A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1.
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Cataplexy↗
Biomedical subjects
M Tafti
Publications and source records attributed to M Tafti.
HLA and genetic susceptibility to sleepwalking.
HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P = 0.0056; odds ratio = 3.5, 95% CI = 1.4-8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission-disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P = 0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep.
Adolescent↗
CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions.
OBJECTIVE: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. PATIENTS: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. RESULTS: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. CONCLUSION: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.
Adolescent↗
Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses.
BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.
Adolescent↗
Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil.
The gene for catechol-O-methyltransferase (COMT) plays a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent evidence suggests that modafinil, like other stimulants, might act through the dopaminergic system. We have reported a sexual dimorphism and a strong effect of the COMT genotype on narcolepsy symptoms and hypothesized that response to modafinil treatment may be associated with the COMT genotype. Here we confirm that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil. In addition, the optimal daily dose of modafinil is approximately 100 mg lower in women narcoleptics and lower in all narcoleptics with low activity COMT genotype. Our results suggest that a sexual dimorphism in COMT activity affects the response to modafinil and probably to other dopaminergic stimulants.
Adolescent↗
The homeostatic regulation of sleep need is under genetic control.
Delta power, a measure of EEG activity in the 1-4 Hz range, in slow-wave sleep (SWS) is in a quantitative and predictive relationship with prior wakefulness. Thus, sleep loss evokes a proportional increase in delta power, and excess sleep a decrease. Therefore, delta power is thought to reflect SWS need and its underlying homeostatically regulated recovery process. The neurophysiological substrate of this process is unknown and forward genetics might help elucidate the nature of what is depleted during wakefulness and recovered during SWS. We applied a mathematical method that quantifies the relationship between the sleep-wake distribution and delta power to sleep data of six inbred mouse strains. The results demonstrated that the rate at which SWS need accumulated varied greatly with genotype. This conclusion was confirmed in a "dose-response" study of sleep loss and changes in delta power; delta power strongly depended on both the duration of prior wakefulness and genotype. We followed the segregation of the rebound of delta power after sleep deprivation in 25 BXD recombinant inbred strains by quantitative trait loci (QTL) analysis. One "significant" QTL was identified on chromosome 13 that accounted for 49% of the genetic variance in this trait. Interestingly, the rate at which SWS need decreases did not vary with genotype in any of the 31 inbred strains studied. These results demonstrate, for the first time, that the increase of SWS need is under a strong genetic control, and they provide a basis for identifying genes underlying SWS homeostasis.
Animals↗
Magnesium involvement in sleep: genetic and nutritional models.
Alterations of peripheral magnesium (Mg) concentration have been reported in association with several behavioral disorders and sleep organization. Blood Mg regulation is under a strong genetic control, whereas brain Mg regulation does not seem to be affected. We have studied peripheral and central levels of Mg and analyzed sleep in two lines of mice selected for low (MGL) and high (MGH) red blood cell (RBC) Mg levels. The same variables were also studied in C57BL/6J mice before and after 3 weeks of Mg deficiency. Whereas blood Mg was highly affected by the selection, brain Mg exhibited only small differences between the two lines. In contrast, Mg deficiency strongly decreased both central and peripheral Mg levels. Sleep analysis indicated that in both models the amount of paradoxical sleep was lower in mice with higher Mg levels. The amplitude of daily variation in sleep and slow-wave sleep delta power was markedly decreased in MGH line. Quantitative electroencephalogram (EEG) analysis also revealed a faster theta peak frequency in MGH mice, irrespective of behavioral states. Central Mg showed significant correlations with the amount of paradoxical sleep and sleep consolidation. However, because the direction of these correlations was not consistent, it is concluded that optimal, (physiological) rather than high or low, Mg levels are needed for normal sleep regulation.
Animals↗
MAO-A and COMT polymorphisms and gene effects in narcolepsy.
Narcolepsy presents one of the tightest associations with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin system in narcolepsy in both humans and animals. In addition, the implication of monoaminergic systems in the pathophysiology of narcolepsy is well established and a significant association between the monoamine oxydase-A (MAO-A) gene and human narcolepsy has recently provided a possible genetic link. We investigated polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease symptoms. No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism and a strong effect of COMT genotype on disease severity were found. Women narcoleptics with high COMT activity fell asleep twice as fast as those with low COMT activity during the multiple sleep latency test (MSLT) while the opposite was true for men. COMT genotype also strongly affected the presence of sleep paralysis and the number of REM sleep onsets during the MSLT. In agreement with well-documented pharmacological results in canine narcolepsy, this study reports the first genetic evidence for the critical involvement of the dopaminergic and/or noradrenergic systems in human narcolepsy.
Cataplexy↗
[Genetics of human narcolepsy].
Narcolepsy is known to be a complex disorder; both genetic and environmental factors play a role in its pathophysiology. Although narcolepsy presents one of the tightest association with a specific HLA antigen (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility, both monoaminergic and hypocretinergic systems seem to be involved and may interfere with the phenotype. Implication of the hypocretin system is well-established in both canine and murine narcolepsy (caused by mutation) and a consistent reduction in hypocretin neuron seems to be the cause of human narcolepsy. An autoimmune process is probable.
Animals↗
The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity.
Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeostatic aspects of sleep regulation by comparing DBP deficient mice (dbp-/-) with their isogenic controls (dbp+/+) under light-dark (LD) and constant-dark (DD) baseline conditions, as well as after sleep loss. Whereas total sleep duration was similar in both genotypes, the amplitude of the circadian modulation of sleep time, as well as the consolidation of sleep episodes, was reduced in dbp-/- under both LD and DD conditions. Quantitative EEG analysis demonstrated a marked reduction in the amplitude of the sleep-wake-dependent changes in slow-wave sleep delta power and an increase in hippocampal theta peak frequency in dbp-/- mice. The sleep deprivation-induced compensatory rebound of EEG delta power was similar in both genotypes. In contrast, the rebound in paradoxical sleep was significant in dbp+/+ mice only. It is concluded that the transcriptional regulatory protein DBP modulates circadian and homeostatic aspects of sleep regulation.
Animals↗
Blood and brain magnesium in inbred mice and their correlation with sleep quality.
A strong genetic component in the regulation of blood magnesium (Mg) levels has been demonstrated. The regulation and distribution of brain Mg levels, however, have never been assessed. Herein we report on the genetic variation of peripheral and central Mg levels in six inbred strains of mice. In addition, the possible involvement of Mg in sleep regulation was assessed by establishing correlations between Mg and sleep parameters obtained before and after a 6-h sleep deprivation. Although genotype strongly determined blood Mg levels, it did not affect brain Mg, suggesting that central and peripheral Mg are regulated differently. Central Mg displayed a highly structure-specific distribution with frontal cortex having the highest and brain stem the lowest values. Whereas for the amount and distribution of baseline sleep only marginal correlations with Mg were found, Mg contents in four of nine brain structures were highly positively correlated with the length of slow-wave sleep episodes during recovery. This relationship suggests that higher levels of Mg in specific brain sites promote sleep quality as part of a recovery process.
Animals↗
Genetic determinants of sleep regulation in inbred mice.
Genetic variation in the expression and regulation of sleep was assessed in six inbred mice strains (AK, C, B6, BR, D2, 129). The amount, distribution, and fragmentation of the behavioral states wakefulness (W), slow-wave sleep (SWS), and paradoxical sleep (PS), as well as EEG delta power in SWS, were determined and compared among strains and between baseline and recovery from a 6-hour sleep deprivation (SD) starting at lights-on. In baseline, the most striking strain differences concerned sleep amount, the onset and duration of the main rest period, and SWS fragmentation. The time course of delta power in SWS during the main rest period was similar between strains. Immediately following the SD, high delta power values were reached (higher for AK than for 129). However, the relative increase in delta power, compared to the first 6 hours of the baseline rest period, was not strain-specific. Over the first 6 hours of recovery, W was decreased and PS increased in AK, B6, BR, and 129. In C and D2, time spent in any of the states was not affected by the SD. In contrast, in the recovery dark period, SWS and PS were invariably increased. In recovery, SWS fragmentation was strongly reduced for D2, resulting in the disappearance of the strain differences observed in baseline. Since these inbred strains are fully homozygous and thus can be considered genetic clones, the sleep-related strain differences reported here can be attributed to differences in genotype. Therefore, this study provides a basis for the identification of genetic factors underlying sleep and its regulation.
Animals↗
Molecular approaches towards the isolation of sleep-related genes.
Behavioural genetics is one of the most enticing fields in modern biology. Owing to straightforward and semiautomated techniques that can be used to measure locomotor activity, circadian rhythmicity is perhaps the best studied behaviour in animals. Thus, during the past decade, five essential circadian clock genes have been isolated in Drosophila, and homologous counterparts for all of these genes have also been found in mammals. As the sleep-wake cycle is under the control of the circadian clock, these circadian master genes are expected to influence sleeping behaviour. However, different vigilance states are regulated by additional mechanisms that also have a genetic basis. In this article we discuss molecular approaches that may prove useful in the search for sleep-related genes.
Animals↗
Quantitative trait loci approach to the genetics of sleep in recombinant inbred mice.
Sleep is a complex trait controlled by many genes, the environment, and probably by gene-environment interactions. Among different approaches to the genetics of sleep, analysis of quantitative traits (QTL) has the advantage of being able to detect, along with major genes, minor and/or modifier genes influencing different quantitative aspects of sleep. We have used QTL analysis in two different sets of recombinant inbred (RI) strains and sought for confirmation of several localizations in eight histocompatibility congenic strains. Several QTLs were identified which influenced the amount of vigilance states. In a first RI series (seven strains) the only QTLs identified were those affecting paradoxical sleep (PS), whereas analysis in a second RI series (25 strains) revealed QTLs influencing PS, slow-wave sleep, and total sleep. Among these, a single QTL on chromosome 5 was associated with all vigilance states, suggesting the presence of a major gene influencing a basic aspect of sleep amount. Search for candidate genes around the identified QTLs indicated several immune related genes that have been implicated in sleep regulation. Transgenic animals carrying loss-of-function and/or gain-of-function mutations affecting these candidate genes should confirm these findings.
Alleles↗
Lack of association between juvenile myoclonic epilepsy and HLA-DR13.
PURPOSE: We sought to replicate and extend a previously reported positive association between juvenile myoclonic epilepsy and HLA-DR13. METHODS: Ninety-three subjects with juvenile myoclonic epilepsy and 93 normal blood donors, entirely of white origin with their families mostly of French extraction, underwent DNA-based HLA-DR13 and DQB6 typing. RESULTS: None of the investigated alleles or combination of alleles (DRB1*1301-DQB1*0603 or DRB1*1302-DQB1*0604) showed a significant difference between patients and controls. CONCLUSIONS: Unlike previously reported positive association, in this population, there is no evidence that susceptibility to juvenile myoclonic epilepsy is associated with HLA-DR13.
Alleles↗
Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines.
Basal forebrain (BF) cholinergic regulation of cataplexy was investigated in narcoleptic canines. Specific cholinergic agonists and antagonists, and excitatory or inhibitory amino acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the BF of narcoleptic canines. Cataplexy was monitored using the food-elicited cataplexy test (FECT) and recordings of electroencephalogram, electrooculogram, and electromyogram. In narcoleptic canines, carbachol and oxotremorine (10(-5)-10(-3) M), but not McN-A-343 or nicotine (10(-4)-10(-3) M), produced a dose-dependent increase in cataplexy. In addition, N-methyl-d-aspartate (10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effects, while muscimol (10(-3) M) produced a weak (P < 0.10) increase in cataplexy. In control canines, carbachol (10(-5)-10(-3) M), but not oxotremorine (10(-4)-10(-3) M), produced muscle atonia after the highest concentration in one of three animals. Carbachol (10(-3) M)-induced cataplexy in narcoleptic canines was blocked by equimolar perfusion with the muscarinic antagonists atropine, gallamine, and 4-DAMP but not pirenzepine. These findings indicate that carbachol-stimulated cataplexy in the BF of narcoleptic canines is mediated by M2, and perhaps M3, muscarinic receptors. The release of acetylcholine in the BF was also examined during FECT and non-FECT behavioral stimulation in narcoleptic and control canines. A significant increase in acetylcholine release was found in both narcoleptic and control BF during FECT stimulation. In contrast, simple motor activity and feeding, approximating that which occurs during an FECT, did not affect acetylcholine release in the BF of narcoleptic canines. These findings indicate that BF acetylcholine release is enhanced during learned emotion/reward associated behaviors in canines.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
Homeostatic process and sleep spindles in patients with sleep-maintenance insomnia: effect of partial (21 h) sleep deprivation.
OBJECTIVES: A low level of process 5 at bed time would be responsible for a reduced amount of slow-wave activity (SWA) leading to increased alpha activity and awakenings at the end of the night. METHODS: Following a base-line night (BLN) recording, 7 sleep-maintenance insomnia (SMI) subjects and 7 sex- and age-matched controls were maintained on 21 h of sleep deprivation. Thereafter, a recovery night (RN) was performed from 2300 h until spontaneous awakening. SWA (power density of the EEG delta band between 0.75 and 4.5 Hz) was monitored by means of spectral analysis (FFT). Sleep spindles and the occupation ratio of Rechtschaffen and Kales EEG bands were observed by integrated digital filtering analysis. RESULTS: SWA was lower in SMI subjects than in controls during RN but was higher than in BLN indicating that the homeostatic process was operating, but weaker in SMI subjects. On the other hand in SMI subjects the sleep spindle index (SSI) did not decrease during slow-wave sleep and was significantly lower than in controls. Moreover during RN the SSI decreased significantly during the first sleep cycle in controls and not in SMI subjects. The existence of an inverse relationship between SWA and SSI was therefore not observed in insomniacs. Finally the mean duration of alpha frequency significantly increased in SMI subjects. CONCLUSIONS: It is hypothesised that in SMI subjects, an alteration of the homeostatic process is responsible for insufficient sleep pressure leading to an inability to maintain sleep for an extended period.
Adult↗
Genetic variation in EEG activity during sleep in inbred mice.
The genetic variation in spontaneous rhythmic electroencephalographic (EEG) activity was assessed by the quantitative analysis of the EEG in six inbred mice strains. Mean spectral EEG profiles (0-25 Hz) over 24 h were obtained for paradoxical sleep (PS), slow-wave sleep (SWS), and wakefulness. A highly significant genotype-specific variation was found for theta peak frequency during both PS and SWS, which strongly suggests the presence of a gene with a major effect. The strain distribution of theta peak frequency during exploratory behavior differed from that during sleep. In SWS, the relative contributions of delta (1-4 Hz) and sigma (11-15) power to the EEG varied with genotype and power in both frequency bands was negatively correlated. In addition, the EEG dynamics at state transitions were analyzed with a 4-s resolution. The onset of PS, but not that of wakefulness, was preceded by a pronounced peak in high-frequency (>11 Hz) power. These findings are discussed in terms of the neurophysiological mechanisms underlying rhythm generation and their control and modulation by the brain stem reticular-activating system.
Animals↗