Abstract: We report a Tunisian patient born from consanguineous marriage affected with progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel c.659T>A mutation on exon 3 of the EPM2A gene, converting a leucine to a glutamine residue at amino acid position 220 (p.Leu220Gln), in the dual-specificity phosphatase domain.
Abstract: Background: Recent studies have reported alterations in protein kinase B (PKB)/Akt and in its downstream target, glycogen synthase kinase 3β, in depression and suicide. The aim of the present study was to investigate possible impairment of the upstream regulators, namely phosphatidylinositol 3-kinase (PI3K) and PTEN. Methods: The ventral prefrontal cortex (Brodmann's area 11) of 24 suicide victims and 24 drug-free nonsuicide subjects was used. The antemortem diagnoses of major depression disorder were obtained from the institutional records or psychological autopsy, and toxicological analyses were performed. Protein levels of PI3K and PTEN were assayed using the immunoblot method, and the kinase activity of PI3K and Akt was determined by phosphorylation of specific substrates. Results: A decrease was observed in the enzymatic activity of PI3K [ANOVA: F(3, 44) = 9.20; p < 0.001] and Akt1 [ANOVA: F(3, 44) = 13.59; p < 0.001], without any change in protein levels, in both depressed suicide victims and depressed nonsuicide subjects (p < 0.01 and p < 0.002, respectively). PTEN protein levels were increased in the same groups [ANOVA: F(3, 44) = 10.5; p < 0.001]. No change was observed in nondepressed suicide victims. Conclusion: This study concludes that attenuation of kinase activity of PKB/Akt in depressed suicide victims may be due to the combined dysregulation of PTEN and PI3K resulting in insufficient phosphorylation of lipid second messengers. The effect is associated with major depression rather than with suicide per se. Given the cellular deficits reported in major depression, the study of enzymes involved in cell survival and neuroplasticity is particularly relevant to neurotrophic factor dysregulation in depression.
Abstract: BACKGROUND: Epigenetic changes may play a role in the etiology of psychotic diseases. It has been demonstrated that the serotonin receptor, 5HTR1A, is implicated in schizophrenia (SCZ) and bipolar disorder (BPD). The aim of this study was to investigate the methylation status of a promoter region of the 5HTR1A gene in BPD and SCZ patients. METHODS: Our study included 58 BPD and 40 SCZ (DSM-IV criteria) as well as 67 control subjects. DNA was extracted from blood leukocytes and high-resolution melt (HRM) method was used for analysis. RESULTS: Non-parametric analysis of variance (Kruskal-Wallis) within groups was significant: H=67.6; p<0.0001. The Mann-Whitney U-test showed increased methylation level in both BPD (Z=-7.4; p<0.0001) and SCZ (Z=4.2; p<0.0001) compared to controls. No effect either of age or gender by own, was observed. ANCOVA revealed a modest effect of age/gender covariance (F=3.99; p<0.048). LIMITATION: We used a peripheral tissue. The relationship between methylation of blood and brain DNA is not well known. Data need to be replicated in a brain tissue. CONCLUSION: We observed increased DNA methylation in the promoter region of the 5HTR1A gene of SCZ and BPD. This could explain the reported decrease of the receptor expression. The current study supports the growing interest of DNA methylation in psychopathology.
Abstract: Clinical studies suggest that childhood maltreatment may cause nervous system changes and consequent cognitive disorder. The persistence of this association in late-life is examined.
Abstract: Aims: This study investigated clinical and genetic predictors of increasing suicidal ideation during antidepressant treatment. Materials & methods: A total of 131 depressed outpatients were allocated to four antidepressants (paroxetine, venlafaxine, clomipramine or nefazodone) in a sequential step procedure until remission. Suicidality was assessed using the 10th item of the Montgomery-Asberg Depression Rating Scale (MADRS). A total of 11 candidate genes involved in different mechanisms of antidepressant action were selected for association with increasing suicidality. Results: Increasing suicidality correlated with depression severity and higher antidepressant blood levels. Risk of increasing suicidal ideation was higher in subjects taking antidepressants other than paroxetine (odds ratio: 1.11). The strongest genetic predictor was found to be rs1360780 within the FKBP5 gene (p = 2.9 × 10(-5)), followed by 2677G>T in the ABCB1 gene. The rs130058 SNP within the 5-HTR1B gene demonstrated a differential association with increasing suicidal ideation depending on antidepressant type. Conclusion: Increasing suicidal ideation might be an adverse effect of antidepressants. The involvement of FKBP5 indicates that dysregulation of the hypothalamic-pituitary-adrenal axis is involved in treatment increasing suicidal ideation. Original submitted 12 October 2010; Revision submitted 18 November 2010.
Abstract: Juvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized epilepsies (IGE) that account for about 5-10% of all types of epilepsies. The first putative locus termed EJM1 is on the human leucocyte antigen (HLA-II) region of chromosome 6p21.3. Interestingly, the EJM1 region includes the Transporter associated with antigen processing 1 (TAP-1) gene encoding the TAP-1, and previous studies have reported associations between HLA-II polymorphisms and different types of epilepsy. In this study, we report an association between two TAP-1 functional polymorphisms the I333V and the D637G and most common IGE in Tunisian population, but we fail to find significant results in Caucasian with JME.
Abstract: 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.
Abstract: Serotonergic signaling abnormalities have been implicated in suicide. Tryptophan hydroxylase (TPH), the rate limiting enzyme of serotonin biosynthesis and the serotonin transporter (SLC6A4), involved in the reuptake of serotonin from the synaptic gap, play major role in serotonergic signaling. In this study, we aimed to compare the levels of expression of these serotonin-related genes between suicide completers and controls and to identify genetic loci involved in their regulation. SLC6A4, TPH1, and TPH2 mRNA levels were measured in the ventral prefrontal cortex (VPFC) of 39 suicide completers and 40 matched controls. To identify the molecular basis of gene expression variation, we performed association studies between cis-acting polymorphisms and SLC6A4, TPH1, and TPH2 transcript levels. Finally, association analyses were carried out between suicide and TPH2 cis-single nucleotide polymorphisms (SNPs) in cohorts of 154 suicide completers and 289 control subjects. Whereas SLC6A4 and TPH1 mRNA expression levels did not differ between suicides and controls, TPH2 levels were found significantly increased (P = 0.003) in suicide completers. We observed that SNP rs10748185 located in the promoter region of TPH2 significantly affect levels of TPH2 mRNA expression. However, we did not find positive association between this eQTL (rs10748185) and suicide. Here, we report the simultaneous analysis of the expression of three serotonin-related genes in the VPFC of suicide victims and controls. This study showed that TPH2 expression levels were increased in the VPFC of suicide victims. Although, we identified a genetic variant that explains variance in TPH2 expression, we did not find evidence associating this cis-regulatory SNP with suicidal behavior.
Abstract: The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.
Abstract: Juvenile myoclonic epilepsy (JME) is a genetically determined common subtype of idiopathic generalized epilepsy. Linkage of JME to the chromosomal region 6p21.3 has been reported. An association has been previously observed between JME and the positional candidate, 6p21.3 linked, BRD2. Another candidate in this region is the TAP-1 gene encoding the Transporter Associated with Antigen Processing. The aim of the present study is to determine whether these two genes modulate the vulnerability to JME. While no difference was observed in the allele and genotype frequencies of BRD2 between JME and controls, an association was found between a TAP-1 haplotype and JME, suggesting that this gene may be another 6p21.3 linked vulnerability factor to JME.
Abstract: Modification of the effect of life events on risk of depression by a polymorphism in the serotonin transporter gene promoter (5-HTTLPR) has been reported in child, adolescent, adult and elderly populations. Replication attempted on data collected from 1421 individuals aged 65 and over from a French community study provided no evidence of a similar modifying effect. In the only analysis known to the authors to be carried out in an exclusively elderly, European population, this null finding remained consistent after restriction of analysis to prevalent or incident cases.
Abstract: Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epilepsies (IGEs), affecting 12-30% of all epilepsies in medical centers. To date genetic linkage studies have revealed putative loci on different chromosomes, but these findings are still inconclusive about which gene precisely is responsible for the disease. Here, we report the genetic and clinical analysis of a (JME) consanguineous Tunisian family with four affected children out of eight. A genome-wide search was carried out by using the Affymetrix GeneChip Mapping 500K NspI chip. Pairewise logarithm of the odds (LOD) scores were calculated with MERLIN (1.1) assuming an autosomal recessive model, and a complementary homozygous mapping analysis was performed with AutoSNPa software. The genome-wide parametric linkage analysis showed suggestive linkage to chromosome 2q. Interactive visual analysis of SNP data using AutoSNPa revealed two large regions of shared homozygosity by descent on 2q23.3 and on 2q24.1. We decided to sequence the exons of the two genes coding for such proteins located in 2q23.3, CACNB4 and 2q24.1, KCNJ3. No nucleotide variation--comprising the previously reported mutations--was detected.
Abstract: Identification of patients with a bipolar disorder (BPD) among those presenting a major depressive episode is often difficult, resulting in common misdiagnosis and mistreatment. Our aim was to identify clinical variables unrelated to current depressive episode and relevant to suicidal behavior that may help to improve the detection of BPD in suicide attempters presenting with recurrent major depressive disorder.
Abstract: Anger-related traits are regulated by genes as well as early environmental factors. Both childhood maltreatment and genes underlie vulnerability to suicidal behaviors, possibly by affecting the constitution of intermediate phenotypes such as anger traits. The aim of this study was to test the interaction between nine candidate genes and childhood maltreatment in modulating anger-related traits in 875 adult suicide attempters. The State-Trait Anger Expression Inventory and the Childhood Trauma Questionnaire were used to examine anger traits and traumatic childhood experiences, respectively. The functional polymorphism of the catecholamine-O-methyl-transferase (COMT) gene Val158Met significantly modulated the association between sexual abuse and anger-trait level (P = 0.001). In the presence of sexual abuse, individuals carrying the Val high-activity allele displayed greater disposition toward anger than individuals homozygous for the Met allele (P = 0.0003). Notably, none of the serotonin-related genes influenced the effect of childhood abuse on anger traits. The results of the present study suggest that anger-trait level is influenced by the interaction between childhood abuse and functional polymorphism in the COMT gene. This study was carried out in a population with a high frequency of childhood abuse and a high disposition toward anger, and replication in healthy subjects is needed.
Abstract: 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.
Abstract: BACKGROUND: In spite of the high prevalence of suicide behaviours and the magnitude of the resultant burden, little is known about why individuals reattempt. We aim to investigate the relationships between clinical risk factors and the repetition of suicidal attempts. METHODS: 1349 suicide attempters were consecutively recruited in the Emergency Room (ER) of two academic hospitals in France and Spain. Patients were extensively assessed and demographic and clinical data obtained. Data mining was used to determine the minimal number of variables that blinded the rest in relation to the number of suicide attempts. Using this set, a probabilistic graph ranking relationships with the target variable was constructed. RESULTS: The most common diagnoses among suicide attempters were affective disorders, followed by anxiety disorders. Risk of frequent suicide attempt was highest among middle-aged subjects, and diminished progressively with advancing age of onset at first attempt. Anxiety disorders significantly increased the risk of presenting frequent suicide attempts. Pathway analysis also indicated that frequent suicide attempts were linked to greater odds for alcohol and substance abuse disorders and more intensive treatment. CONCLUSIONS: Novel statistical methods found several clinical features that were associated with a history of frequent suicide attempts. The identified pathways may promote new hypothesis-driven studies of suicide attempts and preventive strategies.
Abstract: A better understanding of the pathophysiology of suicidal behaviour (SB) may enable the discovery of more specific treatments and a better identification of vulnerable patients. The vulnerability to SB appears to be underlied by genetic factors coding for traits rendering the individual less able to cope with stressing situations, and more likely to be engaged in a suicidal process.
Abstract: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE.
Abstract: The recent development of genomic selection induces dramatic changes in the way genetic selection schemes are to be conducted. This review describes the new context and corresponding needs for genomic based selection schemes and how reproductive technologies can be used to meet those needs. Information brought by reproductive physiology will provide new markers and new improved phenotypes that will increase the efficiency of selection schemes for reproductive traits. In this context, the value of the reproductive techniques including assisted embryo based reproductive technologies (Multiple Ovaluation Embryo Transfer and Ovum pick up associated to in vitro Fertilization) is also revisited. The interest of embryo typing is discussed. The recent results obtained with this emerging technology which are compatible with the use of the last generation of chips for genotype analysis may lead to very promising applications for the breeding industry. The combined use of several embryo based reproductive technologies will probably be more important in the near future to satisfy the needs of genomic selection for increasing the number of candidates and to preserve at the same time genetic variability.
Abstract: Lipids appear to mediate depressive vulnerability in the elderly; however, sex differences and genetic vulnerability have not been taken into account in previous prospective studies.
Abstract: A boy with a clinical history of pharmacologically resistant Dravet syndrome died suddenly after falling asleep. The autopsy concluded that the cause of death was sudden unexpected death in epilepsy (SUDEP). Postmortem molecular analysis of the SCN1A gene by multiplex ligation-dependent probe amplification (MLPA), high-resolution melting curve analysis (HRMCA), and sequencing revealed a frameshift duplication of adenosine at position 504. The incidence of this mutation is discussed as a potential cause of SUDEP.
Abstract: It has recently been proposed that the SSAT gene plays a role in the predisposition to suicidal behavior. SSAT expression was found to be down-regulated in the brain of suicide completers. In addition, a single nucleotide polymorphism (SNP) rs6526342 was associated both with variation in SSAT expression and with suicidal behavior. In this study, we aimed to characterize the relationship between SSAT dysregulation and suicide behavior. To this end, we measured SSAT expression levels in the ventral prefrontal cortex (VPFC) of suicide completers (n = 20) and controls (n = 20) and found them to be significantly down-regulated in suicide victims (P = 0.007). To identify the basis of the regulation of SSAT expression, we performed an association analysis of 309 SNPs with SSAT transcript levels in 53 lymphoblastoid cell lines from the CEPH collection. We then examined the methylation status of the SSAT promoter region in males and females suicide completers and control subjects whose SSAT brain expression had been measured. We found no evidence to support a role for SNPs in controlling the level of SSAT expression. SSAT promoter methylation levels were not different between suicide completers and controls and did not correlate with SSAT expression levels. In addition, we found no indication of a genetic association between suicidal behavior and SNPs located within the SSAT gene. Our study provides new results which show that dysregulation of SSAT expression does play a role in suicide behavior. However, our data do not support any association between rs6526342 and variation in SSAT expression or suicidal behavior.
Abstract: Suicide is one of the ten most common causes of death in Western countries. It involves genetic vulnerability factors and is often associated with major depression. A Japanese team reported an association between the insertion allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with completed suicide. The ACE I/D polymorphism was investigated in two independent case-control studies, one involving 64 suicide completers and 90 controls who all underwent forensic investigations, the second one consisting of 588 suicide attempters and 639 controls. In the two population samples studied a statistically significant risk of suicidal behavior was observed for subjects bearing the DD genotype. These results suggest a possible role of the renin-angiotensin system in suicidal behavior.
Abstract: 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 x 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.
Abstract: Childhood trauma and aggressive traits are considered risk factors for suicidal behavior. The hypothesis we aimed to test in this study was the existence of an association between childhood trauma and aggression in two distinct samples of Italian and French suicide attempters.
Abstract: We assessed whether smoking behavior was associated with nine polymorphisms in genes coding for the nicotinic receptor subunits alpha-4 (rs1044394, rs1044396, rs2236196 and rs2273504), alpha-5 (rs16969968), beta-2 (rs2072661 and rs4845378) and beta-3 (rs4953 and rs6474413).We conducted an Internet survey and collected saliva by mail for DNA and cotinine analyses, in Switzerland in 2003. We conducted DNA analyses for 277 participants and cotinine analyses for 141 current daily smokers. Cotinine levels were higher in carriers of the CC genotype of CHRNA4 rs1044396 (371 ng/ml) than in those with the CT or TT genotypes (275 ng/ml, p=0.049), a difference of 0.53 standard deviation units. However, this difference was not robust to correction for multiple testing using Bonferroni adjustment. These 9 polymorphisms were not otherwise associated with smoking behavior and nicotine dependence. There were possible associations between the temperament trait novelty seeking and CHRNA4 rs1044396, CHRNA5 rs16969968 and CHRNB2 rs4845378, but these associations were not robust to correction for multiple testing. We conclude that the analysis of polymorphisms in genes coding for four nicotinic acetylcholine receptor subunits (CHRNA4, CHRNA5, CHRNB2 and CHRNB3) and several smoking-related phenotypes revealed no statistically significant association.
Abstract: Neurobiological and clinical studies suggest that childhood maltreatment may result in functional and structural nervous system changes that predispose the individual to depression. This vulnerability appears to be modulated by a polymorphism in the serotonin gene-linked promoter region (5-HTTLPR). Little is known, however, about the persistence of this vulnerability across the life span, although clinical studies of adult populations suggest that gene-environment interaction may diminish with aging.
Abstract: In 1994, it was proposed that decision-making requires emotion-related signals, known as somatic markers. In contrast, some authors argued that conscious knowledge of contingencies is sufficient for advantageous decision-making. We aimed to investigate the respective roles of somatic markers and explicit knowledge in decision-making. Thirty healthy volunteers performed the Iowa Gambling Task (IGT). Conscious knowledge was assessed using a sensitive questionnaire and skin conductance responses (SCRs) were recorded. Most participants acquired a preference for advantageous choices during the task and generated larger anticipatory SCRs before disadvantageous relative to advantageous choices. Performance on the IGT and the autonomic response were positively correlated (r=0.38, p=0.045). Moreover, there was a statistically significant difference in performance according to conscious awareness (p=0.009). There was no significant association between level of explicit knowledge and SCR (p=0.1). Finally, we did not find any interaction between explicit knowledge and performance although a lack of statistical power is not to be excluded. Advantageous decision-making therefore seems to be associated with two distinct, namely implicit and explicit, systems.
Abstract: A genetic association between the tryptophan hydroxylase gene (TPH)-1 A218C polymorphism and suicidal behaviour is supported by numerous case-control studies as well as recent meta-analyses. Some data suggest that this polymorphism could also influence individual differences in anger-related personality traits, a phenotype partially under genetic control and known to increase the risk of suicide ideation and attempt. The aim of the present study was to investigate whether the TPH-1 A218C polymorphism affected anger-related personality traits in suicide attempters (n = 544). We hypothesized that suicide attempters carrying the AA genotype would display different scores on a scale measuring anger-related traits compared with suicide attempters carrying the CC genotype. Indeed, the dimension of Anger Control was significantly affected by the TPH-1 A218C polymorphism: suicide attempters carrying the AA genotype scored significantly lower on the Anger Control subscale than suicide attempters carrying the AC and CC genotypes. This polymorphism did not display any influence on the other State-Trait Anger Expression Inventory subscales. This result confirms our working hypothesis and suggests that the TPH-1 genotype could confer a vulnerability to suicidal behaviour through a reduced capacity to control anger, which in turn may represent a common psychopathological and behavioural pathway to suicidal behaviour in an important subgroup of clinical subjects.
Abstract: Genetic factors, specially those related to serotoninergic activities, and childhood maltreatment have both been implicated in suicidal behaviour (SB). However, little attention has been paid to the possible interaction between genes and childhood maltreatment in the comprehension of SB. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth of serotoninergic neurons during childhood and therefore is a good candidate for studies on SB. Moreover, decreased levels of BDNF have been found in the prefrontal cortex of suicide victims. In our study we wanted to see if Val66Met (a BDNF functional single-nucleotide polymorphism) could moderate the effect of childhood maltreatment on the onset, number and violence of SB in a sample of 813 Caucasian suicide attempters. Childhood maltreatment was evaluated using the Childhood Trauma Questionnaire. We used a regression framework to test the interaction between Val66Met and childhood maltreatment. Childhood sexual abuse was associated with violent suicide attempts (SA) in adulthood only among Val/Val individuals and not among Val/Met or Met/Met individuals (P = 0.05). The severity of childhood maltreatment was significantly associated with a higher number of SA and with a younger age at onset of suicide attempt. This result suggests that Val66Met modulates the effect of childhood sexual abuse on the violence of SB. It is proposed that childhood sexual abuse elicits brain structural modifications through BDNF dysfunction and enhances the risk of violent SB in adulthood.
Abstract: Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other.
Abstract: Humans have an individual profile of the electroencephalographic power spectra at the 8 to 16 Hz 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.
Abstract: The objective of this study is to replicate previously published results regarding the involvement of several susceptibility genes in temporal lobe epilepsy (TLE): interleukin 1beta (IL-1beta), interleukin 1beta (IL-1alpha), interleukin 1RA (IL-1RA), apolipoprotein E (ApoE) and prodynorphin (PDYN). We used a case-control approach comparing several polymorphisms within these candidate genes between unrelated TLE patients and matched controls. We were thus able to confirm the role of ApoE, IL-1alpha and IL-1RA genes in TLE disease, but failed to confirm the involvement of IL-1beta and PDYN. This failure should be interpreted with caution, as this may be due to the small size of our study groups and the resultant lack of statistical power.
Abstract: Decision-making has been found to be altered in suicide attempters and may represent a neuropsychological trait of vulnerability to suicidal behaviour. Environmental stressors such as adverse life events and interpersonal problems have been demonstrated to precipitate suicidal acts in vulnerable people. However, the link between vulnerability and stressors is complex and may even be circular. In the present study, we hypothesized that impaired decision-making may be associated with an increased risk of negative life events in suicide attempters.
Abstract: Past studies in the neurobiology of suicide have reported alterations in serotonin and downstream effectors, such as Akt/protein kinase B. In this study, we aimed to examine possible abnormality in the Akt/glycogen synthase kinase-3beta (GSK-3beta) axis of depressed suicide victims' brains.
Abstract: Genetic factors have been associated with the vulnerability to suicidal behavior. We previously reported decision-making impairment in suicide attempters and hypothesized that these cognitive alterations may represent an endophenotype of suicidal behavior. In this study, we aimed to investigate the influence of four serotonin-related genes relevant to suicidal behavior on decision-making, in a large population of suicide attempters. The Iowa Gambling Task was used to assess decision-making in 168 patients with a personal history of attempted suicide. Patients were genotyped for four serotonergic polymorphisms: 5HTTLPR, TPH1 A218C, MAOA u-VNTR, and TPH2 rs1118997. Patients carrying the 5HTTLPR-ll and -sl, TPH1-CC and -AC, MAOA-HH (in women) and TPH2-AA genotypes significantly improved their performance during the task, suggesting a genetic modulation of the learning process required for advantageous decision-making. In contrast, genotypes previously associated with a higher risk of suicidal behavior, a greater sensitivity to the environment and a higher propensity to negative feelings are those conferring poorer learning abilities. We hypothesize that the influence of genetic factors on the vulnerability to suicidal behavior may partly be achieved through their modulation of decision-making and particularly its learning component.
Abstract: In an attempt to reduce the phenotypical heterogeneity in an ongoing genetic study of suicidal behavior, we investigated the impact of comorbid anxiety disorders on suicidal behavior in bipolar disorder (BD) patients.
Abstract: Anger-related personality traits are considered contributory risk factors for suicidal behavior. According to twin studies, they are partially under genetic control and their various clinical expressions have been associated with serotonergic and catecholaminergic activities. A functional polymorphism on the human catechol-O-methyltransferase (COMT) gene, which codes for the catecholamines inactivating enzyme COMT, has been shown to influence aggressive and anger-related traits in various clinical populations. The aim of the present study was to investigate the association between anger traits (as characterized by the State-Trait Anger Expression Inventory, STAXI) and COMT Val158Met polymorphism in suicide attempters (n = 427) and control subjects (n = 185). Results showed that the high activity genotype (Val/Val) was more frequent in suicide attempters than in normal controls. Moreover, the Val/Val genotype markedly affected the scores on two STAXI subscales--Trait Anger and Anger Control--in female suicide attempters, thus suggesting a possible gender effect of the COMT genotype on a stable personality trait. These results are discussed in the light of recently published data on the effect of COMT Val158Met polymorphism on different cognitive and behavioral traits.
Abstract: Decision-making impairment is an important feature of psychiatric disorders. In a large comorbid psychiatric population, we explored the link between decision-making deficit and clinical variables.
Abstract: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects).
Abstract: Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01-0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.
Abstract: The basis of suicidal behavior (SB) is complex and multifactorial. Numerous risk factors have been identified. Epidemiological genetics studies (family studies, twin studies, adoption studies) suggest that there is a genetic basis to SB and that this genetic basis is specific and independent from the genetic factors implicated in predisposition to psychiatric disorders associated with SB (bipolar disorder, schizophrenia, alcoholism). Recently, new molecular genetics tools have been designed to identify the genetic factors that predispose certain individuals to disorders of complex etiology. Biological psychiatry studies have suggested that the physiopathology of SB involves dysfunctioning of the serotonin system. The first genetic association studies tested candidate genes encoding proteins involved in serotonin metabolism. The results of these studies suggest that the gene coding for the limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH), and the gene encoding the serotonin transporter are involved in predisposition to SB. Furthermore, it is likely that these genes interact with each other and with environmental factors (early) and that they have different phenotypic consequences. One of the main aims of studies currently underway is to identify the precise phenotypes associated with genes that predispose to SB or intermediate phenotypes (impulsivity, inability to control anger, etc.).
Abstract: Most of the candidate gene studies in bipolar disorder have focused on the major neurotransmitter systems that are influenced by drugs used in the treatment of this disorder. The monoamine oxidase A (MAOA) and the tryptophan hydroxylase (TPH1, TPH2) genes are two of the candidates that have been tested in a series of association studies using unrelated or family-based controls. This review summarizes the existing association studies regarding these genes. Most of these studies were based on the unrelated case-control design with samples of 50 to 600 subjects. Regarding MAOA, three meta-analyses with partially overlapping samples supported a modest effect of this gene in bipolar disorder in female Caucasians. However, as several studies could not replicate these findings, more work is necessary to demonstrate unequivocally the involvement of MAOA in bipolar disorder and establish the biological mechanism underlying the genetic association. With respect to TPH1 and TPH2, the majority of studies did not provide evidence for an association between these genes and bipolar disorder. The genes are more likely to be related to suicidal behavior than to bipolar disorder.
Abstract: The understanding of suicidal behavior is incomplete. The stress-diathesis model suggests that a deficit in serotonergic projections to the orbitofrontal cortex is involved in susceptibility to suicidal behavior. The orbitofrontal cortex has been implicated in decision making, a cognitive function dealing with complex choices that may be under serotonergic modulation. In this preliminary study, the authors assessed decision making in suicide attempters.
Abstract: Compelling evidence suggests that serotonin system dysfunction is associated with certain behavioral disorders, including suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the monoamine oxidase A gene (uVNTR) was recently identified and the presence of the 2-3 alleles was found to be associated with a higher level of transcription, central nervous system serotonergic responsivity and impulsive aggression. A dinucleotide repeat in intron 2 of the gene (monoamine oxidase A-CAn) has been described previously, and is in linkage disequilibrium with the variable number of tandom repeats (VNTR). The aim of the study was to investigate, in a large sample, whether the monoamine oxidase A gene was involved in the susceptibility to suicidal behavior.
Abstract: The authors assessed whether collection by mail of saliva and buccal cells for genetic analysis was feasible in participants recruited through the Internet. In 2003, 14,773 visitors of a smoking cessation website were invited by e-mail to take part in the study. Salivettes (plastic vials containing a cotton roll) were mailed to participants, for collection of saliva and buccal cells. Because of limited resources, the authors stopped recruitment when 392 participants (3% of 14,733) were registered. They received 315 saliva samples back (80% of 392). Salivary cotinine was analyzed in 145 daily smokers. Cotinine concentration could be assessed in 141 samples (97%) (range 0.7-899 ng/ml, median 260 ng/ml). DNA extraction was achieved in all the 285 samples in which it was attempted. Quality of DNA was assessed by optical density measurements and by polymerase chain reaction amplification of a gene coding for the alpha-4 nicotinic receptor, with the detection of a known polymorphism. Successful results were obtained in 235 samples (82% of 285). Thus collecting saliva by mail for cotinine and DNA analysis in participants recruited through the internet produced samples of good quality at a reasonable cost. This approach should be valuable for genetic epidemiology and pharmacogenetic research.
Abstract: To reevaluate the genetic contribution of the polymorphism G1465A of the gene coding for gamma-aminobutyric acid (GABA)(B) receptor 1 subunit [GABA(B)(1)] in a sample of French patients with temporal lobe epilepsy (TLE) and to perform an exploratory analysis in other phenotypic subgroups.
Abstract: France has high rates of psychotropic drug consumption and suicide in the elderly population, but it has not yet been possible to determine whether this is due to exceptionally high morbidity rates.
Abstract: In the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior.
Abstract: 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.
Abstract: The inconsistency of the results obtained in biological studies of suicidal behavior may be due to the use of broad categories lacking validity. In previous genetic studies, in which we identified an association between a serotonin-related gene and violent suicide attempts, we suggested that a history of major depressive disorder (MDD) might influence this association. In this study, we aimed to clarify the relationships between the violence of suicide attempts, intent to die, and depression in a large sample of suicide attempters.
Abstract: There are many risk factors associated with vulnerability to suicidal behaviour, and the results of family studies, twin studies and adoption studies suggest that they include a genetic predisposition. Moreover, this gentic susceptibility may be specific and independent of the genetic susceptibility to psychiatric disorders associated with suicidal behaviour (e.g., bipolar disorders, schizophrenia, alcoholism). Several groups have carried out association studies using a "candidate gene strategy", with the goal of identifying the genes involved in susceptibility to suicidal behavior. There is compelling evidence from research in biological psychiatry that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of suicidal behavior, and the results of association studies suggest that the gene coding for tryptophan hydroxylase, which is the serotonin synthesis enzyme, and the serotonin transporter gene are involved in susceptibility to suicidal behavior. Furthermore, these genes may influence the suicidal phenotype through different gene-gene interactions and gene-early environment interactions. Current studies aim to identify either the precise phenotypes associated with genes for vulnerability to suicidal behaviour or the intermediate phenotypes (e.g., impulsivity, anger dyscontrol) associated with these genes.
Abstract: Gratacos et al. [2001: Cell 106:367-379] described an interstitial duplication dup(15)q24q26 (DUP25) in patients with anxiety disorders; this duplication was found in approximately 90% of patients and in 7% of controls. In order to determine if DUP25 is present in additional individuals susceptible to panic attacks, we tested 44 patients with anxiety disorders, using probes 251c23 and 216c14 mapping in the 15q24 and 15q26 region. We have not detected any DUP25. Our results suggest that DUP25 is not common in people with anxiety disorders in the population tested here.
Abstract: Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.
Abstract: Preliminary data suggested that there are three subgroups of bipolar affective disorder based on age at onset. The authors sought to replicate those findings and determine the cut-off age of each subgroup.
Abstract: A joint analysis of five paternal half-sib Holstein families that were part of two different granddaughter designs (ADR- or Inra-design) was carried out for five milk production traits and somatic cell score in order to conduct a QTL confirmation study and to increase the experimental power. Data were exchanged in a coded and standardised form. The combined data set (JOINT-design) consisted of on average 231 sires per grandsire. Genetic maps were calculated for 133 markers distributed over nine chromosomes. QTL analyses were performed separately for each design and each trait. The results revealed QTL for milk production on chromosome 14, for milk yield on chromosome 5, and for fat content on chromosome 19 in both the ADR- and the Inra-design (confirmed within this study). Some QTL could only be mapped in either the ADR- or in the Inra-design (not confirmed within this study). Additional QTL previously undetected in the single designs were mapped in the JOINT-design for fat yield (chromosome 19 and 26), protein yield (chromosome 26), protein content (chromosome 5), and somatic cell score (chromosome 2 and 19) with genomewide significance. This study demonstrated the potential benefits of a combined analysis of data from different granddaughter designs.
Abstract: There is compelling evidence that suicidal behavior is associated with the dysfunction of the serotonin system. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele was associated with lower gene expression, lower 5-HT uptake and violent suicidal behavior. Thus, we attempted to determine whether 5-HTTLPR is also involved in the susceptibility to non-violent suicidal behavior. We compared the genotype from 166 West European Caucasians who attempted suicide by a non-violent mean with 139 controls with no history of suicidal behavior from the same ethnic origin. The frequencies of the S allele and the SS genotype in the sample who attempted non-violent suicide were not statistically different to those in the controls. Thus, the genetically altered expression of the 5-HT transporter might be associated with more severe or violent suicidal behavior, but not with non-violent suicidal behavior.
Abstract: The genes involved in the serotonin system are major candidates in association studies on affective disorders and responses to antidepressants. We studied a functional polymorphism of the serotonin transporter (5-HTT) gene (a 44 bp insertion/deletion in the 5-HTT-linked polymorphic region (5-HTTLPR)) and lifetime history of antidepressant-induced mania (AIM) in a population of 305 patients with bipolar affective disorder. AIM was defined using a broad definition and a restrictive definition. No association was found between the "s" allele of the 5-HTTLPR and AIM for either definition. However, we found an association between the 5-HTTLPR and lifetime history of rapid cycling in a subsample of patients (for allele and genotype distributions: exact probability, p=0.0009 and chi(2)=9.4; df=1; p=0.002, respectively). These results may help to explain the conflicting association results obtained with the 5-HTT gene polymorphism, in particular with AIM. Indeed, the precise phenotype associated with the 5-HTT gene is unclear. The association between the "s" allele and rapid cycling may provide further evidence for an association between the 5-HTTLPR "s" allele and a pattern of affective instability.
Abstract: Unverricht-Lundborg disease (ULD) is the most frequent form of progressive myoclonus epilepsy. ULD is caused mostly by a homozygous expansion of a dodecamer repeat in the cystatin B gene (CSTB) promoter. We present here a clinical and molecular study of 14 ULD patients originating from Reunion Island, a French island in the Indian Ocean.
Abstract: Rapidly advancing knowledge concerning the genetic aspects of epilepsy have led us to complete a recent article on the subject published in the journal. A contrasting picture is emerging, particularly between symptomatic and idiopathic epilepsy. For symptomatic epilepsy, divers gene products implicated in brain development and neuron survival have been identified. Inversely, for idiopathic epilepsy, the latest discoveries confirm their canalopathic nature. In addition, rapid progress in the field of mendelian inherited epilepsy has pointed out the lack of notable progress concerning common epilepsy with a complex hereditary pattern. These forms are one of the major challenges for genetic analysis of epilepsy.
Abstract: Recently, major advances have been obtained concerning the molecular genetic basis of Mendelian inherited epilepsies. Several responsible genes have been identified, leading to a better understanding of the pathophysiology of epilepsy, as well as new approaches in its diagnosis and treatment. However, several questions remain. Indeed, Mendelian epilepsies are rare and few patients are concerned. Despite several lines of evidence demonstrating the involvement of genetic factors in the common forms of epilepsy, no progress has been made in this field. Statistical and molecular strategies adapted to identify susceptibility genes for common epilepsies are now available. But these approaches require large samples of patients and relatives, and a collaborative network will be required for characterisation.
Abstract: 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 alpha4beta2 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.
Abstract: Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.
Abstract: 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.
Abstract: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme of serotonin synthesis. In this case-control study, we investigated whether the TPH gene was a susceptibility factor for suicidal behavior. Seven polymorphisms spanning the entire gene were studied in a case-control study including 231 individuals who had attempted suicide and 281 controls. Significant associations were found between variants in introns 7, 8 and 9 (chi(2) = 11.2, df = 1, P< 0.0008 for the allele distribution; these loci are in complete linkage disequilibrium) and in the 3' noncoding region (chi(2) = 30.94, P = 0.0014) and suicide attempt. The association was strongest for subjects who had attempted suicide by violent means and who had a history of major depression. No significant association was observed between suicide attempts and polymorphisms in the promoter, intron 1 and intron 3. The results presented here, and those of previous studies, suggest that a genetic variant of the 3' part of the TPH gene may be a susceptibility factor for a phenotype combining suicidal behavior, mood disorder and impulsive aggression.
Abstract: Cyclic AMP-dependent protein kinase (PKA) activity was involved in a number of brain functions such as cognitive process or aging. The measurement of PKA activity is traditionally based on the use of [(32)P]ATP in phosphorylation of specific protein. Recently non-isotopic PKA assays have been developed, but none has been tested on brain homogenates. This work aimed to adapt a fluorimetric method of PKA activity into a novel assay never applied before in brain homogenate, and to characterize the enzyme activity and ratio in hippocampus and cortex from rats of different ages. Optimal conditions of homogenization and enzyme protection were determined. The method was sensitive and reproducible (intra-assay and interassay variation was 5.0% and 9.0%, respectively). In hippocampal cytosol, PKA activity was 27+/-8 and 80+/-9 nmol/min per mg protein in basal and cAMP-stimulated activity, respectively, and accounted for 80% of total cell PKA activity. The non-PKA activity, assessed by the use of the PKA specific inhibitor (PKI) accounted for 49.0% and 65.0% of endogenous levels in cytosol and membrane, respectively. cAMP-augmenting drugs effects were measured and increase of 53%, 273% and 118% over basal by 10 microM isoproterenol, 100 microM forskolin, 1 microM Sp-AMP, respectively, was observed. With respect to the changes in animal age, PKA activity increased from newborn to the mature rats but decreased in older rats. The PKA ratio was higher in cytosol than in particulate fraction, and was decreased in hippocampal sample from old rats (P<0.05). This last result was interpreted as related to the loss of cognitive capacities in old animals.
Abstract: 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.
Abstract: The discovery of genetically transmissible form of epilepsy associated with a mutation in a gene that codes for a subunit of a ligand-gated channel shined a new light in this field of neurological diseases. Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, functional studies could be designed to evaluate the alterations caused by this mutation. Since this initial observation, five mutations were identified and determination of their functional properties initiated. These experiments were extended to pairwise expression of the control and mutated allele to mimic the heterozygote human genotype. The first common functional trait identified so far, in four of these mutants, is an increased sensitivity to the acetylcholine, suggesting that these mutations may cause a gain of function. An alternative possibility that cannot be excluded is that conditions in the brain are such that these higher responding receptors may be more prone to desensitization. The importance of ionic channels as cause of epilepsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for potassium channel subunits (KCNQ2, KCNQ3). Additional evidences were brought by the identification of mutations in voltage-dependent sodium channels (SCN1A, SCN1B) in a form of generalized epilepsy with febrile seizures.
Abstract: The Cu,Zn superoxide dismutase (Cu,Zn SOD) mutations described in amyotrophic lateral sclerosis (ALS) have, for the most part, a dominant influence. However, while a few cases with a heterozygous D90A mutation have been described in different countries, D90A has been recently proven to be recessively inherited with a common founder effect in Scandinavia. We screened French ALS families for Cu,Zn SOD mutations. The presence of the D90A allele was found in two index-cases, and their families were subsequently studied. In the first family the ALS patients were homozygotes for D90A, while in the second, all ALS patients were heterozygotes. In both families the disease was found to initially involve the lower limbs with slower progression than in sporadic cases, and frequent atypical signs such as paresthesia and urgency of micturition. We determined the D90A allele frequency in controls (n = 200) and sporadic ALS patients (n = 408). No D90A allele was found. This is the first report of coexistence of dominant and recessive families with the D90A Cu,Zn SOD mutation within the same country.
Abstract: The tryptophan hydroxylase (TpH) gene codes for the rate-limiting enzyme in serotonin biosynthesis. It is one of the major candidate genes for psychiatric and behavioral disorders. A polymorphism in TpH intron 7 has been shown to be associated with suicidal attempts, aggressive behavior and psychiatric illnesses. By systematically screening the TpH genomic sequence, we identified and confirmed an earlier report of four variants in the promoter region and localized six new sequence variants, ie two in intron 1b, one in exon 1c, one in intron 8, one in intron 9 and a microsatellite in the 3' region, 5687 bp downstream of the last exon 11. We analyzed these polymorphisms, as well as the one in intron 7, by Single Strand Conformation Analysis, microsatellite or restriction analysis in a collection of 175 West European Caucasian healthy subjects. The four variants in the promoter region are in complete linkage disequilibrium (frequencies of G-T-G-T and T-C-A-G haplotypes are 0. 41 and 0.59, respectively). Deletion of GTT in intron 1b is rare (0. 7%) and so not informative. The rarer allele T of intron 1b polymorphism T3792A has a frequency of 0.34 and is in partial linkage disequilibrium with the more common alleles of intron 7, 8 and 9. The polymorphisms of these three introns are in complete linkage disequilibrium and the frequencies of haplotypes A-T-C and C-C-T are 0.36 and 0.64 respectively. We detected 10 different alleles in the microsatellite localized in the 3' region; allele '194' is in partial linkage disequilibrium with haplotype A-T-C of introns 7, 8, and 9. Analysis of these different polymorphisms will constitute an important tool for future studies between the TpH gene and psychiatric disorders. Molecular Psychiatry (2000) 5, 49-55.
Abstract: Although genetic factors have been implicated in the etiology of bipolar disorder, no specific gene has been conclusively identified. Given the link between abnormalities in serotonergic neurotransmission and bipolar disorder, a candidate gene association approach was applied to study the involvement of the monoamine oxidase A (MAOA) gene, which codes for a catabolic enzyme of serotonin, in the susceptibility to bipolar disorder.
Abstract: The present work was aimed at assessing the GTP-binding (Galphas subunit) protein expression in lithium-treated bipolar patients (BP). Mononuclear leukocyte Galphas protein and mRNA were measured both in patients and in a comparison group. The patient group consisted of 15 lithium-treated patients with bipolar affective disorder, all diagnosed as euthymic bipolars, and a comparison group of 15 drug-free healthy subjects. The method of competitive Reverse Transcriptase coupled to Polymerase Chain Reaction (RT-PCR) was used to estimate the relative abundance of Galphas mRNA, whereas the Western-immunoblot method was used to estimate Galphas levels. Results of both Galphas proteins and Galphas mRNA levels from patients were compared to those of non-treated control subjects. By using the competitive RT-PCR method, the Galphas mRNA displayed a significant decrease in the lithium-treated bipolar patients compared to non-treated controls: the ratio / was 1\81+/-0\05 versus 2\51+/-0\6 for BP and controls, respectively (Mann-Whitney test, < 0%sol;001). Studying the same groups with respect to their protein levels, it was shown that Galphas levels were also significantly decreased in the group of bipolar patients (normalized values to a standard yielded 81\2+/-21 per cent versus 122\5+/-25 per cent for BP and controls, respectively; Mann-Whitney test, < 0\001). Data indicated that lithium induces a decrease both in Galphas protein levels and in Galphas mRNA synthesis in BP with respect to drug-free healthy subjects. Copyright 2000 John Wiley & Sons, Ltd.
Abstract: We present here recent insight into idiopathic epilepsies and febrile convulsions. For each case, main clinical features are presented, concomitantly with genetic advances (transmission, penetrance and expressivity, locus, gene, gene function, identified mutations).
Abstract: 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.
Abstract: Benign familial infantile convulsions (BFIC) is a rare autosomal dominant epilepsy syndrome. This syndrome has been recently described in Italian and French pedigrees. Patients present with partial, then generalized seizures, with onset at age three months. The seizures usually spontaneously cease after one year without treatment, leaving no neurological abnormalities. We have mapped BFIC to chromosome 19q in five Italian pedigrees. The sodium channel beta1 subunit gene (SCN1B) maps to this candidate region and has been shown to be involved in one Australian pedigree with generalized epilepsy and febrile seizures "plus" (GEFS +). In this family, a missense mutation in SCN1B cosegregates with the GEFS+ phenotype. BFIC and GEFS+ have clinical features in common, therefore SCN1B is a candidate gene for BFIC. We studied SCN1B exons 1, 2, 3, 4, and 5, using four SSCP methods in 10 Caucasian BFIC probands of Western Europe. We found no exon variants. One variant was identified in intron 5 (IVS5-10C>G), which did not segregate with BFIC and was observed in 9.2% controls. A second variant in intron 5 was identified (IVS5+30G>A). It was rare, as not observed in controls, but not segregating with the BFIC phenotype.
Abstract: Benign familial infantile convulsion is a syndrome recently identified among the epileptic seizures of infancy. The main characteristics are: occurrence before one year of age, brief epileptic bursts of partial type seizures with secondary generalization, excellent prognosis with normal mental and motor development, high familial incidence. This syndrome appears genetically heterogeneous.
Abstract: 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.
Abstract: Despite numerous suggestions of the involvement of GTP-binding proteins in the mechanisms of action of psychoactive drugs in bipolar affective disorder, few studies have been conducted during the drug treatment of patients. The aim of the present study was to investigate the effects of a mood stabilizer and an antipsychotic drug on Galphas proteins. Patients with bipolar affective disorder under lithium treatment with or without haloperidol were assessed with respect to their mononuclear leukocyte (MNL) Galphas subunit protein. Galphas-45 protein subunit levels were analyzed by the Western immunoblot method. The subjects consisted of a group of 20 patients, all diagnosed as euthymic bipolars, and a comparison group of 15 drug-free healthy subjects. Results showed that Galphas levels were significantly decreased in the bipolar patients (BP) compared to drug-free healthy subjects (Mann-Whitney U test, p < 0.002). The drug effect was evaluated by a factorial analysis of variance and showed significant differences between groups (Kruskal-Wallis H test, p < 0.02). Lithium-treated patients displayed the most decreased Galphas levels (normalized mean values 53.2 +/- 31 vs. 122 +/- 45% for BP and controls, respectively, p < 0.001), while no change was observed in Galphas levels of haloperidol-treated patients compared to controls (mean values: 124.9 +/- 37%; NS). The data indicate that lithium and haloperidol affect the mechanism of Galphas protein signal transduction differently, consistent with previous animal studies.
Abstract: The purpose of this study was to assess the acceptability and validity of the French cross-cultural translation of a semistructured interview for seizure classification (SISC). We used the first revised version, the original of which was validated in 1990.
Abstract: We analyzed the distribution of FMR1, FXR1, FXR2 mRNA, and FMRP in whole normal human embryos and in the brains of normal and fragile X fetuses. The distributions of mRNA for the 3 genes in normal whole embryos and in the brains of normal male and female carrier fetuses were similar, with large amounts of mRNA in the nervous system and in several non-nervous system tissues. No FMR1 (mRNA and protein) was detected and no evident neuropathologic abnormalities found in the brains of male carrier fetuses, suggesting that the FMR1 product (FMRP) may have no crucial function in early stages of nervous system development. FXR1 and FXR2 mRNA had the same distribution and similar intensity in the brains of normal and pathologic fetuses (female and male carriers). The coexpression in the same tissues of FMR1, FXR1, and FXR2, associated with the normal expression of FXR1 and FXR2 and the absence of obvious neuropathological abnormalities in pathological brains, supports the notion that the FXR1 and FXR2 proteins partially compensate for FMRP function. However, the absence of significant overexpression of FXR1 and FXR2 in pathological brains suggests that these genes do not compensate for the lack of FMR1 expression. Alternatively, FMR1, FXR1, and FXR2 proteins may not have compensatory functions, but instead may regulate functions by hetero or homo oligomerization, as suggested by other studies. Thus, a dominant negative effect of abnormal multimeric protein complexes lacking FMRP (e.g. by modification of FXR1 and FXR2 protein functions) may result in the fragile X syndrome phenotype.
Abstract: We report the identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+). Six family members manifested isolated typical febrile seizures (FS), and five had typical FS associated with generalized epilepsy (FS+, generalized tonic/clonic seizures). Afebrile seizures occurred from childhood until the teenage years. The maximum two-point LOD score was 3.99 for markers D2S294 and D2S2314. Flanking markers place the GEFS+ locus between D2S141 and D2S116, with multipoint analysis favoring the 13-cM interval spanned by D2S294 and D2S364. This locus is the second GEFS+ locus to be reported, which suggests that this syndrome is genetically heterogeneous.
Abstract: The aim of this study was to determine the regional distribution in situ of the mRNA for the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor in human fetal brain. We found high levels of alpha 7 gene expression in nuclei that receive sensory information, such as those of the neocortex and hippocampus, the thalamic nuclei, the reticular thalamic nucleus, the pontine nuclei and the superior olive complex. These data support a possible regulatory function for alpha 7-containing receptors in sensory processing, which may be involved in the pathological physiology of schizophrenia and autism. Early alpha 7 gene expression is also consistent with a morphogenetic role for alpha 7 receptors in central nervous system development.
Abstract: Platelet G protein subunits (G alpha i2, G alpha q and Gbeta) were measured in 15 non-treated depressed patients (recurrent major depression) and 15 age- and sex-matched healthy controls by using the Western immunoblot method. The depression severity was measured by the AMDP depression rating scale before start of treatment. The AMDP score ranged between 12 and 44. Patients were then treated with different antidepressant drugs (ATD) for 1 month, after which G protein and depression were reassessed. Results indicated that drug-free depressed patients displayed increased levels of G proteins subunits, in comparison to healthy controls. Antidepressant drug administration resulted in decrease of depression severity but only seven patients showed a net response to drugs (AMDP depression score less than 12). These drug-responding patients have also reduced G protein levels, while patients without significant improvement continued to display either the same levels of G proteins or higher, whatever the class of the drug administered. These results suggest that depression is associated to increase in G protein subunit levels and that the clinical outcome seemed to be the determining factor in further decrease occurring in G protein levels.
Abstract: The telomeric copy (t) of the survival motor neuron (SMN) gene is homozygously deleted in more than 90% of patients with infantile motor neuron disease (MND). In the general population, no homozygous SMNt deletion has been found, whereas 5% of centromeric SMN (SMNc) deletions can be observed. Although SMNt deletions appear causal for infantile and at least some adult-onset spinal muscular atrophy (SMA) (type IV), the respective role of SMN deletions remains unclear in adult-onset MNDs. We studied SMN gene in three different groups of patients with adult-onset MNDs. In sporadic amyotrophic lateral sclerosis (ALS; n = 177) and familial ALS (n = 66), no SMNt deletion had been found, and the frequency of SMNc deletions was not increased. Conversely, among the 14 patients with sporadic pure lower MND (LMND), we found 2 patients with homozygous SMNt deletions (14%) and 5 patients with homozygous SMNc deletions (36%). These data suggest that (1) SMNt deletions do not account for the major part, if any, of adult-onset LMND cases; and (2) SMNc deletions act as a susceptibility factor for LMNDs in adults. The clinical and genetic heterogeneity of LMND cases, including SMA type IV, are yet to be unexplained. Further studies on large groups of adult-onset LMND patients are warranted to refine its nosology.
Abstract: Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts.
Abstract: Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences.
Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) present in the central nervous system (CNS), are multimeric proteins constituted of two different subunits, alpha and beta, with different subtype arrangements and different pharmacological and functional properties. By in situ hybridization, we studied the distribution of the mRNA for the alpha4 subunit of nAChRs in brains of human 25-week old normal and fragile X fetuses. A strong hybridization signal was detected throughout the thalamus, cortex, pyramidal layer of the Ammon's horn, and the granular layer of the dentate gyrus. Several other areas including the claustrum, caudate nucleus, putamen, globus pallidus, subthalamic nucleus, subiculum, entorhinal cortex, and Purkinje cell layer displayed a low to moderate radiosignal. With few exceptions, our data in the human brain agree those previously reported in the rat. Also, our data indicate that the alpha4 subunit mRNA is produced early in the development, in the more differentiated cells, and in a site-specific manner. Additionally, the alpha4 mRNA is produced in the brain of fragile X fetuses with the same pattern and same intensity than in the normal fetal brain suggesting that alpha4 subunit mRNA production is not altered in the fragile X syndrome. High levels of alpha4 subunit mRNA in human fetal brain support the hypothesis of a morphogenic role of nAChRs during the early CNS development.
Abstract: We describe clinical, electrophysiological and genetic features in 44 patients with Unverricht-Lündborg disease from 19 families living in North African countries (Tunisia, Algeria and Morocco). The mean age of patients was 25.3 years; mean age was at onset 11.3 years. The disease began more frequently with seizures (91 per cent) or myoclonus (80 p. 100) than ataxia (16 p. 100). Subsequently myoclonus and generalized seizures were present in all patients, cerebellar signs were absent in four cases. EEG findings included normal background activity (90 p. 100), spontaneous fast generalized spikes (93 p. 100) and photosensitivity (70 p. 100). Antiepileptic polytherapy (clonazepam and/or phenobarbital and/or valporic acid) was used in 84 per cent of cases. Antiepileptic drugs were more effective in controlling epileptic seizures (less than one seizure/month in 60 p. 100) than myocloni which persisted daily in 64 p. 100 of cases. Mean duration of the disease was 13.5 years. One patient died of status epilepticus. Consanguinity was noted in 17 families (first degree in 15 families). Linkage to chromosome 21q 22.3 was confirmed in 11 families. We noted an inter and intrafamilial variability of clinical signs and disease course.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SOD1 mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.
Abstract: 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.
Abstract: Progressive myoclonus epilepsy (EPM1) is an autosomal recessive disorder, characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The EPM1 locus was mapped to within 0.3 cM from PFKL in chromosome 21q22.3. The gene for the proteinase inhibitor cystatin B was recently localized in the EPM1 critical region, and mutations were identified in two EPM1 families. We have identified six nucleotide changes in the cystatin B gene of non-Finnish EPM1 families from northern Africa and Europe. The 426G-->C change in exon 1 results in a Gly4Arg substitution and is the first missense mutation described that is associated with EPM1. Molecular modeling predicts that this substitution severely affects the contact of cystatin B with papain. Mutations in the invariant AG dinucleotides of the acceptor sites of introns 1 and 2 probably result in abnormal splicing. A deletion of two nucleotides in exon 3 produces a frameshift and truncates the protein. Therefore, these four mutations are all predicted to impair the production of functional protein. These mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. The remaining two sequence changes, 431G-->T and 2575A-->G, probably represent polymorphic variants. In addition, a tandem repeat in the 5' UTR (CCCCGCCCCGCG) is present two or three times in normal alleles. It is peculiar that in the majority of patients no mutations exist within the exons and splice sites of the cystatin B gene.
Abstract: Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.
Abstract: Benign familial infantile convulsions (BFIC) are an autosomal-dominant epileptic syndrome characterized by an age of onset within the first year of life. Although they were first reported in families of Italian descent, BFIC have also been described in non-Italian families. We have mapped the BFIC gene to chromosome 19 by linkage analysis in five Italian families with a maximum two-point lod score of 6.36 at D19S114; maximum multipoint lod scores > 8 were obtained for the interval D19S250-D19S245. BFIC are therefore the third idiopathic partial epileptic syndrome to be mapped on the human genome.
Abstract: In previous reports, we showed that plasma and erythrocyte magnesium were increased in many drug-free hospitalized depressed patients. Furthermore, we observed that erythrocyte magnesium content was related to the intensity of the symptoms. Highly depressed patients had the highest magnesium values. Today, we report the results of plasma and erythrocyte sodium and potassium, and of total and ultrafilterable plasma calcium in 66 hospitalized patients with major depression compared to 58 healthy controls. No consistent differences in these biochemical parameters are observed between patients when separated according to intensity of anxiety, psychomotor retardation, and moral distress. Plasma sodium is higher and plasma potassium lower in female patients of all subgroups as compared to controls. Both male patients and controls have erythrocyte sodium and potassium levels that are significantly different from those of females. This clearly suggests a separation into genders in such studies. In conclusion--in contrast to blood magnesium--sodium, potassium, and calcium levels do not seem to be related to the intensity of the main clinical symptoms in hospitalized patients with major depression.
Abstract: Alpha 5 and beta 3 GABAA receptor genes are major candidates for epilepsy, as they code for subunits of the most important human inhibitory neurotransmitter. Moreover, they are located within a region of the human genome previously implicated in disorders including epilepsy. We carried out an association study between dinucleotide repeat polymorphisms in these two genes and juvenile myoclonic epilepsy (JME). JME is the most common idiopathic epilepsy and is characterized by a complex mode of inheritance. We did not find significant differences between controls and patients for allele or genotype frequencies.
Abstract: Quantitative trait loci (QTL) approach was used in CXB recombinant inbred mice for preliminary identification of candidate regions on the mouse genome that influence sleep. The only provisional QTLs identified were associated with paradoxical sleep (PS). PS during the light period was associated with markers on chromosome 7 between 7 and 20 centimorgan from the centromere. For PS during the dark period, a single QTL was identified on chromosome 5, near the Clock gene. The 24 h amount of PS was influenced by markers on chromosomes 2, 17, and 19. This first QTL mapping study strongly suggests that a complex behaviour like PS can be controlled by only a few genes.
Abstract: Mediterranean myoclonus is a progressive myoclonus epilepsy with autosomal recessive inheritance. Another form has been described in Finland, the so-called Baltic myoclonus. Mediterranean myoclonus and Baltic myoclonus are also known as Unverricht-Lundborg disease. Linkage analyses have shown that the genes for both these forms of myoclonus are closely linked to 21q22.3 DNA markers, suggesting that they are caused by mutations at the same locus (EPM1). Recently, two heterozygous mutations were found in the cystatin B gene in patients with Unverricht-Lundborg disease. We report recombinational and linkage disequilibrium mapping of EPM1, and cystatin B gene sequencing, in 14 consanguineous pedigrees with Mediterranean myoclonus. Linkage to 21q22.3 DNA markers was observed in all these families. Haplotype analysis suggests that a common mutation segregates within these pedigrees, and that this mutation is different from the common one responsible for the Finnish form of Unverricht-Lundborg disease. No mutation was found in the exons or splice junctions of the cystatin B gene in the 14 pedigrees.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving both upper and lower motor neurons. The disease is possibly due to several factors, including a genetic one. This is supported by the existence of 5 to 10 p. 100 familial cases. In these pedigrees, the transmission is autosomal dominant, with a high penetrance (> 90 p. 100). We studied the phenotypes of these familial cases, in reviewing the literature on familial ALS (FALS). It has been noted that FALS are heterogeneous, with different age of onset, site of onset and disease duration. Moreover, in FALS, onset is earlier than in the sporadic form (48 vs 60 years, as usually reported in the literature). We also frequently noted sensory disorders (20 p. 100), onset on the lower limbs (46 p. 100) and decreased or absent ankle-jerks (75 p. 100) in FALS patients.
Abstract: Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder with onset between 6 and 13 years followed by variable progression to mental deterioration and cerebellar ataxia. It is a rare disorder but more common in Finland (1 in 20,000) and the western Mediterranean. Two point mutations in the cysteine proteinase inhibitor gene cystatin B (CSTB), proved that this gene is responsible for EPM1 (ref. 3). An extensive search in the CSTB gene revealed mutations accounting only for 14% of the 58 unrelated EPM1 alleles studied. Here we report that the majority of EPM1 alleles contain expansions of a dodecamer (12-mer) repeat located about 70 nucleotides upstream of the transcription start site nearest to the 5' end of the CSTB gene. Normal alleles contain 2 or 3 copies of this repeat whereas mutant alleles contain more than 60 such repeats and have reduced levels of CSTB messenger RNA in blood but not in cell lines. 'Premutation' CSTB alleles with 12-17 repeats show marked instability when transmitted to offspring.
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disorder of unknown etiology. Recently, in Alzheimer's disease (AD) apolipoprotein E (APOE) alleles have been shown to play an important role in disease phenotype. To determine whether APOE have a similar influence in other neurodegenerative disorders, we studied APOE genotypes in 130 sporadic ALS patients, compared with controls. We also analyzed APOE genotypes regarding ALS clinical criteria. The frequency of APOE genotypes was not different between ALS and controls. However, subjects with the APOE2/E3 genotype showed a significantly longer duration of the disease: 51 months vs. 28.5 for APOE3/E3 and 27.5 for APOE3/E4 (p = 0.001 and p = 0.02, respectively). There was a significantly higher proportion of bulbar ALS patients in the APOE3/E4 group (72% of the cases), whereas 90% of patients in the APOE2/E3 group showed limb onset (p = 0.01). In the bulbar group, patients with APOE4 showed earlier onset of the disease: 60 vs. 66 years (mean age, p = 0.05). These results are consistent with a protective role of APOE2 and a deleterious role of APOE4 in ALS as already found for AD. This parallel supports the idea of a general role of APOE in neuronal degeneration or regeneration rather than a specific role in ALS or AD etiopathogenesis.
Abstract: The current understanding of suicidal behaviors is that such behaviors are multidetermined and mental state and trait related. Genetic factors appear to be of great importance, as suggested by the findings of family, twin, and adoption studies. Whether these genetic factors are similar to those involved in the susceptibility to psychiatric disorders closely related to suicidal behavior (eg, manic depressive illness, schizophrenia or substance use disorders) is yet unknown. However, a genetic factor of susceptibility to suicide, independent or additive to the genetic transmission of the psychiatric disorders that are related to suicidal behavior, is strongly suggested by the data of the Copenhagen adoption study and a study of Amish families. Recently, new approaches have been proposed to identify the genetic component of such complex traits. Association studies between genetic markers and a disease phenotype has been successfully applied to several complex disease such as essential hypertension. One candidate gene for suicidal behaviors is the tryptophane hydroxylase (TPH) gene which is the first and possibly rate-limiting enzyme of the metabolic pathway for serotonin. Indeed, altered serotoninergic function in both completed suicide and suicide attempt has been one of the most replicated findings in modern biological psychiatry. In our knowledge, only two studies have tested the association between suicide attempt and the TPH gene and their authors found negative results. Despite these negative results, association studies that use candidate gene remain one of the methods of choice for studying the genetic component of suicidal behaviors.
Abstract: To determine whether the tryptophan hydroxylase gene (ie, the gene that codes for the rate-limiting enzyme in the metabolic pathway of serotonin) may be a susceptibility factor for suicidal behavior.
Abstract: Benign cryptogenic infantile epilepsy occurred in 6 infants of 3 families, with similar characteristics suggesting a common physiopathology: onset between 3 and 12 months of age, clusters of brief generalized seizures easily controlled by anti-epileptic drugs, normal psychomotor development, usually normal EEG with, rarely, generalized interictal spike-waves, no recurrence after drug discontinuation, the treatment being no longer than 16 months in most cases. Identical histories were found in parents, uncles and aunts, suggesting an autosomal dominant mode of inheritance. This seems to correspond to an original form of early onset, benign infantile epilepsy.
Abstract: Out of a population of 188 unrelated narcoleptic probands, we identified 14 probands (7.44%) with a family history of narcolepsy, 23 (12.23%) with a family history of isolated repeated episodes of naps and/or lapses into sleep and 151 (80.31%) without a family history of either condition. Clinical, polysomnographic or zygotic differences could not be evidenced in the three groups. Empirical risk for narcolepsy was 40.7 times greater among first-degree relatives of narcoleptics than in the general population. Narcolepsy and the condition characterized by isolated repeated episodes of naps and/or lapses into sleep have a common genetic component. This finding has important implications. Indeed, when the latter condition is included in the spectrum of narcolepsy, the empirical risk figure is relatively close to that expected in cases of simple mode of inheritance. A trend in favor of a more frequent transmission through mothers than fathers is emphasized.
Abstract: Benign infantile familial convulsions (BIFC) and benign familial neonatal convulsions (BFNC) are two forms of familial convulsions having an age of onset within the first year of life. The gene responsible for BFNC has been mapped to chromosome 20q in the close vicinity of D20S19 and D20S20 markers. We performed linkage analysis between BIFC and D20S19-D20S20 in eight families in order to know whether the BFNC gene is also implicated in BIFC. Several apparent obligate crossovers between affected members were detected. The data here presented demonstrate that the BFNC gene is not responsible for BIFC.
Abstract: Benign Familial Neonatal Convulsions (BFNC) is an epileptic disorder with an autosomal dominant mode of transmission. It has been shown that about 80% of BFNC pedigrees are linked to a genetic defect on chromosome 20q13.3. A candidate gene for the epilepsies, the gene coding for the alpha4 subunit of the nicotinic cholinergic receptor (CHRNA4), has previously been localized on chromosome 20. Here we report a single point mutation converting a serine codon to a stop codon in the exon 5 of CHRNA4, in one BFNC family. Identification of CHRNA4 as the defective gene in 20q-BFNC represents the first example of a human idiopathic epilepsy caused by a mutation directly affecting a neurotransmitter receptor in the central nervous system.
Abstract: Benign neonatal familial convulsions comprise a distinct epileptic syndrome with an autosomal mode of transmission. The electroclinical signs of seizures in this syndrome are not yet well defined. In 3 children from two families presenting with benign neonatal familial convulsions, 14 seizures were recorded during electroencephalographic (EEG)-video sessions. All seizures occurred during sleep, after a short arousal reaction. Seizures started with bilateral, symmetrical flattening of the EEG for 5 to 19 seconds; simultaneously there was apnea and tonic motor activity. The EEG flattening was followed by a long (1-2-minute) bilateral discharge of spikes and sharp waves; simultaneously, there were vocalizations, chewing, and focal or generalized clonic activity. The prominence of EEG and motor abnormalities varied between the left and the right from one seizure to the next in any given child. The seizures stopped without EEG or clinical postictal depression. These electroclinical observations suggest that the convulsions of benign neonatal familial convulsions are a form of generalized tonic-clonic seizure whose expression may be asymmetrical, probably because of the immaturity of the corpus callosum or other structures ensuring seizure synchronization.
Abstract: Benign familial neonatal convulsions (BFNC) is an idiopathic form of epilepsy beginning within the first six months of life. Its genetic origin and autosomal dominant mode of inheritance have been suspected since its first description. Recently, the BFNC gene has been localised within chromosome 20q in one large pedigree. For the first time, we confirm here (with D20S19 and D20S20) the close linkage of BFNC to chromosome 20q in six French pedigrees. In addition, the existence in these families of several cases of febrile convulsions (FC), another epileptic syndrome with an autosomal dominant genetic component, led us to study the possibility of a genetic background identical to BFNC. Our results suggest the existence of different susceptibility genes for BFNC and FC.
Abstract: Genetic linkage analysis shows that Baltic and Mediterranean myoclonus, two forms of progressive myoclonus epilepsy, are closely linked to marker D21S113 on the long arm of chromosome 21. Baltic and Mediterranean myoclonus are most probably due to mutations of the same gene.
Abstract: Because of an association between sexual aneuploidies and schizophrenia, and because schizophrenic siblings have been found to be more often of the same than of the opposite sex, the susceptibility locus for schizophrenia is thought to lie within the pseudoautosomal region of the sex chromosomes. We analysed 33 sibships comprising 18 pairs, 13 trios, and 2 quartets of affected siblings, and found support for non-random segregation of of alleles at the DXYS14 locus in affected siblings. These findings are consistent with the pseudoautosomal hypothesis for schizophrenia and favour a genetic linkage between DXYS14 and the disease.
Abstract: Sherrington et al. (1988) reported linkage between markers located on the 5q11-q13 region of chromosome 5 and schizophrenia in five Icelandic and two British families. To date, however, all attempts to replicate the initial finding have failed. Using three markers of chromosome 5, we have studied 28 additional French pedigrees. When our data were analyzed both with parametric (i.e., lod scores) and nonparametric methods, we found no evidence of linkage. Thus, we were unable to replicate the earlier report by Sherrington et al.
Abstract: The original finding of genetic linkage in an Old Order Amish pedigree has been contradicted by the results of several subsequent studies. Using the same genetic parameter values, diagnostic criteria, and 11p15 genetic markers as those used to study the initial Amish population, the authors performed a linkage study of a four-generation informative pedigree in Belgium.
Abstract: Artificial insemination (AI) and embryo transfer (ET) are not just reproductive techniques, but indispensable tools for genetic improvement. In this sense, they play an effective part in propagating improved breeds. Analysis of the development of insemination of French cattle breeds since 1960 shows how breeders can alter their genetic choices to meet economic needs. AI and ET also have their place in selection programmes: evaluating bulls by progeny testing, exerting greater selection pressure on the dams of bulls, and shortening the generation interval of breeding animals. Finally, the income of breeders is closely linked to the genetic level of the livestock which they utilise.
Abstract: The role of serotonin (5-HT) in the kindling model of epilepsy was investigated by performing specific lesions of the 5-HT innervation at the level of the primary epileptogenic focus. We injected bilaterally 5,6-dihydroxytryptamine in the olfactory bulb (OB) of adult rats which were submitted to electrical stimulations of the OB until the occurrence of stage-5 seizures. Immunohistochemical controls of lesions were realized with a specific anti-5-HT antibody. Results revealed that the lesions facilitated the initial development of kindling (increase of afterdischarge duration and of kindling rate), suggesting that 5-HT terminals exert a modulatory effect on the propagation of the epileptic activity.
