Genetics of essential tremor.

Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.

The efficiency of a carbamazepine-mianserin combination scheme in opiate detoxification.

A recent comparative randomized double-blind study has suggested the utility of a carbamazepine/mianserin combination as a treatment for opiate withdrawal. The aim of the present study was to explore the feasibility and efficiency of this combination under naturalistic conditions. Five hundred and fifty mostly polysubstance abusing patients treated with a standardized scheme combining carbamazepine and mianserin were assessed with regard to deviations to the protocol, used co-medications and retention in treatment.Three hundred and sixty three patients (66.0%) received the carbamazepine/mianserin combination as specified by the standardized protocol. In 350 patients (63.7%) the whole 10 days was completed. The most frequently used p.r.n. medications were for anxiety (47.5%) and insomnia (54.5%).The treatment of opiate withdrawal with a carbamazepine/mianserin combination scheme in an inpatient setting seems to be feasible and applicable with few adaptations to most patients, and may represent an interesting treatment option for multidrug users.

Cytochrome P450 2D6 genotype and methadone steady-state concentrations

A genetic polymorphism of cytochrome P450 2D6 has been described with the existence of poor (zero functional genes), extensive (one or two functional genes), and ultrarapid metabolizers (three or more functional genes). The authors measured the steady-state trough (R)- (i.e., the active enantiomer), (S)-, and (R,S)-methadone plasma levels in opiate-dependent patients receiving methadone maintenance treatment (MMT) and genotyped them for cytochrome P4502D6. The patients' medical records were reviewed to assess the outcome of the MMT with regard to the absence of illicit opiate consumption and to the absence of withdrawal complaints in ultrarapid and poor metabolizers. Of 256 patients included, 18 were found to be poor metabolizers, 228 to be extensive metabolizers, and 10 to be ultrarapid metabolizers. Significant differences were found between genotypes for (R)- (p = 0.024), (S)- (p = 0.033), and (R,S)-methadone (p = 0.026) concentrations to dose-to-weight ratios. For (R)-methadone, a significant difference was found between ultrarapid metabolizers and poor metabolizers (p = 0.009), with the median value in the former group being only 54% of the median value in the latter group. These results confirm the involvement of cytochrome P450 2D6 in methadone metabolism. Although the difference was nonsignificant (p = 0.103), 13 (72%) of the 18 poor metabolizers and only 4 (40%) of the 10 ultrarapid metabolizers were considered successful in their treatment. More studies are needed to examine the influence of the ultrarapid metabolizer status on the outcome of the MMT.

Overview of primary monogenic dystonia.

Primary monogenic forms of dystonia manifest solely or mainly with dystonia; they have been linked to a number of genes and loci and assigned "DYT" numbers. The pure dystonia syndrome early-onset primary dystonia (DYT1) manifests with dominantly-inherited generalized dystonia, often with focal onset in a limb. DYT1 is caused by a GAG deletion in the TOR1A gene. Mutations in the THAP1 gene cause DYT6, a form of pure dystonia that primarily involves cranio-cervical and upper limb muscles. Patients with the dystonia plus syndrome DYT5 display levodopa-responsive dystonia sometimes associated with tremor or parkinsonism (DYT5a, mutations in GCH1); a more severe phenotype with psychomotor involvement can be seen in recessive forms (DYT5b with TH mutations, SPR-deficiency syndrome). Other forms of dystonia plus syndromes include myoclonic dystonia (DYT11) and rapid-onset dystonia-parkinsonism (DYT12). Finally, paroxysmal exertion-induced dystonia (DYT18, GLUT1 deficiency) is caused by mutations in the SLC2A1 gene (DYT9 and DYT18). It is part of the paroxysmal dystonia group and manifests with paroxystic movements sometimes associated with seizures and psychomotor developmental delay.

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Evidence of altered antioxidant systems and signs of elevated oxidative stress are reported in peripheral tissue and brain of schizophrenic patients, including low levels of glutathione (GSH), a major thiol antioxidant and redox buffer. Functional and genetic data indicate that an impaired regulation of GSH synthesis is a vulnerability factor for the disease. Impaired GSH synthesis from a genetic origin combined with environmental risk factors generating oxidative stress (e.g., malnutrition, exposure to toxins, maternai infection and diabetes, obstetrical complications, and psychological stress) could lead to redox dysregulation. This could subsequently perturb normal brain development and maturation with delayed functional consequences emerging in early adulthood. Depending on the nature and the time of occurrence of the environmental insults, the structural and functional delayed consequences could vary, giving rise to various endophenotypes. The use of animal models of GSH deficit represents a valuable approach to investigate how interactions between genetic and environmental factors lead to the emergence of pathologies found in the disease. Moreover, these models of GSH can be useful to investigate links between schizophrenia and comorbid somatic disorders, as dysregulation of the GSH system and elevated oxidative stress are also found in cardiovascular diseases and diabetes. This chapter reviews pharmacological and genetic rodent models of GSH synthesis dysregulation used to address some of the aforementioned issues. Up to date, these models revealed that GSH deficits lead to morphological, physiological, and behavioral alterations that are quite analogous to pathologies observed in patients. This includes hypofunction of NMDA receptors, alteration of dopamine neurotransmission, anomalies in parvalbumin-immunoreactive fast-spiking interneurons, and reduced myelination. In addition, a GSH deficit affects the brain in a region-specific manner, the anterior cingulate cortex and the ventral hippocampus being the most vulnerable regions investigated. Interestingly, a GSH deficit during a limited period of postnatal development is sufficient to have long-lasting consequences on the integrity of PV-IR interneurons in the anterior cingulate cortex and impairs cognitive functions in adulthood. Finally, these animal models of GSH deficit display behavioral impairments that could be related to schizophrenia. Altogether, current data strongly support a contributing role of a redox dysregulation on the development of pathologies associated with the illness and demonstrate the usefulness of these models to better understand the biological mechanisms leading to schizophrenia.

Genetics of Parkinson's disease: the yield.

The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.

DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions.

The recent release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association has led to much debate. For this forum article, we asked BMC Medicine Editorial Board members who are experts in the field of psychiatry to discuss their personal views on how the changes in DSM-5 might affect clinical practice in their specific areas of psychiatric medicine. This article discusses the influence the DSM-5 may have on the diagnosis and treatment of autism, trauma-related and stressor-related disorders, obsessive-compulsive and related disorders, mood disorders (including major depression and bipolar disorders), and schizophrenia spectrum disorders.

Mitochondrial Fatty Acid Oxidation in Obesity

Significance: Current lifestyles with high-energy diets and little exercise are triggering an alarming growth in obesity. Excess of adiposity is leading to severe increases in associated pathologies, such as insulin resistance, type 2 diabetes, atherosclerosis, cancer, arthritis, asthma, and hypertension. This, together with the lack of efficient obesity drugs, is the driving force behind much research. Recent Advances: Traditional anti-obesity strategies focused on reducing food intake and increasing physical activity. However, recent results suggest that enhancing cellular energy expenditure may be an attractive alternative therapy. Critical Issues: This review evaluates recent discoveries regarding mitochondrial fatty acid oxidation (FAO) and its potential as a therapy for obesity. We focus on the still controversial beneficial effects of increased FAO in liver and muscle, recent studies on how to potentiate adipose tissue energy expenditure, and the different hypotheses involving FAO and the reactive oxygen species production in the hypothalamic control of food intake. Future Directions: The present review aims to provide an overview of novel anti-obesity strategies that target mitochondrial FAO and that will definitively be of high interest in the future research to fight against obesity-related disorders. Antioxid. Redox Signal. 00, 000000.

L'induction rapide du sevrage par des antagonistes des opiacés sous anesthésie: une alternative dans le traitement de la dépendance aux opiacés [Rapid induction of withdrawal with opiate antagonists under anesthesia: an alternative to treatment of opiate dependence?]

Rapid induction of withdrawal by opiate antagonists under anesthesia is an opiate detoxification technique. This technique is useful to reduce intensity and duration of withdrawal. Therefore, this technique represents an alternative strategy in the treatment of opiate addicted patients. This paper attempts to present a brief history of this technique, and a critical review of related issues.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.