Neurodevelopmental Anomalies Research Articles

A tubulin alpha 8 mouse knockout model indicates a likely role in spermatogenesis but not in brain development.

Tubulin alpha 8 (Tuba8) is the most divergent member of the highly conserved alpha tubulin family, and uniquely lacks two key post-translational modification sites. It is abundantly expressed in testis and muscle, with lower levels in the brain. We previously identified homozygous hypomorphic TUBA8 mutations in human subjects with a polymicrogyria (PMG) syndrome, suggesting its involvement in development of the cerebral cortex. We have now generated and characterized a Tuba8 knockout mouse model. Homozygous mice were confirmed to lack Tuba8 protein in the testis, but did not display PMG and appeared to be neurologically normal. In response to this finding, we re-analyzed the human PMG subjects using whole exome sequencing. This resulted in identification of an additional homozygous loss-of-function mutation in SNAP29, suggesting that SNAP29 deficiency, rather than TUBA8 deficiency, may underlie most or all of the neurodevelopmental anomalies in these subjects. Nonetheless, in the mouse brain, Tuba8 specifically localised to the cerebellar Purkinje cells, suggesting that the human mutations may affect or modify motor control. In the testis, Tuba8 localisation was cell-type specific. It was restricted to spermiogenesis with a strong acrosomal localization that was gradually replaced by cytoplasmic distribution and was absent from spermatozoa. Although the knockout mice were fertile, the localisation pattern indicated that Tuba8 may have a role in spermatid development during spermatogenesis, rather than as a component of the mature microtubule-rich flagellum itself.

Cullin 7 mediates proteasomal and lysosomal degradations of rat Eag1 potassium channels

Mammalian Eag1 (Kv10.1) potassium (K+) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K+ channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner. Immunoprecipitation analyses confirmed the interaction between Cul7 and rEag1 in heterologous cells and neuronal tissues. Cul7 and rEag1 also exhibited significant co-localization at synaptic regions in neurons. Over-expression of Cul7 led to reduced protein level, enhanced ubiquitination, accelerated protein turn-over, and decreased current density of rEag1 channels. We provided further biochemical and morphological evidence suggesting that Cul7 targeted endoplasmic reticulum (ER)- and plasma membrane-localized rEag1 to the proteasome and the lysosome, respectively, for protein degradation. Cul7 also contributed to protein degradation of a disease-associated rEag1 mutant. Together, these results indicate that Cul7 mediates both proteasomal and lysosomal degradations of rEag1. Our findings provide a novel insight to the mechanisms underlying ER and peripheral protein quality controls of Eag1 channels.

Infantile Cirrhosis, Growth Impairment, and Neurodevelopmental Anomalies Associated with Deficiency of PPP1R15B

To assess the utility of whole-exome sequencing (WES) in a sibling pair with undetermined liver disease and describe the phenotype associated with mutations discovered therein. Next-generation WES was performed on 2 siblings (S1 and S2) who were born to nonconsanguineous parents of European extraction. Both siblings developed cirrhosis of indeterminate etiology and required liver transplantation; S1 at 7 months and S2 at 22 months. Sequencing of germline DNA identified compound heterozygous mutations in PPP1R15B resulting in increased levels of phosphorylated eukaryotic translation initiation factor 2α. The first demonstration of PPP1R15B associated with liver disease expands the phenotypic spectrum of PPP1R15B related diseases. Our findings validate the application of WES in the diagnosis of children with undetermined liver disease. Understanding the genetic basis of liver disease may allow the development of targeted therapies for treatment and adequate counseling of families.

Neurological soft signs in Chinese adolescents with schizophrenia and schizotypal personality traits

ObjectiveNeurological soft signs (NSSs) may reflect neurodevelopmental anomalies in association with the spectrum of schizophrenia disorders. We examined NSSs in Chinese adolescents with schizophrenia and schizotypal personality traits. MethodsEighty-seven schizophrenic adolescents (SCH group), 85 adolescents with only schizotypal personality traits (SPT group), and 88 healthy controls (HC group) were enrolled. The NSS subscales of the Cambridge Neurological Inventory (CNI) were administered to all 260 participants. ResultsThe NSS prevalence rates were higher in the SCH group than in the other two groups for both hands in the fist-edge-palm, Oseretsky, and graphesthesia tests. Relative to HCs, the SCH group also showed higher NSS prevalence rates in the right finger agnosia and right mirror movement of finger opposition tests. SCH>SPT>HC trends were observed for all NSS subscale scores and for the left, right, and total NSS scores. ConclusionsTo our knowledge, the present study is the first to examine NSSs in adolescents with schizophrenia and adolescents with schizotypal personality traits. These results provide preliminary findings suggesting that schizophrenia spectrum disorders may be characterized by developmental abnormalities in the central nervous system, and support the notion that NSSs may be schizophrenia spectrum disorder biomarkers.

Altered expression and localization of synaptophysin in developing cerebellar cortex of neonatal rats due to maternal diabetes mellitus

There is sufficient evidence that diabetes during pregnancy is associated with a higher risk of neurodevelopmental anomalies including learning deficits, behavioral problems and motor dysfunctions in the offspring. Synaptophysin (SYP) is an integral membrane protein of synaptic vesicles and is considered as a marker for synaptogenesis and synaptic density. This study aimed to examine the effects of maternal diabetes in pregnancy on the expression and localization of SYP in the developing rat cerebellum. Wistar female rats were maintained diabetic from a week before pregnancy through parturition and male offspring was euthanized at postnatal day (P) 0, 7, and 14. The results revealed a significant down-regulation in the mRNA expression of SYP in the offspring born to diabetic animals at both P7 and P14 (P<0.05 each). One week after birth, there was a significant reduction in the localization of SYP expression in the external granular (EGL) and in the molecular (ML) layers of neonates born to diabetic animals (P<0.05 each). We also found a marked decrease in the expression of SYP in all of the cerebellar cortical layers of STZ-D group pups at P14 (P<0.05 each). Moreover, our results revealed no significant changes in either expression or localization of SYP in insulin-treated group pups when compared with the controls (P≥0.05 each). The present study demonstrated that maternal diabetes has adverse effects on the synaptogenesis in the offspring's cerebellum. Furthermore, the rigid maternal blood glucose control in the most cases normalized these negative impacts.

Genetics of multifactorial disorders: proceedings of the 6th Pan Arab Human Genetics Conference.

The 6th Pan Arab Human Genetics Conference (PAHGC), “Genetics of Multifactorial Disorders” was organized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in Dubai, United Arab Emirates from 21 to 23 January, 2016. The PAHGCs are held biennially to provide a common platform to bring together regional and international geneticists to share their knowledge and to discuss common issues. Over 800 delegates attended the first 2 days of the conference and these came from various medical and scientific backgrounds. They consisted of geneticists, molecular biologists, medical practitioners, postdoctoral researchers, technical staff (e.g., nurses and lab technicians) and medical students from 35 countries around the world. On the 3rd day, a one-day workshop on “Genetic Counseling” was delivered to 26 participants. The conference focused on four major topics, namely, diabetes, genetics of neurodevelopmental disorders, congenital anomalies and cancer genetics. Personalized medicine was a recurrent theme in most of the research presented at the conference, as was the application of novel molecular findings in clinical settings. This report discusses a summary of the presentations from the meeting.

Psychosis and polydrug abuse in a patient with Dandy-Walker variant

Background and purposeDandy Walker “syndrome” (DWS) was firstly defined by Dandy and Blackfan, and then described by Hart et al. [1] as a series of neurodevelopmental anomalies in the posterior fossa, including Dandy-Walker (DW) malformation, DW variant (cerebellar hypoplasia/aplasia of the cerebellar vermis and cystic dilatation of the fourth ventricle), mega-cisterna magna and posterior fossa arachnoid cyst. Mental symptoms have been associated with DWS in previous reports, but the spectrum of mental symptomatology widely varies between clinical cases, ranging from psychotic/schizophrenia-like to mood/cognitive symptoms [2].MethodsHere we describe a case of psychosis and polydrug abuse in a 27-year-old man with DW variant a 4-year history of polydrug abuse, sporadic alcohol abuse, epilepsy and psychotic symptoms including delusions of reference/persecution, suspiciousness, associated with obsessive thoughts, mood lability and persistent anxiety.ResultsHe was recovered for a 28-day program of detoxification from drug addiction/stabilization of psychiatric symptoms. Family history of Bipolar Disorder, gambling disorder (father) and depression (mother). The mental status examination at baseline revealed slowness of thought, psychomotor retardation, aboulia/anhedonia/apathy/hypomimic facies/asthenia/social withdrawal/deflected mood/poor thought content/blunted affect/self-neglect/poor insight, cognitive impairment and oppositive and partially collaborative attitude and behaviour. Borderline intelligence activity was found on WAIS-R (IQ = 79). At the baseline, he was taking carbamazepine 400 mg BID (baseline serum level: 6.720 μg/ml), gabapentin (400 mg BID), paroxetine (20 mg/d), olanzapine (10 mg/d) and methadone (70 ml/d), with a poor response/control both on psychotic and seeking drug symptomatology.References not available.ConclusionsFurther DWS clinical cases should be evaluated in order to better investigate the role of this variant to addictive and psychotic symptoms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Ocular, Neurologic and Systemic Findings of the Cases with Optic Nerve Hypoplasia

Aim: To describe the associated ocular, neurologic, and systemic findings in a population of children with optic nerve hypoplasia (ONH) and to evaluate the relationship between ocular signs and neurologic findings. Method: A retrospective chart review of 53 patients with the diagnosis of ONH seen between December 1998 and September 2012 was performed. All neurodevelopmental anomalies, neuroradiologic findings, endocrinologic and systemic findings were recorded. Poor vision was defined as the visual acuity poorer than logMAR 1.0 or inadequate central steady maintained fixation. Results:Thirty (56.6%) of the 53 children with ONH were boys. Mean age at presentation was 56.2±46.8 months (range; 3 months to 18 years). Poor vision defined for the purpose of this study was found in 47.2% of 53 patients. Thirty-three (62.3%) children had nystagmus. Thirty-four (64.2%) children had strabismus. Thirteen (38.2%) of those with strabismus had esotropia, 20 (58.8%) had exotropia. The total number of the children with neurodevelopmental deficit was 22 (41.5%) in our study. Conclusion:The vision of young children with ONH should be monitored at least annually, and any refractive errors should be treated. Neuroimaging of the brain and endocrinologic evaluation is necessary in all cases with ONH.

Preterm birth and periodontal disease: A medical perspective

Births occurring before 37 weeks resulting in prematurity poses serious hazards to the baby from delayed growth, neurodevelopmental anomalies to death and unfortunately India is in the top four countries with maximum preterm births and leads globally in deaths by prematurity. Infection is a very important component of the etiopathogenesis of preterm labor and periodontal disease is a rather unexplored aspect of infection very often overlooked by the general gynecologist and the dental practitioner equally. Periodontal disease is a potential foci of infectious pathogens which may disseminate hematogenously and effect the fetus. In this article, an effort has been made to find an evidence-based link between periodontal disease and preterm labor to drive home the conclusion that an early screening and diagnosis in pregnancy followed up with effective treatment of periodontal disease may significantly reduce the burden of preterm births.

Comorbid Epilepsy and Developmental Disorders in Congenital Long QT SyndromeWith Life-Threatening PerinatalArrhythmias.

Given the association of long QT syndrome (LQTS) and neurological disorders, we speculated that the more severe LQTS phenotype, perinatal LQTS, would exhibit more frequent comorbid neurodevelopmental anomalies than LQTS without perinatal arrhythmias (nonperinatal LQTS). Congenital LQTS with life-threatening perinatal arrhythmias (perinatal LQTS) has a poor life prognosis. Twenty-one consecutive LQTS patients diagnosed before 1 year of age at our institution and 3 previously reported perinatal LQTS patients with neurological seizures were enrolled. In total, the clinical course was evaluated in 24patients. Among 21 infantile LQTS patients, 5 of 6 with perinatal LQTS (83%) were diagnosed with epilepsy and 4 (67%) with developmental disorders, but none with nonperinatal LQTS were. The total development quotient by Kinder Infant Development Scale scores was 17 to 72 (median 67) in 5 epileptic perinatal LQTS. Inthe 8 perinatal LQTS patients with neurological disorders, including 3 previously reported cases, epileptic seizures occurred at 2 days to 2.5 years of age and 5 had developmental disorders. Mutations in these 8patients were located in the transmembrane loop of KCNH2, and D3/S4-S5 linker, D4/S4, or the D4/S6 segment of SCN5A. A high comorbidity of neurodevelopmental anomalies was observed in perinatal LQTS. Mutations in patients with neurological comorbidities were in loci linked to LQTS with a severe cardiac phenotype. These observations indicate the possibility that neurological disorders in perinatal LQTS are manifested as neurological phenotypes associated with severe cardiac phenotypes, while we could not completely exclude another possibility that those were causedby a brain perfusion injury.

Analysis of supratentorial cystic abnormalities using in utero MR imaging.

Our anecdotal experience from foetal neuroimaging studies suggests that there are often significant disagreements between the findings of ultrasonography (USS) and in utero MR (iuMR) imaging in cases of antenatally detected supratentorial extra-axial cysts. Although this is a relatively rare clinical situation, it warrants further investigation because of the high risk of other intracranial abnormalities that are likely to cause long-term neurodevelopmental problems. We reviewed 957 consecutive referrals for iuMR of the foetal brain over a 3.5-year period and studied all cases where the referral from USS described supratentorial extra-axial cysts in the foetus. The iuMR imaging was reviewed, and a comparison between the results of the two examinations was made. Supratentorial extra-axial cysts were an unusual referral for iuMR occurring in only 13/957 (1.4%) of cases. The findings on USS and iuMR imaging were conflicting in all 13 cases with intracranial pathology being excluded on iuMR imaging in 4 cases and more significant pathology being shown in 9 cases. Abnormalities of the corpus callosum were recognized in association with a cyst in eight cases, and this was recognized in only two cases on USS. Six of those cases also had abnormalities of cortical formation. iuMR imaging should be used in the assessment of pregnancies in which a supratentorial extra-axial cyst has been detected on USS. This is based on the improved primary diagnosis and a high rate of associated brain abnormalities not detected on USS. Our retrospective observational study examines a range of foetal intracranial abnormalities which are better defined using iuMRI. This is a previously described spectrum of neurodevelopmental anomalies which we suggest would benefit from MRI.

PP05.9 – 2366: Neurodevelopmental and immunological features in a child presenting 22q13.2 microdeletion

Introduction Phelan-Mc Dermid syndrome (PMD) is a contiguous disorder resulting from the deletion of the distal arm of chromosome 22, generally implicating the SHANK3 gene on 22q13.3. Patients typically present neonatal hypotonia, developmental and speech delay, autistic features, normal or accelerated growth and minor morphological anomalies. In addition, several patients with 22q13 microdeletion proximal to SHANK3 and typical features of PMD are described. Case description We describe a 7-year old girl presenting a 0.54-Mb interstitial 22q13.2 microdeletion associated with neurological and immunological features. The patient presents different dysmorphic signs and macrocephaly. Neurological features include psychomotor and language retardation, coordination difficulties, repetitive behaviors and perseverations. In addition, the girl was affected by repetitive bronchiolitis since the age of 5 months, allergy to mites, treatment resistant asthma and vernal conjunctivitis. Discussion The chromosomal region deleted in our patient includes a dozen of genes including TNFRSF13C and NFAM1, two genes involved in B-cell development and related to autoimmunity. Therefore, this microdeletion probably explains not only neurodevelopmental anomalies evoking PMD but also immunological features including treatment-resistant vernal conjunctivitis, asthma and allergy. Recently, one other patient with a larger 22q13.2 microdeletion and similar clinical features has been described, thus helping for patient's diagnostic work up. The case illustrates the importance to assess the full clinical picture. Genetic abnormalities might not only explain neurological features but also extra-neurological diseases, important for patients, their follow up and possible treatments.

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III–related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

Ventriculopleural Shunt Surgery in A Patient with Multiple Skeletal and Neurodevelopmental Anomalies: A True Perioperative Challenge

Introduction: Ventriculopleural shunt placement for decompression of hydrocephalous is an uncommon procedure. The usual indications are adhesions, infection, thrombosis or obliteration of the more commonly done ventriculoperitoneal shunt or an anatomical non-availability of the peritoneum. We present a clinical case of a patient with congenital hydrocephalous complicated by multiple skeletal and neurodevelopmental anomalies who presented for thoracoscopic placement of a ventriculopleural shunt. The anesthetic challenges and perioperative management constituted a complex multi-disciplinary challenge. Case presentation: We present a clinical case of a 42 years old woman with congenital hydrocephalous complicated by multiple skeletal and neurodevelopmental anomalies who presented for thoracoscopic placement of a ventriculopleural shunt. Some of the perioperative concerns included initiation and maintenance of one-lung ventilation in a patient with short stature, dysmorphic skeletal features, severe kyphoscoliosis, restrictive underlying lung disease and multiple neurodevelopmental midline defects. Conclusion: Our presentation highlights the special challenges in this patient based on the need for lung collapse in a severely short statured individual with a dysmorphic severely kyphoscoliotic thoracic cavity along with underlying restrictive lung disease and background neurodevelopmental midline defects.

O-210 Obstetrical Complications Associated With Preterm Delivery And Intraventricular Haemorrhage In Preterm Infants: Results From The French National Cohort Epipage 2

Backgrouds and aim Despite the improvement in neonatal care, intraventricular haemorrhage (IVH) remains an important cause of neurodevelopmental anomalies in preterm infants (PI). This event is usually associated with gestational age (GA). Others factors like maternal complications associated with preterm delivery could be implicated. We studied the association between these maternal complications and IVH in a large cohort of PI. Methods The data were extracted from the national Epipage 2 study, which included PI born before 32 weeks gestation during the year 2011 (n = 3492). Neonatal and Obstetrical data were collected from the medical records including the postnatal cerebral ultrasound results. We used a polytomic logistic regression to compare the risk of the different grades of IVH according to the usual obstetrical complications associated with preterm birth. Results The incidence of grade 1 IVH was 16.7% [95% CI: 15.2–17.7], grade 2 was 10.5% [95% CI: 9.6–11.6], grade 3 was 5.6% [95% CI: 4.8–6.3] and grade 4: 3.7% [95% CI: 3.1–4.3%]. Infants born when preterm labour with inflammatory syndrome was present had significantly more grade 3 and IV IVH than those exposed to maternal vascular disease (respectively 12.6% and 7.3% vs 1.8% and 3.4%). After adjustment for GA and others confounding factors, grade 4 IVH was strongly associated with preterm labour with inflammation (OR: 1.56 [95% CI: 1.3–18.5]) and placental abruption (OR: 2.3 [95% CI: 1.7–38.0]). Grade 3 IVH was only associated with placental abruption (OR: 4.6 [95% CI: 1.3–16.8]). Discussion This study demonstrates that IVH is associated with other factors independent of GA, as well as certain maternal complications. These results are useful for the management of preterm birth and help better understand the mechanisms of IVH.

Şizofreni ile kavum septum pellusidum arasındaki ilişki: Bir olgu sunumu

The relationship between schizophrenia and cavum septum pellucidum: a case study Septum pellucidum that forming the medial wall of the lateral ventricles, a thin layer is formed by two laminae. Cavum septum pellucidum (CSP), a space between the two leaflets of the septi pellucidi, is thought to be a neurodevelopmental anomaly associated with schizophrenia. In normal fetal development, the formation of septum pellucidum occurs at the same time with the development of the neighboring limbic system structures such as hippocampus, amygdala, corpus callosum, septal nucleus. Therefore, the anatomical differences that are detected in the septum pellucidum may reflect the embryonal development disorders of the adjacent anatomical structures. Several magnetic resonance imaging studies have reported a higher prevalence of enlarged CSP in patients with schizophrenia than in normal subjects. In the literature of psychiatric disorders, CSP is most associated with schizophrenia. Wide CSP may support the neurodevelopmental etiology of schizophrenia. In this report we present a schizophrenia case. And we tried to discuss the patient’s clinical appearance and neurocognitive disability.

Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: Implications in transitional care

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects.

Altered asymmetry of the anterior cingulate cortex in subjects at genetic high risk for psychosis

ObjectiveMany studies have reported that patients with schizophrenia often have structural abnormalities of the anterior cingulate cortex (ACC) and that some of these seem to be of genetic origin, therefore predating the onset of illness. The present study aimed to investigate whether these alterations in the ACC are genetic in origin by comparing the morphological patterns of three groups: normal controls, subjects at genetic high risk (GHR) for psychosis, and patients with schizophrenia. The relationships between morphological variations and executive function were also investigated. MethodsThis study examined the magnetic resonance images of cingulate sulcus/paracingulate sulcus (CS/PCS) folding patterns in 222 subjects (103 normal subjects, 30 individuals at GHR, and 89 patients with schizophrenia) and evaluated differences in the morphological and asymmetrical patterns of the ACC among groups. Neurocognitive tests were then performed and differences in cognitive performance were analyzed according to morphological variation. ResultsDifferences in PCS folding were detected; the control group was significantly more likely than were other groups to show a well-developed left PCS (p=0.009) and leftward asymmetry of the PCS (p<0.001). However, neither GHR subjects (p=0.346) nor patients (p=0.784) showed this leftward asymmetry. No statistically significant differences in CS continuity were observed. A more prominent left PCS (p=0.031) and leftward PCS asymmetry (p=0.030) were both associated with higher scores on the working memory task. ConclusionThe results suggest that GHR subjects have distinct neurodevelopmental anomalies that resemble those of patients with schizophrenia even though they do not display any psychotic symptoms. Certain developmental alterations in the ACC, such as the loss of leftward sulcal asymmetry in patients with schizophrenia, might be related to genetic factors. Additionally, this morphological alteration might partly account for the impaired executive function in schizophrenia.

Low-Dose Thyroxine Attenuates Autism-Associated Adverse Effects of Fetal Alcohol in Male Offspring's Social Behavior and Hippocampal Gene Expression

Fetal alcohol spectrum disorder (FASD) is characterized by neurodevelopmental anomalies manifesting in cognitive and behavioral deficits in the offspring with diverse severities. Social behavior is affected in FASD, and these deficits overlap with those of autism spectrum disorder (ASD). Identifying some of the molecular characteristics related to ASD in an animal model of FASD could ultimately provide details on the underlying molecular mechanisms of both disorders that could lead to novel treatments. Pregnant Sprague-Dawley rats received the following diets: control (C; ad libitum standard laboratory chow), nutritional control pair-fed (PF), ethanol (EtOH), or an EtOH diet supplemented with 0.3, 1.5, or 7.5mg thyroxine (T4)/l in the diet. Social behavior and memory were tested in the adult offspring. Plasma total T4, free T3 (fT3), and thyroid-stimulating hormone (TSH) levels were measured. Hippocampal expression of Gabrb3, Ube3a, Nr2b, Rasgrf1, and Dio3 were measured by RT-qPCR and protein levels of Mecp2 and Slc25a12 by Western blotting. Adult male offspring of EtOH dams showed elevated fT3 and low TSH levels. Adult male, but not female, offspring of EtOH dams exhibited social behavior and memory deficits. Expression of autism candidates, Gabrb3, Ube3a, Mecp2, and Slc25a12, was significantly increased in the hippocampus of male offspring of EtOH dams. Hippocampal Nr2b and Dio3 were also increased, while Rasgrf1 was decreased in the same population. Peripheral thyroid function, social behavioral deficits, and altered expression of the above genes were normalized by simultaneous administration of 0.3mg/l T4 in the EtOH diet. Our data suggest that social interaction deficits of FASD share molecular mechanism with ASD by showing altered hippocampal expression of several ASD candidate genes. Social interaction deficits as well as the gene expression changes in the offspring of EtOH-consuming dams can be reversed by low dose of thyroid hormone supplementation to the mothers.

White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS), Fragile X syndrome (FXS), or Turner syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.