselves are among the predisposing factors in narcolepsy.

Causality↗
PubMed1997

Pharmacological aspects of human and canine narcolepsy.

Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.

Animals↗
PubMed1997

Familial aspects of narcolepsy-cataplexy in the Czech Republic.

A group of 153 probands with narcolepsy included 38 subjects (24.8%) with a familial incidence of excessive daytime sleepiness (EDS). In 15 cases (9.8%), at least one additional family member suffered from narcolepsy-cataplexy; only EDS was present in the remaining 23 cases (15.0%). One thousand eighty-two relatives were evaluated. The percentage of first degree relatives affected with narcolepsy-cataplexy was 2.28% (1.20% if only clinically confirmed cases were accounted); the adequate value for second degree relatives was 1.49%. The occurrence of EDS exceeded these values several times (4.28% in first degree relatives, 6.57% in second degree relatives). The vertical mode of transmission was found in most families. Human leukocyte antigen (HLA) typing was performed in six families with multiple-case incidence of narcolepsy. Forty-one blood samples were analyzed (12 patients with narcolepsy, 7 with only EDS, 2 with sleep apnea syndrome, and 20 healthy relatives). HLA DR2+ and DQB1*0602+ were found in only 8 out of 12 narcoleptic patients with cataplexy and in six out of seven patients with isolated attacks of sleepiness. These findings support the hypothesis that there is a common genetic basis for narcolepsy associated with cataplexy and "monosymptomatic" forms of narcolepsy and suggest the existence of non-major histocompatibility complex (MHC) susceptibility factors for narcolepsy.

Adolescent↗
PubMed1997

The complex mutation pattern of a microsatellite.

DQCAR is a (CA)n microsatellite located in the HLA class II region and tightly linked to HLA-DQB1. Previous studies showed a strikingly low level of size variation in DQCAR alleles within an extensive subfamily of HLA-DQ subtypes (DQ1). DQCAR alleles in non-DQ1 subtypes showed a higher degree of size polymorphism. In this study sequence analysis demonstrates that DQ1-associated DQCAR alleles have a single C-->A nucleotide substitution interrupting the CA repeat array. Frequent CA-->GA mutations are also observed in DQ1-associated microsatellites with identical allele sizes. In contrast, DQCAR alleles associated with non-DQ1 haplotypes display a perfect CA repeat sequence and the variation in allele size is attributable only to differences in the number of CA repeats. Our results imply that several mutational mechanisms are involved in the generation of allelic diversity within the same microsatellite locus. The possibility of different mutation rates in the same locus should to be taken into account when using these markers in evolutionary and disease studies.

Alleles↗
PubMed1997

Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy.

Narcolepsy is a sleep disorder that has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58 non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from multiplex families. Additional markers studied in the class II region were the promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII) located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus. Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic subjects. Additional microsatellite and DQA1 promoter diversity was found in some of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602 subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes for narcolepsy in the HLA class II region.

Cataplexy↗
PubMed1997

DQ microsatellite association studies in three ethnic groups.

Polymorphism at the level of three microsatellite markers (DQCAR, DQCARII, G51152) located in the HLA-DQ region was characterized in 78 10th International Histocompatibility Workshop B-cell lines, 718 random Japanese Asians, 99 Norwegian Caucasians and 95 New Guinean Aborigines with established HLA-DRB1, -DQA1 and -DQB1 typing. DQCAR, DQCARII, and G51152 result in 13, 13, and 11 alleles respectively. All three markers were in tight linkage disequilibrium with HLA-DRB1, -DQA1 and -DQB1. DRB1, DQA1, DQCARII, DQCAR, DQB1, and G51152 haplotypes could be defined for all subjects. In fact, DQ microsatellite typing data could predict DQA1 and DQB1 genotypes with high accuracy and may be used as a simple first pass HLA-DQ typing method. The haplotype data was also used to determine recombination in the DRB1-DQA1 (about 80 kb), DQA1-DQCARII (about 4.5 kb), DQCARII-DQCAR (about 7.5 kb), DQCAR-DQB1 (about 1-1.5 kb) and DQB1-G51152 (about 20-25 kb) genomic segments and the relative rate of slippage microsatellite mutations for DQCAR, DQCARII, and G51152. This led us to conclude that recombination is more frequent in the DRB1-DQA1 and DQCAR-DQCARII segments, thus suggesting cross-overs within small genomic segments are not proportional to genetic distance. We also observed that DQCAR had a higher mutation rate than DQCARII or G51152 and that 1 or 2 CA slippage mutations were arising more frequently from large size microsatellite alleles.

DNA, Satellite↗
PubMed1997

HLA DR15 (DR2) and DQB1*0602 typing studies in 188 narcoleptic patients with cataplexy.

Narcolepsy is considered a homogeneous clinical entity when excessive daytime sleepiness and cataplexy are present. Cataplexy is a polymorphic symptom that can be very mild and is thus subjectively defined. The Multiple Sleep Latency Test (MSLT) is widely used as a diagnostic test for narcolepsy. A short mean sleep latency and multiple sleep onset REM periods (SOREMPs) are typically observed in narcoleptic patients. The discovery of a tight association of narcolepsy with HLA class II antigens offers a unique opportunity to explore the respective value of the MSLT or of the presence of clear-cut cataplexy in defining an etiologically homogeneous group of narcoleptic patients. In this study, we carried out HLA typing for DR15(DR2) and DQB1*0602 in 188 narcoleptic patients with cataplexy in three ethnic groups (24 Asians, 61 Blacks, and 103 Caucasians). These results confirm the importance of DQB1*0602 typing rather than DR15 (DR2) typing in Black narcoleptic patients and demonstrate that the presence of clear-cut cataplexy is a better predictor for DQB1*0602 positivity than the presence of abnormal MSLT results.

Asian People↗
PubMed1997

Circadian distribution of rest/activity in narcoleptic and control dogs: assessment with ambulatory activity monitoring.

Like human narcoleptics, narcoleptic dogs display cataplexy, fragmented sleep and excessive daytime sleepiness. Cataplexy in dogs can easily be quantified using a simple behavioural bioassay, the Food Elicited Cataplexy Test. In contrast, daytime sleepiness and fragmented sleep are more difficult to measure, as long-term, labour-intensive polygraphic recordings in surgically-implanted animals are needed. In the current study, 24-h rest/activity patterns in genetically narcoleptic, asymptomatic heterozygous and control Dobermans were compared using small sized ambulatory activity monitoring devices under 12-h light/dark conditions. Control and heterozygous dogs were found to be more active during the light period than during the dark period, thus demonstrating a clear 24-h rest/activity cycle. In contrast, narcoleptic dogs were relatively inactive during the light period and did not show a clear rest/activity pattern, a result similar to that of human narcoleptics. Considering the fact that narcoleptic dogs show shorter sleep latency and sleep significantly more during the daytime than control dogs, the decrease in activity in narcoleptic dogs during the daytime is most likely a reflection of increased daytime napping in these animals. Ambulatory activity monitoring may be a useful non-invasive method for future pharmacological and development studies in the narcoleptic canine model.

Animals↗
PubMed1997

HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.

Narcolepsy is a sleep disorder associated with HLA DR15 (DR2) and DQB1*0602. We HLA typed 509 patients enrolled in a clinical trial for the drug modafinil and analyzed the results in relation to cataplexy, a symptom of narcolepsy characterized by muscle weakness triggered by emotions. The patients were either subjects with cataplexy who had a mean sleep latency (SL) of less than 8 minutes and two or more sleep onset rapid eye movement (REM) periods (SOREMPs) during a multiple sleep latency test, or narcoleptic patients without cataplexy but with a mean SL shorter than 5 minutes and two or more SOREMPs. The respective values of DRB1*15 (DR2) and DQB1*0602 as markers for narcolepsy were first compared in different ethnic groups and in patients with and without cataplexy. DQB1*0602 was found to be a more sensitive marker for narcolepsy than DRB1*15 across all ethnic groups. DQB1*0602 frequency was strikingly higher in patients with cataplexy versus patients without cataplexy (76.1% in 421 patients versus 40.9% in 88 patients). Positivity was highest in patients with severe cataplexy (94.8%) and progressively decreased to 54.2% in patients with the mildest cataplexy. A voluntary 50-item questionnaire focusing on cataplexy was also analyzed in 212 of the 509 HLA-typed patients. Subjects with definite cataplexy as observed by an experienced clinician were more frequently HLA DQB1*0602-positive than those with doubtful cataplexy, and the manifestations of cataplexy were clinically more typical in DQB1*0602-positive patients. These results show that the HLA association is as tight as previously reported (85-95%) when cataplexy is clinically typical or severe. We also found that patients with mild, atypical, or no cataplexy have a significantly increased DQB1*0602 frequency (40-60%) in comparison with ethnically matched controls (24%). These results could be explained by increased disease heterogeneity in the noncataplexy group or by a direct effect of the HLA DQB1*0602 genotype on the clinical expression of narcolepsy.

Adolescent↗
PubMed1996

Mutation rate varies among alleles at a microsatellite locus: phylogenetic evidence.

The understanding of the mutational mechanism that generates high levels of variation at microsatellite loci lags far behind the application of these genetic markers. A phylogenetic approach was developed to study the pattern and rate of mutations at a dinucleotide microsatellite locus tightly linked to HLA-DQB1 (DQCAR). A random Japanese population (n = 129) and a collection of multiethnic samples (n = 941) were typed at the DQB1 and DQCAR loci. The phylogeny of DQB1 alleles was then reconstructed and DQCAR alleles were superimposed onto the phylogeny. This approach allowed us to group DQCAR alleles that share a common ancestor. The results indicated that the DQCAR mutation rate varies drastically among alleles within this single microsatellite locus. Some DQCAR alleles never mutated during a long period of evolutionary time. Sequencing of representative DQCAR alleles showed that these alleles lost their ability to mutate because of nucleotide substitutions that shorten the length of uninterrupted CA repeat arrays; in contrast, all mutating alleles had relatively longer perfect CA repeat sequences.

Alleles↗
PubMed1996

Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine.

Cataplexy in the narcoleptic canine may be modulated by systemic administration of monoaminergic compounds. In the present study, we have investigated the effects of monoaminergic drugs on cataplexy in narcoleptic canines when perfused locally via microdialysis probes in the amygdala, globus pallidus/putamen, basal forebrain, pontine reticular formation and ventral tegmental area of narcoleptic and control Doberman pinchers. Cataplexy was quantified using the Food-Elicited Cataplexy Test and analyzed by electroencephalogram, electroculogram and electromyogram. Local perfusion with the monoaminergic agonist quinpirole, 7-OH-DPAT and BHT-920, into the ventral tegmental area produced a dose-dependent increase in cataplexy without significantly reducing basal muscle tone. Perfusion with the antagonist raclopride in the same structure produced a moderate reduction in cataplexy. Local perfusion with quinpirole, 7-OH-DPAT and BHT-920 into the globus pallidus/putamen also produced an increase, while raclopride produced a decrease, in cataplexy in narcoleptic canines. In control animals, none of the above drugs produced cataplexy or muscle atonia when perfused into either the ventral tegmental area or the globus pallidus/putamen. Other monoaminergic drugs tested in these two brain areas; prazosin, yohimbine, amphetamine, SKF 38393 and SCH 23390 had no effects on cataplexy. Local perfusion with each of the above listed drugs had no effect on cataplexy in any of the other brain regions examined. These findings show that cataplexy may be regulated by D2/D3 dopaminergic receptors in the ventral tegmental area and perhaps the globus pallidus/ putamen. It is suggested that neurons in the mesolimbic dopamine system of narcoleptics are hypersensitive to dopaminergic autoreceptor agonists.

Amygdala↗