Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity.

Neuroligins are post-synaptic, cellular adhesion molecules implicated in synaptic formation and function. NLGN2 is strongly linked to inhibitory, GABAergic signaling and is crucial for maintaining the excitation-inhibition balance in the brain. Disruption of the excitation-inhibition balance is associated with neuropsychiatric disease. In animal models, altered NLGN2 expression causes anxiety, developmental delay, motor discoordination, social impairment, aggression, and sensory processing defects. In humans, mutations in NLGN3 and NLGN4 are linked to autism and schizophrenia; NLGN2 missense variants are implicated in schizophrenia. Copy number variants encompassing NLGN2 on 17p13.1 are associated with autism, intellectual disability, metabolic syndrome, diabetes, and dysmorphic features, but an isolated NLGN2 nonsense variant has not yet been described in humans. Here, we describe a 15-year-old male with severe anxiety, obsessive-compulsive behaviors, developmental delay, autism, obesity, macrocephaly, and some dysmorphic features. Exome sequencing identified a heterozygous, de novo, c.441C>A p.(Tyr147Ter) variant in NLGN2 that is predicted to cause loss of normal protein function. This is the first report of an NLGN2 nonsense variant in humans, adding to the accumulating evidence that links synaptic proteins with a spectrum of neurodevelopmental phenotypes. © 2016 Wiley Periodicals, Inc.

Profiles of Executive Function Across Children with Distinct Brain Disorders: Traumatic Brain Injury, Stroke, and Brain Tumor.

OBJECTIVES: This study examined whether children with distinct brain disorders show different profiles of strengths and weaknesses in executive functions, and differ from children without brain disorder. METHODS: Participants were children with traumatic brain injury (N=82; 8-13 years of age), arterial ischemic stroke (N=36; 6-16 years of age), and brain tumor (N=74; 9-18 years of age), each with a corresponding matched comparison group consisting of children with orthopedic injury (N=61), asthma (N=15), and classmates without medical illness (N=68), respectively. Shifting, inhibition, and working memory were assessed, respectively, using three Test of Everyday Attention: Children's Version (TEA-Ch) subtests: Creature Counting, Walk-Don't-Walk, and Code Transmission. Comparison groups did not differ in TEA-Ch performance and were merged into a single control group. Profile analysis was used to examine group differences in TEA-Ch subtest scaled scores after controlling for maternal education and age. RESULTS: As a whole, children with brain disorder performed more poorly than controls on measures of executive function. Relative to controls, the three brain injury groups showed significantly different profiles of executive functions. Importantly, post hoc tests revealed that performance on TEA-Ch subtests differed among the brain disorder groups. CONCLUSIONS: Results suggest that different childhood brain disorders result in distinct patterns of executive function deficits that differ from children without brain disorder. Implications for clinical practice and future research are discussed. (JINS, 2017, 23, 529-538).

WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome.

BACKGROUND: Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described. METHODS: Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation. RESULTS: Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted. CONCLUSIONS: Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.

Association learning-dependent increases in acetylcholine release in the rat auditory cortex during auditory classical conditioning.

The cholinergic system has been implicated in sensory cortical plasticity, learning and memory. This experiment determined the relationship between the acquisition of a Pavlovian conditioned approach response (CR) to an auditory conditioned stimulus (CS) and the release of acetylcholine (ACh) in the primary auditory cortex in rats. Samples of ACh were collected via microdialysis during behavioral training in either an auditory classical conditioning task or in a non-associative control task. The conditioning group received daily pairings of a white noise CS with a sucrose pellet unconditioned stimulus (US), while the control group received an equal number of CS and US presentations, but with these stimuli being presented randomly. Training was conducted on three consecutive days, with microdialysis samples being collected on Days 1 and 3 in separate sub-groups. The level of ACh released in the auditory cortex during conditioning trials increased from the first to the third day of training in the conditioning group as rats acquired the CR, but did not change in the control group, which did not acquire a CR. These data provide direct evidence for the hypothesis that ACh release increases in the primary auditory cortex during natural memory formation, where cholinergic activation is known to contribute to the formation of specific associative representational plasticity in conjunction with specific memory formation.

Response monitoring in children with phenylketonuria.

Phenylketonuria (PKU) is characterized by a disruption in the metabolism of phenylalanine and is associated with dopamine deficiency (Diamond, Prevor, Callender, & Druin, 1997) and cerebral white matter abnormalities (e.g., Anderson et al., 2007). From a neuropsychological perspective, prefrontal dysfunction is thought to underlie the deficits in executive abilities observed in individuals with PKU (Christ, Steiner, Grange, Abrams, & White, 2006; Diamond et al., 1997; White, Nortz, Mandernach, Huntington, & Steiner, 2001, 2002). The purpose of our study was to examine a specific aspect of executive ability, response monitoring, as measured by posterror slowing. The authors examined posterror reaction time (RT) in 24 children with well-controlled, early treated PKU and 25 typically developing control children using a go/no-go task. Results showed that RTs of both controls and children with PKU slowed significantly following the commission of errors. The magnitude of posterror slowing, however, was significantly less for children with PKU. These findings indicate deficient response monitoring in children with PKU.

Lateralizing seizure focus in presurgical patients with temporal lobe epilepsy: utility of the Ruff-Light Trail Learning Test.

From a neuropsychological perspective, left or right temporal lobe abnormalities underlying seizures in patients with temporal lobe epilepsy (TLE) are thought to contribute to selective deficits in verbal or nonverbal memory abilities, respectively. The Ruff-Light Trail Learning Test (RULIT) is specifically designed to detect right hemisphere dysfunction. The purpose of our study was to examine the utility of the RULIT in distinguishing between patients with right (n=20) and patients with left (n=32) TLE in presurgical evaluations. We identified a significant between-group difference in RULIT scores, but not in the expected direction; that is, patients with right TLE had significantly better scores than patients with left TLE. These findings indicate that the RULIT may not be an appropriate test for presurgical epilepsy evaluations. Findings are discussed within the context of results from other lateralizing neuropsychological tests.

Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities.

BACKGROUND: Dynamin 1 is a protein involved in the synaptic vesicle cycle, which facilitates the exocytosis of neurotransmitters necessary for normal signaling and development in the central nervous system. Pathogenic variants in DNM1 have been implicated in global developmental delay (DD), severe intellectual disability (ID), and notably, epileptic encephalopathy. All previously reported DNM1 pathogenic variants causing this severe phenotype occur in the GTPase and Middle domains of the dynamin 1 protein. METHODS: We used whole-exome sequencing to characterize the molecular basis of DD and autistic symptoms in two identical siblings. RESULTS: The twin siblings exhibit mild to moderate ID and autistic symptoms but no epileptic encephalopathy. Exome sequencing revealed a genetic variant, c.1603A>G (p.Lys535Glu), in the PH domain of dynamin 1. Previous in vitro studies showed that mutations at Lys535 inhibit endocytosis and impair PH loop binding to PIP2. CONCLUSIONS: Our data suggest a previously undescribed milder phenotype associated with a missense genetic variant in the PH domain of dynamin 1.

High risk drinking and college students' self-perceptions.

The present study examined the relationship between high risk drinking and college students' self-perceptions. High risk drinking was defined as the consumption of four or more drinks in a row for women and five or more drinks in a row for men during a single sitting (within the last year). Historical trends regarding college-age drinking indicate that 44% of college students fit the criteria for high risk drinking at least once over the past year. A survey was administered to 210 college students (52 men and 158 women) between 18 and 22 years of age (M = 20.9, SD = 1.3) to assess their use of alcohol and their self-perceptions. Students' self-perceptions were measured with four subscales from the Neemann-Harter Self-perception Profile for College Students. Students either volunteered to participate in this study outside of class or were solicited during class. It was predicted that students' self-perceptions would differ significantly depending upon their alcohol consumption, i.e., 17.1% were Abstainers, 25.2% were Nonproblem Drinkers, and 57.6% were High Risk Drinkers. Analysis gave significant difference on Global Self-worth between students who abstained and those who were High Risk Drinkers. However, students' perceptions of Scholastic Competence, Intellectual Ability, and Social Acceptance did not differ significantly for the alcohol consumption groups. In addition to high risk drinking, a number of other variables were associated with self-perceptions, such as high school alcohol use, low high school GPA, and students' reported academic involvement. These relations are discussed.

The relationship between suboptimal effort and post-concussion symptoms in children and adolescents with mild traumatic brain injury.

This retrospective chart review study explored the relationship between suboptimal effort and post-concussion symptoms in pediatric mild traumatic brain injury (mTBI). Participants were 382 clinically referred children and adolescents between 8 and 16 years of age who sustained an mTBI. Suboptimal effort was identified using reliable digit span and age-corrected scaled scores from the Numbers subtest of the Children's Memory Scale (CMS); 20% of the sample were classified as non-credible performers. Chi-square analyses and t-tests were used to examine differences in post-concussion symptoms and neuropsychological test performance between credible and non-credible performers. Linear regression was used to examine whether CMS Numbers performance predicted post-concussion symptoms after controlling for baseline symptoms and other relevant demographic- and injury-related factors. We found that non-credible performers presented with a greater number of post-concussion symptoms as compared with credible performers. Additionally, non-credible performers demonstrated comparatively poorer performance on neuropsychological tests of focused attention and processing speed. These results suggest that children and adolescents with mTBI who fail effort testing might have a greater tendency to exaggerate post-concussion symptoms and cognitive impairment. The clinical implications of these findings are discussed.

Executive response monitoring and inhibitory control in children with phenylketonuria: effects of expectancy.

Response monitoring (post-error slowing) and inhibitory control (commission errors) were examined in children with phenylketonuria (PKU) and controls (6-18 years) using Go/No-Go tasks with higher (PKU n = 37; control n = 55) versus lower (PKU n = 24; control n = 25) non-target expectancy. On both tasks children with PKU exhibited impaired monitoring and inhibitory control, but the post-error slowing pattern was different. With higher expectancy children with PKU slowed more (less efficient monitoring) and with lower expectancy slowed less (less monitoring) than controls. No effects of age or phenylalanine level were noted. These results indicate that expectancy differentially effects monitoring and inhibitory control in PKU.