The Impact of Stressful Life Events on Suicidal Ideation in Gender Dysphoria: A Moderator Effect of Perceived Social Support.

Factors associated with suicidal ideation in the gender dysphoria population are not completely understood. This high-risk population is more likely to suffer stressful events such as assault or employment discrimination. This study aimed to determine the association of stressful events and social support on suicidal ideation in gender dysphoria and to analyze the moderator effect of social support in relation to stressful events and suicidal ideation. A cross-sectional design was used in a clinical sample attending a public gender identity unit in Spain that consisted of 204 individuals (51.7% birth-assigned males and 48.3% birth-assigned females), aged between 13 and 59 (M = 27.95 years, SD = 9.58). A Structured Clinical Interview, a list of 16 stressful events, and a functional social support questionnaire (Duke-UNC-11) were used during the initial visits to the unit. The data were collected between 2011 and 2012. A total of 50.1% of the sample have had suicidal ideation. The following stressful events were associated with suicidal ideation: homelessness, eviction from home, and having suffered from physical or verbal aggression. Also, there was an inverse relation between perceived social support and suicidal ideation. There was a statistically significant interaction between a specific stressful event (eviction) and perceived social support. The study suggests that the promotion of safer environments could be related to lower suicidal ideation and that networks that provide social support could buffer the association between specific stressful events and suicidal ideation.

Decoding Neuromuscular Disorders Using Phenotypic Clusters Obtained From Co-Occurrence Networks.

Neuromuscular disorders (NMDs) represent an important subset of rare diseases associated with elevated morbidity and mortality whose diagnosis can take years. Here we present a novel approach using systems biology to produce functionally-coherent phenotype clusters that provide insight into the cellular functions and phenotypic patterns underlying NMDs, using the Human Phenotype Ontology as a common framework. Gene and phenotype information was obtained for 424 NMDs in OMIM and 126 NMDs in Orphanet, and 335 and 216 phenotypes were identified as typical for NMDs, respectively. 'Elevated serum creatine kinase' was the most specific to NMDs, in agreement with the clinical test of elevated serum creatinine kinase that is conducted on NMD patients. The approach to obtain co-occurring NMD phenotypes was validated based on co-mention in PubMed abstracts. A total of 231 (OMIM) and 150 (Orphanet) clusters of highly connected co-occurrent NMD phenotypes were obtained. In parallel, a tripartite network based on phenotypes, diseases and genes was used to associate NMD phenotypes with functions, an approach also validated by literature co-mention, with KEGG pathways showing proportionally higher overlap than Gene Ontology and Reactome. Phenotype-function pairs were crossed with the co-occurrent NMD phenotype clusters to obtain 40 (OMIM) and 72 (Orphanet) functionally coherent phenotype clusters. As expected, many of these overlapped with known diseases and confirmed existing knowledge. Other clusters revealed interesting new findings, indicating informative phenotypes for differential diagnosis, providing deeper knowledge of NMDs, and pointing towards specific cell dysfunction caused by pleiotropic genes. This work is an example of reproducible research that i) can help better understand NMDs and support their diagnosis by providing a new tool that exploits existing information to obtain novel clusters of functionally-related phenotypes, and ii) takes us another step towards personalised medicine for NMDs.

Detection of Early Warning Signs in Autism Spectrum Disorders: A Systematic Review.

Due to the exponential increase of autism spectrum disorders' prevalence in Western countries, it is necessary to improve early detection and intervention to enhance developmental milestones. This systematic review identified the most effective screening instrument, which can be used at an early age and which identifies the maximum number of autism cases. We identified several instruments with adequate predictive properties-the Autism Parent Screen for Infants (APSI), Battelle Development Inventory, second edition (BDI-2); Brief Infant-Toddler Social and Emotional Assessment (BITSEA); First Year Inventory (FYI); Infant-Toddler Checklist/Communication and Symbolic Behavior Scales Developmental Profile (ITC/CSBS-DP); Program of Research and Studies on AUTISM (PREAUT-Grid); Checklist for Early Signs of Developmental Disorders (CESDD); Social Attention and Communication Study (SACS); and the Screening Tool for Autism in Toddlers and Young Children (STAT)-that can be applied from 12 months of age in Western countries. The ITC/CSBS-DP has been proposed for universal screening from 12 months of age onwards, complemented by the Modified Checklist for Autism in Toddlers, Revised/Revised with Follow-Up (M-CHAT-R/F), which can be used from 15 months of age onwards. This strategy could improve early detection in at-risk children within the current health system, thus allowing for early intervention.

Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families.

The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.

Pigment epithelium-derived factor (PEDF) and PEDF-receptor in the adult mouse brain: Differential spatial/temporal localization pattern.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein which was initially described in the retina, although it is also present in other tissues. It functions as an antioxidant agent promoting neuronal survival. Recently, a PEDF receptor has shown an elevated binding affinity for PEDF. There are no relevant data regarding the distribution of both proteins in the brain, therefore the main goal of this work was to investigate the spatiotemporal presence of PEDF and PEDFR in the adult mouse brain, and to determine the PEDF blood level in mouse and human. The localization of both proteins was analyzed by different experimental methods such as immunohistochemistry, western-blotting, and also by enzyme-linked immunosorbent assay. Differential expression was found in some telencephalic structures and positive signals for both proteins were detected in the cerebellum. The magnitude of the PEDFR labeling pattern was higher than PEDF and included some cortical and subventricular areas. Age-dependent changes in intensity of both protein immunoreactions were found in the cortical and hippocampal areas with greater reactivity between 4 and 8 months of age, whilst others, like the subventricular zones, these differences were more evident for PEDFR. Although ubiquitous presence was not found in the brain for these two proteins, their relevant functions must not be underestimated. It has been described that PEDF plays an important role in neuroprotection and data provided in the present work represents the first extensive study to understand the relevance of these two proteins in specific brain areas.

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome.

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS.

Inflammatory gene expression in adipose tissue according to diagnosis of anxiety and mood disorders in obese and non-obese subjects.

Psychiatric disorders have been widely reported to be associated with systemic inflammation upregulation and adiposity. However, there are no data that link adipose tissue inflammation to these mental disorders. The analysis of adipokines and inflammation-related markers in adipose tissue could help to elucidate the potential association between obesity and mental health. An observational study was conducted in samples of patients consisting of non-obese and obese subjects, who were diagnosed with anxiety or mood disorders. Gene expression of adiponectin (ADIPOQ), leptin (LEP) and inflammatory markers (IL6, IL1B, TNF, CCL2, CSF3, ITGAM, and PLAUR) were determined in visceral (VAT) and subcutaneous (SAT) adipose tissues. Our results showed that the gene expression of adipokines and inflammation-related markers was higher in the VAT and SAT of obese subjects compared with non-obese subjects. Regarding mental disorders, all the inflammatory genes in the VAT were significantly higher in non-obese subjects with anxiety or mood disorders than in subjects without mental disorders, except for TNF and ITGAM. Additionally, IL6 expression was significantly lower in SAT. In contrast, obese patients diagnosed with anxiety or mood disorders only showed significantly lower expression levels of IL1B in VAT and ADIPOQ in SAT when compared with obese subjects without mental disorders. These data suggest the potential involvement of VAT inflammation in anxiety and mood disorders, involving complex mechanisms which are strongly affected by obesity.

The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description. / El estudio Andalusian Bipolar Family (ABiF): protocolo y descripción de la muestra.

INTRODUCTION: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited. METHOD: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies. RESULTS: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families. DISCUSSION: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences.

Gender Dysphoria and Social Anxiety: An Exploratory Study in Spain.

INTRODUCTION: Social anxiety in gender dysphoria is still under investigation. AIM: To determine the prevalence and associated factors of social anxiety in a sample of individuals with gender dysphoria. METHODS: A cross-sectional design was used in a clinical sample attending a public gender identity unit in Spain. The sample consisted of 210 individuals (48% trans female and 52% trans male). MAIN OUTCOME MEASURES: Mini-International Neuropsychiatric Interview (MINI) for diagnosis of social anxiety disorder, Structured Clinical Interview, Exposure to Violence Questionnaire (EVQ), Beck Depression Inventory (BDI-II), and Functional Social Support Questionnaire (Duke-UNC-11). RESULTS: Of the total sample, 31.4% had social anxiety disorder. Social anxiety disorder was highly correlated with age (r = -0.181; CI = 0.061-0.264; P = .009) and depression (r = 0.345; CI = 0.213-0.468; P < .001); it is strongly associated to current cannabis use (relative risk [RR] = 1.251; CI = 1.070-1.463; P = .001) and lifetime suicidal ideation (RR = 1.902; CI 1.286-2.814; P < .001). Moreover, it is significantly associated to lifetime nonsuicidal self-injury (RR = 1.188; CI 1.018-1.386; P = .011), nationality (RR = 7.792; CI 1.059-57.392; P = .013), perceived violence at school during childhood and adolescence (r = 0.169; CI = 0.036-0.303; P = .014), unemployment (RR = 1.333; CI 1.02-1.742; P = .021), and hospitalization of parents in childhood (RR = 1.146; CI = 1.003-4.419; P = .046). Using multivariable analysis, the highly significant variables within the model were depression score (odds ratio [OR] = 1.083; CI = 1.045-1.123; P < .001) and current cannabis use (OR = 3.873; CI = 1.534-9.779, P = .004), also age (OR = 0.948; CI = 0.909-0.989; P = .012), hospitalization of parents during childhood (OR = 2.618; CI = 1.107-6.189; P = .028), and nationality (OR = 9.427; CI = 1.065-83.457; P = .044) were associated with social anxiety disorder. CONCLUSION: This study highlights the necessity of implementing actions to prevent and treat social anxiety in this high-risk population.

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability.

BACKGROUND: Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. METHODS: This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. RESULTS: Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. CONCLUSIONS: These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome.

Coping strategies for postpartum depression: a multi-centric study of 1626 women.

The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.

Sociodemographic Characteristics and Psychological Adjustment Among Transsexuals in Spain.

This study examined the sociodemographic characteristics and the psychological adjustment of transsexuals in Andalusia (Spain), and also analyzed the differences between female-to-male (FtM) and male-to-female (MtF) transsexuals. The sample included 197 transsexuals (101 MtF and 96 FtM) selected from those who visited the Transsexual and Gender Identity Unit at the Carlos Haya Hospital in Malaga between 2011 and 2012. Our analyses indicated that MtF transsexuals were more likely to have lower educational levels, live alone, have worked less frequently throughout their lifetime, and have engaged in prostitution. For FtM transsexuals, there were more frequent references to the mother's psychiatric history and more social avoidance and distress. Multivariate analysis showed that the number of personality dysfunctional traits and unemployment status were associated with depression in the entire sample. The following three conclusions can be made: there are significant differences between MtF and FtM transsexuals (mainly related to sociodemographic variables), depression was high in both groups, and a remarkable percentage of transsexuals have attempted suicide (22.8 %) or have had suicidal thoughts (52.3 %).

[Space-time suicide clustering in the community of Antequera (Spain)]. / Clusters de casos de suicidio espacio-temporal en la comunidad de Antequera (España).

INTRODUCTION: Approximately 3,500 people commit suicide every year in Spain. The main aim of this study is to explore if a spatial and temporal clustering of suicide exists in the region of Antequera (Málaga, España). METHODS: Sample and procedure: All suicides from January 1, 2004 to December 31, 2008 were identified using data from the Forensic Pathology Department of the Institute of Legal Medicine, Málaga (España). Geolocalisation. Google Earth was used to calculate the coordinates for each suicide decedent's address. Statistical analysis. A spatiotemporal permutation scan statistic and the Ripley's K function were used to explore spatiotemporal clustering. Pearson's chi-squared was used to determine whether there were differences between suicides inside and outside the spatiotemporal clusters. RESULTS: A total of 120 individuals committed suicide within the region of Antequera, of which 96 (80%) were included in our analyses. Statistically significant evidence for 7 spatiotemporal suicide clusters emerged within critical limits for the 0-2.5 km distance and for the first and second semanas (P<.05 in both cases) after suicide. There was not a single subject diagnosed with a current psychotic disorder, among suicides within clusters, whereas outside clusters, 20% had this diagnosis (X2=4.13; df=1; P<.05). CONCLUSIONS: There are spatiotemporal suicide clusters in the area surrounding Antequera. Patients diagnosed with current psychotic disorder are less likely to be influenced by the factors explaining suicide clustering.

Substance use and social anxiety in transsexual individuals.

OBJECTIVE: This study examined social anxiety and use of cannabis and cocaine among transsexuals. METHODS: A total of 379 transsexuals seeking treatment or consultation participated in this study, providing data on sociodemographics, substance use, and anxiety. Analyses were based on (a) lifetime but not current use versus never used and (b) current use only versus no current use (lifetime only or never used). RESULTS: Lifetime only cannabis users (n = 72, 19%) and lifetime only cocaine users (n = 36, 9.8%) were older, had more victimization, and received more mental health treatment that those who never used. Current cannabis users (n = 47, 12.4%) had higher scores on fear of negative evaluation and social avoidance than those not currently using (p <.01). Multivariate analysis showed that social avoidance and fear of negative evaluation were associated with current cannabis use (p <.05), but not cocaine. Further, being single was associated with current cannabis use, after controlling for social avoidance and fear of negative evaluation (p <.05). CONCLUSIONS: Transsexuals' levels of anxiety and cannabis/cocaine use are comparable to those in the general population. Cannabis may be used to control anxiety and can have detrimental clinical implications for transsexuals.

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

BACKGROUND: Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN: A phase II randomized, double-blind pilot clinical trial. SCOPE: male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION: clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION: A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families--performed in 12 clinical laboratories in Spain.

Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.

Analysis of two language-related genes in autism: a case-control association study of FOXP2 and CNTNAP2.

Impairment of language abilities is a common feature in autistic individuals. Heterozygous mutations in the Forkhead Box P2 (FOXP2) gene lead to a severe spoken language disorder. Recently, several studies have pinpointed the involvement of common variants of the Contactin-Associated Protein-Like 2 (CNTNAP2) gene, whose transcription is regulated by the product of FOXP2, in several disorders characterized by language impairments such as autism, specific language impairment (SLI), and selective mutism (SM). In the present study, common variants of the FOXP2 and the CNTNAP2 genes were analyzed through a case-control association study in 322 Spanish autistic patients and 524 controls. The results of this study suggest that common variants of FOXP2 are unlikely to contribute to autism susceptibility, in agreement with previous findings. Furthermore, we failed to replicate in our sample a previous association finding of two single nucleotide polymorphisms (rs2710102 and rs7794745) in the CNTNAP2 gene with autism. No evidence for the association of these genes with language traits was observed in our analysis.

Males but not females show differences in calbindin immunoreactivity in the dorsal thalamus of the mouse model of fragile X syndrome.

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of the Fmr1 gene product, fragile X mental retardation protein. Here we analyze the immunohistochemical expression of calcium-binding proteins in the dorsal thalamus of Fmr1 knockout mice of both sexes and compare it with that of wildtype littermates. The spatial distribution pattern of calbindin-immunoreactive cells in the dorsal thalamus was similar in wildtype and knockout mice but there was a notable reduction in calbindin-immunoreactive cells in midline/intralaminar/posterior dorsal thalamic nuclei of male Fmr1 knockout mice. We counted the number of calbindin-immunoreactive cells in 18 distinct nuclei of the dorsal thalamus. Knockout male mice showed a significant reduction in calbindin-immunoreactive cells (range: 36-67% lower), whereas female knockout mice did not show significant differences (in any dorsal thalamic nucleus) when compared with their wildtype littermates. No variation in the calretinin expression pattern was observed throughout the dorsal thalamus. The number of calretinin-immunoreactive cells was similar for all experimental groups as well. Parvalbumin immunoreactivity was restricted to fibers and neuropil in the analyzed dorsal thalamic nuclei, and presented no differences between genotypes. Midline/intralaminar/posterior dorsal thalamic nuclei are involved in forebrain circuits related to memory, nociception, social fear, and auditory sensory integration; therefore, we suggest that downregulation of calbindin protein expression in the dorsal thalamus of male knockout mice should be taken into account when analyzing behavioral studies in the mouse model of FXS.