1. Akintunde ME, Rose M, Krakowiak P, Heuer L, Ashwood P, Hansen R, Hertz-Picciotto I, Van de Water J. {{Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma}}. {J Neuroimmunol};2015 (Sep 15);286:33-41.
Inflammation and asthma have both been reported in some children with autism spectrum disorder (ASD). To further assess this connection, peripheral immune cells isolated from young children with ASD and typically developing (TD) controls and the production of cytokines IL-17, -13, and -4 assessed following ex vivo mitogen stimulation. Notably, IL-17 production was significantly higher following stimulation in ASD children compared to controls. Moreover, IL-17 was increased in ASD children with co-morbid asthma compared to controls with the same condition. In conclusion, children with ASD exhibited a differential response to T cell stimulation with elevated IL-17 production compared to controls.
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2. Ayvazoglu NR, Kozub FM, Butera G, Murray MJ. {{Determinants and challenges in physical activity participation in families with children with high functioning autism spectrum disorders from a family systems perspective}}. {Res Dev Disabil};2015 (Sep 11);47:93-105.
The underlying factors affecting physical activity (PA) participation of children with high-functioning autism spectrum disorders (HFASDs) and their family members were investigated using a mixed method research design. Six families with children with HFASD aged 4 through 13 participated in the study. Findings revealed that levels of moderate to vigorous physical activity (MVPA) in children with HFASD varied between 85min and 405min for seven days. Parents of children with HFASD in this study were inactive (levels of MVPA varied between 6min and 53min) during this period. Qualitative data from parents highlighted many essential issues. Those issues are categorized under three main themes: (a) understanding PA in children with HFASD, (b) living with a child with HFASD, and (c) awareness of autism spectrum disorders (ASD) at school and community settings. Social skills, issues related to bullying, fear of injury to the child, as well as support from family members and lack of understanding of the disability emerged as subthemes extracted from these data.
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3. Canitano R. {{Mood Stabilizers in Children and Adolescents With Autism Spectrum Disorders}}. {Clin Neuropharmacol};2015 (Sep 11)
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders including autistic disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified as to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. All these categories are grouped together in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, classification under the category of Autism Spectrum Disorders.Behavioral disorders including irritability, attention-deficit/hyperactivity disorder (ADHD) symptoms, and aggression are additional symptoms found in up to 20% of children and adolescents with ASD and require careful evaluation for appropriate treatment. Attention-deficit/hyperactivity disorder is defined by impaired attention, hyperactivity, and impulsivity, whereas ASD is defined by social dysfunction, communicative impairment, and restricted/repetitive behaviors. They should be distinctly evaluated in children and adolescents with ASD and intellectual disability in contrast to individuals without intellectual disability, because significant differences between these conditions exist. Mood disorders are also common in ASD and should be systematically investigated in this population of children and adolescents. Approximately 50% of children and adolescents with ASD receive medication for comorbid behavioral/ADHD and mood symptoms, mostly stimulants, antiepileptics and antipsychotics. Guidelines for the evaluation and treatment including medications for ADHD-like symptoms have recently been provided and should be carefully considered. Antiepileptic drugs are commonly used in ASDs with epilepsy, because seizures are associated with ASD in 10% to 30% of young patients, and as mood stabilizers. Lithium is another option for children and adolescents with ASD who present with symptoms of a mood disorder, such as elevated moods/euphoria, mania, and paranoia, whether accompanied or not by irritability. Experimental treatments are under investigation and currently include arbaclofen, a gamma-aminobutyric acid agent, and N-acetylcisteine, a glutamate agent.
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4. Chevreul K, Berg Brigham K, Brunn M, des Portes V. {{Fragile X syndrome: economic burden and health-related quality of life of patients and caregivers in France}}. {J Intellect Disabil Res};2015 (Sep 15)
BACKGROUND: Fragile X syndrome (FXS) is the main hereditary cause of intellectual disability. Although the associated burden appears to be considerable, to date no study has comprehensively assessed the cost incurred because of FXS, including its specific impact on health-related quality of life and the burden on caregivers using standardised quantitative tools. The aim of this article is to provide data in order to increase awareness of the repercussions of FXS on patients and caregivers as well as on the health and social care systems in France. METHODS: A retrospective cross-sectional study was carried out on 145 patients recruited through Le Goeland X-Fragile and Mosaiques, the French FXS patient associations. Data on their demographic characteristics and resource use were obtained from an online questionnaire, and costs were estimated by a bottom-up approach. The EQ-5D health questionnaire was used to measure patients’ and caregivers’ health-related quality of life. Perceived burden of care was measured using the Zarit Caregiver Burden Interview. The Barthel index, a non-utility-based assessment, was used to measure patients’ level of dependence. RESULTS: The annual total direct cost of FXS was estimated at euro25 800 per patient. The main contributors were informal care provided by the main caregiver (euro10 500) and social services (euro8400). Healthcare costs, estimated at euro2700, represented only a minor share. Mean EQ-5D utility scores were 0.49 for patients and 0.75 for caregivers. The mean burden for caregivers as measured by the Zarit Caregiver Burden Interview was 39.9. CONCLUSIONS: Fragile X syndrome requires significant resources that are mainly of a non-medical nature and are higher for children than for adults. Compared with related diseases, it constitutes a particularly high burden for caregivers. Using a bottom-up approach and a wide range of standardised measures, this study underscores the need for greater awareness of the burden of FXS as well as an assessment of new and existing interventions to address it.
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5. Deschrijver E, Bardi L, Wiersema JR, Brass M. {{Behavioral measures of implicit theory of mind in adults with high functioning autism}}. {Cogn Neurosci};2015 (Sep 14)
Theory of mind (ToM) research has shown that adults with high functioning autism (HFA) demonstrate typical performance on tasks that require explicit belief reasoning, despite clear social difficulties in everyday life situations. In the current study, we used implicit belief manipulations that are task-irrelevant and therefore less susceptible to strategies. In a ball detection task, it was shown that neurotypical individuals detect a ball faster if an agent believed the ball was present. We predicted that adults with high functioning autism (HFA) would not show this effect. While we found a numerical difference in the hypothesized direction, we did not find a reliable group. Interestingly, the implicit ToM-index showed a strong negative correlation with both self-reported and observational measures of social difficulties in the HFA group. This suggests that the relationship between implicit ToM reasoning and the symptomatology of HFA might be subtler than assumed.
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6. Harrison AJ, Gamsiz ED, Berkowitz IC, Nagpal S, Jerskey BA. {{Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders}}. {Am J Med Genet B Neuropsychiatr Genet};2015 (Sep 14)
Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype-phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485-1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3′ untranslated region (3′-UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3’UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis. (c) 2015 Wiley Periodicals, Inc.
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7. Jin Y, Wee CY, Shi F, Thung KH, Ni D, Yap PT, Shen D. {{Identification of infants at high-risk for autism spectrum disorder using multiparameter multiscale white matter connectivity networks}}. {Hum Brain Mapp};2015 (Sep 14)
Autism spectrum disorder (ASD) is a wide range of disabilities that cause life-long cognitive impairment and social, communication, and behavioral challenges. Early diagnosis and medical intervention are important for improving the life quality of autistic patients. However, in the current practice, diagnosis often has to be delayed until the behavioral symptoms become evident during childhood. In this study, we demonstrate the feasibility of using machine learning techniques for identifying high-risk ASD infants at as early as six months after birth. This is based on the observation that ASD-induced abnormalities in white matter (WM) tracts and whole-brain connectivity have already started to appear within 24 months after birth. In particular, we propose a novel multikernel support vector machine classification framework by using the connectivity features gathered from WM connectivity networks, which are generated via multiscale regions of interest (ROIs) and multiple diffusion statistics such as fractional anisotropy, mean diffusivity, and average fiber length. Our proposed framework achieves an accuracy of 76% and an area of 0.80 under the receiver operating characteristic curve (AUC), in comparison to the accuracy of 70% and the AUC of 70% provided by the best single-parameter single-scale network. The improvement in accuracy is mainly due to the complementary information provided by multiparameter multiscale networks. In addition, our framework also provides the potential imaging connectomic markers and an objective means for early ASD diagnosis. Hum Brain Mapp, 2015. (c) 2015 Wiley Periodicals, Inc.
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8. Kalra S, Burbelo PD, Bayat A, Ching KH, Thurm A, Iadarola MJ, Swedo SE. {{No Evidence of Antibodies against GAD65 and Other Specific Antigens in Children with Autism}}. {BBA Clin};2015 (Dec 1);4:81-84.
BACKGROUND: The presence of autoantibodies has been proposed as evidence for a role of autoimmunity in autism. This report investigates the prevalence of autoantibodies in children with autism using the luciferase immunoprecipitation systems (LIPS) immunoassay technology. A panel of autoantibody targets against several known and candidate neurological autoantigens, autoimmune-associated autoantigens and viruses was employed. METHODS: Serological analysis was performed on typically developing children (n = 55), developmentally delayed children without autism (n = 24) and children diagnosed with autism (n=104). Autoantibodies were measured against glutamic acid decarboxylase-65 (GAD65), a CNS autoantigen proposed to be associated with autism and against Ro52, glial fibrillary acidic protein, tyrosine hydroxylase, aquaporin-4, and gamma-enolase, the mouse mammary tumor virus and the xenotropic murine leukemia virus. Antibody levels and seropositivity prevalence were analyzed for statistically significant differences between the three groups. RESULTS: The majority of the children (98%) were seronegative for all targets in the antigen panel. No GAD65 seropositive children were detected in the cohort. Several low level seropositive sera against several of the protein targets were identified in isolated children in each of the three groups, but there was no difference in prevalence. CONCLUSION: Using this panel of antigens and a sensitive, robust assay, no evidence of unusual immunoreactivity was detected in children with autism, providing evidence against a role of autoimmunity against several previously implicated proteins in autism spectrum disorder pathogenesis. GENERAL SIGNIFICANCE: The idea that autoantibodies represent an underlying cause or are biomarkers for autism pathophysiology is not supported by this report.
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9. Krach S, Kamp-Becker I, Einhauser W, Sommer J, Frassle S, Jansen A, Rademacher L, Muller-Pinzler L, Gazzola V, Paulus FM. {{Evidence from pupillometry and fMRI indicates reduced neural response during vicarious social pain but not physical pain in autism}}. {Hum Brain Mapp};2015 (Sep 14)
Autism spectrum disorder (ASD) is characterized by substantial social deficits. The notion that dysfunctions in neural circuits involved in sharing another’s affect explain these deficits is appealing, but has received only modest experimental support. Here we evaluated a complex paradigm on the vicarious social pain of embarrassment to probe social deficits in ASD as to whether it is more potent than paradigms currently in use. To do so we acquired pupillometry and fMRI in young adults with ASD and matched healthy controls. During a simple vicarious physical pain task no differences emerged between groups in behavior, pupillometry, and neural activation of the anterior insula (AIC) and anterior cingulate cortex (ACC). In contrast, processing complex vicarious social pain yielded reduced responses in ASD on all physiological measures of sharing another’s affect. The reduced activity within the AIC was thereby explained by the severity of autistic symptoms in the social and affective domain. Additionally, behavioral responses lacked correspondence with the anterior cingulate and anterior insula cortex activity found in controls. Instead, behavioral responses in ASD were associated with hippocampal activity. The observed dissociation echoes the clinical observations that deficits in ASD are most pronounced in complex social situations and simple tasks may not probe the dysfunctions in neural pathways involved in sharing affect. Our results are highly relevant because individuals with ASD may have preserved abilities to share another’s physical pain but still have problems with the vicarious representation of more complex emotions that matter in life. Hum Brain Mapp, 2015. (c) 2015 Wiley Periodicals, Inc.
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10. Lee MS, Kim YJ, Kim EJ, Lee MJ. {{Overlap of autism spectrum disorder and glucose transporter 1 deficiency syndrome associated with a heterozygous deletion at the 1p34.2 region}}. {J Neurol Sci};2015 (Sep 15);356(1-2):212-214.
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11. Martinez-Cerdeno V, Lechpammer M, Lott A, Schneider A, Hagerman R. {{Fragile X-Associated Tremor/Ataxia Syndrome in a Man in His 30s}}. {JAMA Neurol};2015 (Sep 1);72(9):1070-1073.
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12. Ning Z, McLellan AS, Ball M, Wynne F, O’Neill C, Mills W, Quinn JP, Kleinjan DA, Anney RJ, Carmody RJ, O’Keeffe G, Moore T. {{Regulation of SPRY3 by X chromosome and PAR2-linked promoters in an autism susceptibility region}}. {Hum Mol Genet};2015 (Sep 15);24(18):5126-5141.
Sprouty proteins are regulators of cell growth and branching morphogenesis. Unlike mouse Spry3, which is X-linked, human SPRY3 maps to the pseudoautosomal region 2; however, the human Y-linked allele is not expressed due to epigenetic silencing by an unknown mechanism. SPRY3 maps adjacent to X-linked Trimethyllysine hydroxylase epsilon (TMLHE), recently identified as an autism susceptibility gene. We report that Spry3 is highly expressed in central and peripheral nervous system ganglion cells in mouse and human, including cerebellar Purkinje cells and retinal ganglion cells. Transient over-expression or knockdown of Spry3 in cultured mouse superior cervical ganglion cells inhibits and promotes, respectively, neurite growth and branching. A 0.7 kb gene fragment spanning the human SPRY3 transcriptional start site recapitulates the endogenous Spry3-expression pattern in LacZ reporter mice. In the human and mouse the SPRY3 promoter contains an AG-rich repeat and we found co-expression, and promoter binding and/or regulation of SPRY3 expression by transcription factors MAZ, EGR1, ZNF263 and PAX6. We identified eight alleles of the human SPRY3 promoter repeat in Caucasians, and similar allele frequencies in autism families. We characterized multiple SPRY3 transcripts originating at two CpG islands in the X-linked F8A3-TMLHE region, suggesting X chromosome regulation of SPRY3. These findings provide an explanation for differential regulation of X and Y-linked SPRY3 alleles. In addition, the presence of a SPRY3 transcript exon in a previously described X chromosome deletion associated with autism, and the cerebellar interlobular variation in Spry3 expression coincident with the reported pattern of Purkinje cell loss in autism, suggest SPRY3 as a candidate susceptibility locus for autism.
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13. Owen-Smith AA, Bent S, Lynch FL, Coleman KJ, Yau VM, Pearson KA, Massolo ML, Quinn V, Croen LA. {{Prevalence and Predictors of Complementary and Alternative Medicine Use in a Large Insured Sample of Children with Autism Spectrum Disorders}}. {Res Autism Spectr Disord};2015 (Sep 1);17:40-51.
PURPOSE: The purpose of the present study was to examine the prevalence and predictors of complementary and alternative medicine (CAM) use as well as parental perceptions of CAM efficacy in a large, geographically diverse sample of children with Autism Spectrum Disorders (ASD). METHODOLOGY: Data were obtained from a web-based survey administered to parents of children with ASD at four sites participating in the Mental Health Research Network (MHRN). The web survey obtained information about services and treatments received by children with ASD as well as the caregivers’ experiences with having a child with ASD. RESULTS: Approximately 88% of the sample had either used CAM in the past or had recently used some type of CAM. The following characteristics were associated with CAM use: greater parental education, younger child age, a mix of regular and special classroom settings and prescription drug use in the past three months. CONCLUSIONS: The use of CAM was very prevalent in this large, geographically diverse sample of children with ASD. It is critical that providers be prepared to discuss the advantages and potential side effects with families to help them make well-informed health care decisions and prevent possible CAM-drug interactions.
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14. Pilorge M, Fassier C, Le Corronc H, Potey A, Bai J, De Gois S, Delaby E, Assouline B, Guinchat V, Devillard F, Delorme R, Nygren G, Rastam M, Meier JC, Otani S, Cheval H, James VM, Topf M, Dear TN, Gillberg C, Leboyer M, Giros B, Gautron S, Hazan J, Harvey RJ, Legendre P, Betancur C. {{Genetic and functional analyses demonstrate a role for abnormal glycinergic signaling in autism}}. {Mol Psychiatry};2015 (Sep 15)
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the alpha2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR alpha2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2Deltaex8-9). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2Deltaex8-9 protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2Deltaex8-9 or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.Molecular Psychiatry advance online publication, 15 September 2015; doi:10.1038/mp.2015.139.
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15. Qin M, Zeidler Z, Moulton K, Krych L, Xia Z, Smith CB. {{Endocannabinoid-mediated improvement on a test of aversive memory in a mouse model of fragile X syndrome}}. {Behav Brain Res};2015 (Sep 15);291:164-171.
Silencing the gene FMR1 in fragile X syndrome (FXS) with consequent loss of its protein product, FMRP, results in intellectual disability, hyperactivity, anxiety, seizure disorders, and autism-like behavior. In a mouse model (Fmr1 knockout (KO)) of FXS, a deficit in performance on the passive avoidance test of learning and memory is a robust phenotype. We report that drugs acting on the endocannabinoid (eCB) system can improve performance on this test. We present three lines of evidence: (1) Propofol (reported to inhibit fatty acid amide hydrolase (FAAH) activity) administered 30 min after training on the passive avoidance test improved performance in Fmr1 KO mice but had no effect on wild type (WT). FAAH catalyzes the metabolism of the eCB, anandamide, so its inhibition should result in increased anandamide levels. (2) The effect of propofol was blocked by prior administration of the cannabinoid receptor 1 antagonist AM-251. (3) Treatment with the FAAH inhibitor, URB-597, administered 30 min after training on the passive avoidance test also improved performance in Fmr1 KO mice but had no effect on WT. Our results indicate that the eCB system is involved in FXS and suggest that the eCB system is a promising target for treatment of FXS.
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16. Shen Q, Wang G, Li S, Liu X, Lu S, Chen Z, Song K, Yan J, Geng L, Huang Z, Huang W, Chen G, Zhang J. {{ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks}}. {Nucleic Acids Res};2015 (Sep 13)
Allosteric regulation, the most direct and efficient way of regulating protein function, is induced by the binding of a ligand at one site that is topographically distinct from an orthosteric site. Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information featuring allosteric regulation. With increasing data, fundamental questions pertaining to allostery are currently receiving more attention from the mechanism of allosteric changes in an individual protein to the entire effect of the changes in the interconnected network in the cell. Thus, the following novel features were added to this updated version: (i) structural mechanisms of more than 1600 allosteric actions were elucidated by a comparison of site structures before and after the binding of an modulator; (ii) 261 allosteric networks were identified to unveil how the allosteric action in a single protein would propagate to affect downstream proteins; (iii) two of the largest human allosteromes, protein kinases and GPCRs, were thoroughly constructed; and (iv) web interface and data organization were completely redesigned for efficient access. In addition, allosteric data have largely expanded in this update. These updates are useful for facilitating the investigation of allosteric mechanisms, dynamic networks and drug discoveries.
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17. Tastet J, Decalonne L, Marouillat S, Malvy J, Thepault RA, Toutain A, Paubel A, Tabagh R, Benedetti H, Laumonnier F, Barthelemy C, Bonnet-Brilhault F, Andres CR, Vourc’h P. {{Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism}}. {Psychiatr Genet};2015 (Sep 11)
Many genes are now thought to confer susceptibility to autism. Despite the fact that this neuropsychiatric disease appears to be related to several different causes, common cellular and molecular pathways have emerged and point to synaptic dysfunction or cellular growth. Several studies have indicated the importance of the ubiquitin pathway in synaptic function and the aetiology of autism. Here, we focused on the ring finger protein 135 (RNF135) gene, encoding an E3 ubiquitin ligase expressed in the cortex and cerebellum, and located in the NF1 gene locus in 17q11.2, a region linked to autism. We carried out a genetic analysis of the coding sequence of RFN135 in a French cohort of patients with autism and observed a significantly increased frequency of genotypes carrying the rare allele of the rs111902263 (p.R115K) missense variant in patients (P=0.0019, odds ratio: 4.23, 95% confidence interval: 1.87-9.57). Particularly, three unrelated patients showed a homozygous genotype for K115, a situation not observed in the 1812 control individuals. Further cellular and molecular studies are required to elucidate the role of this gene and the variant K115 in brain development and neuronal function.
