Alain Malafosse

Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2

Generalized epilepsy with febrile seizures plus type 2 (GEFS+2, MIM 604233) is an autosomal dominant disorder characterized by febrile seizures in children and afebrile seizures in adults. We describe here two mutations of the gene encoding the neuronal voltage-gated sodium channel (SCN1A), Thr875Met and Arg1648His, that co-segregate with the disorder in two families with GEFS+ linked to chromosome 2q. These mutations identify a new disease gene for human inherited epilepsy.

15q13.3 microdeletions increase risk of idiopathic generalized epilepsy

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.

Increased methylation of glucocorticoid receptor gene ( NR3C1 ) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

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.

The electroencephalographic fingerprint of sleep is genetically determined: a twin study.

Humans have an individual profile of the electroencephalographic power spectra at the 8 to 16Hz frequency during non–rapid eye movement sleep that is stable over time and resistant to experimental perturbations. We tested the hypothesis that this electroencephalographic “fingerprint” is genetically determined, by recording 40 monozygotic and dizygotic twins during baseline and recovery sleep after prolonged wakefulness. We show a largely greater similarity within monozygotic than dizygotic pairs, resulting in a heritability estimate of 96%, not influenced by sleep need and intensity. If replicated, these results will establish the electroencephalographic profile during sleep as one of the most heritable traits of humans. Ann Neurol 2008

Association between violent suicidal behavior and the low activity allele of the serotonin transporter gene

There is compelling evidence that serotonin system dysfunction is associated with certain behavioral disorders, such as suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele found to be associated with a lower level of expression of the gene, lower levels of 5-HT uptake, suicidal behavior and anxiety-related traits. We genotyped 51 West European Caucasians who had made violent suicide attempts and 139 controls of the same ethnic origin, with no history of suicidal behavior. The frequencies of the S allele and the SS genotype were significantly higher in the violent suicide attempters than in the controls. The odds ratio for the SS genotype vs the LL genotype was 3.63 (95% CI (1.27–10.40)). This suggests that a change in expression of the gene encoding the 5-HT transporter may be involved in violent suicidal behavior.

How mutations in the nAChRs can cause ADNFLE epilepsy.

Summary:  Purpose: The linkage between autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and neuronal nicotinic acetylcholine receptor has been strongly reinforced by the report of five distinct mutations in the two genes coding for the major brain α4β2 nicotinic acetylcholine (ACh) receptors. As a first step toward understanding the basic mechanisms underlying this genetically transmissible neurologic disorder, we examined the similarities and differences of the functional properties displayed by naturally occurring mutant forms of this ligand‐gated channel.

Association between the TPH gene A218C polymorphism and suicidal behavior: A meta-analysis

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of suicidal behavior. The tryptophan hydroxylase (TPH) gene, which codes for the rate‐limiting enzyme of serotonin biosynthesis, is a major candidate gene and has been extensively studied in association studies of suicidal behavior, providing conflicting results. It is difficult to interpret these conflicting results due to lack of power, ethnic heterogeneity, and variations in the sampling strategies (in particular for controls) and in the polymorphism of the TPH gene studied. Meta‐analyses can improve the statistical power for the analysis of the effects of candidate vulnerability factors. The analysis of the sources of heterogeneity that contribute to these conflicting results is an important step in the interpretation of these conflicting association results and in the interpretation of the results of a meta‐analysis. We selected all of the published association studies between the TPH gene polymorphism and suicidal behavior. Nine association studies between the A218C TPH polymorphism and suicidal behavior fulfilled the inclusion criteria. A significant association was observed between the A218C polymorphism and suicidal behavior using the fixed effect method (odds ratio (OR) = 1.62; 95% confidence interval (CI) = [1.26; 2.07]) and the random effect method (OR = 1.61; 95% CI = [1.11; 2.35]). The analysis of the sources of heterogeneity showed that two studies (one positive and one negative) significantly deviated from the calculated global effect. The meta‐analysis performed after removing those two studies also revealed a significant association between the TPH A218C polymorphism and suicidal behavior. Both analyses suggested that the A allele has a dose‐dependent effect on the risk of suicidal behavior.

Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior

Decision-making impairment has been linked to orbitofrontal cortex lesions and to different disorders including substance abuse, aggression and suicidal behavior. Understanding the neurocognitive mechanisms of these impairments could facilitate the development of effective treatments. In the current study, we aimed to explore the neural and cognitive basis of poor decision-making ability associated with the vulnerability to suicidal behavior, a public health issue in most western countries. Twenty-five not currently depressed male patients, 13 of whom had a history of suicidal acts (suicide attempters) and 12 of whom had none (affective controls), performed an adapted version of the Iowa Gambling Task during functional Magnetic Resonance Imaging. Task-related functional Regions-of-Interest were independently defined in 15 male healthy controls performing the same task (Lawrence et al., 2009). In comparison to affective controls, suicide attempters showed 1) poorer performance on the gambling task 2) decreased activation during risky relative to safe choices in left lateral orbitofrontal and occipital cortices 3) no difference for the contrast between wins and losses. Altered processing of risk under conditions of uncertainty, associated with left lateral orbitofrontal cortex dysfunction, could explain the decision-making deficits observed in suicide attempters. These impaired cognitive and neural processes may represent future predictive markers and therapeutic targets in a field where identification of those at risk is poor and specific treatments are lacking. These results also add to our growing understanding of the role of the orbitofrontal cortex in decision-making and psychopathology.