Kate M. Lawrence

Social communication competence and functional adaptation in a general population of children: preliminary evidence for sex-by-verbal IQ differential risk.

OBJECTIVE The proportion of schoolchildren with mild social communicative deficits far exceeds the number diagnosed with an autistic spectrum disorder (ASD). We aimed to ascertain both the population distribution of such deficits and their association with functional adaptation and cognitive ability in middle childhood. METHOD The parent-report Social and Communication Disorders Checklist was administered to participants (n = 8,094) in the Avon Longitudinal Study of Parents and Children. We correlated impairment severity with independent clinical diagnoses of ASD, cognitive abilities, and teacher-rated maladaptive behavior. RESULTS Social and Communication Disorders Checklist scores were continuously distributed in the general population; boys had mean scores 30% higher than girls. Social communicative deficits were associated with functional impairment at school, especially in domains of hyperactivity and conduct disorders. A sex-by-verbal IQ interaction effect occurred: verbal IQ was protective against social communication impairments across the range of abilities in female subjects only. In male subjects, this protective effect did not exist for those with above-average verbal IQ. CONCLUSIONS Social communicative deficits are of prognostic significance, in terms of behavioral adjustment at school, for boys and girls. Their high general population prevalence emphasizes the importance of measuring such traits among clinically referred children who do not meet diagnostic ASD criteria. Above-average verbal IQ seems to confer protection against social communication impairments in female subjects but not in male subjects.

Glucose Transporter 1 Deficiency as a Treatable Cause of Myoclonic Astatic Epilepsy

OBJECTIVE To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. DESIGN Genetic analysis. SETTING Ambulatory and hospitalized care. PATIENTS Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. MAIN OUTCOME MEASURE Any SLC2A1 mutations. RESULTS Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. CONCLUSIONS Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.

Glucose transporter 1 deficiency in the idiopathic generalized epilepsies

We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs).

Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations

De novo mutations are a cause of sporadic disease, but little is known about the developmental timing of such mutations. We studied concordant and discordant monozygous twins with de novo mutations in the sodium channel α1 subunit gene (SCN1A) causing Dravets syndrome, a severe epileptic encephalopathy. On the basis of our findings and the literature on mosaic cases, we conclude that de novo mutations in SCN1A may occur at any time, from the premorula stage of the embryo (causing disease in the subject) to adulthood (with mutations in the germ-line cells of parents causing disease in offspring).

Meanings in motion and faces: Developmental associations between the processing of intention from geometrical animations and gaze detection accuracy

Aspects of face processing, on the one hand, and theory of mind (ToM) tasks, on the other hand, show specific impairment in autism. We aimed to discover whether a correlation between tasks tapping these abilities was evident in typically developing children at two developmental stages. One hundred fifty-four normal children (6-8 years and 16-18 years) and 13 high-IQ autistic children (11-17 years) were tested on a range of face-processing and IQ tasks, and a ToM test based on the attribution of intentional movement to abstract shapes in a cartoon. By midchildhood, the ability accurately and spontaneously to infer the locus of attention of a face with direct or averted gaze was specifically associated with the ability to describe geometrical animations using mental state terms. Other face-processing and animation descriptions failed to show the association. Autistic adolescents were impaired at both gaze processing and ToM descriptions, using these tests. Mentalizing and gaze perception accuracy are associated in typically developing children and adolescents. The findings are congruent with the possibility that common neural circuitry underlies, at least in part, processing implicated in these tasks. They are also congruent with the possibility that autism may lie at one end of a developmental continuum with respect to these skills, and to the factor(s) underpinning them.

Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency.

Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike‐waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in‐frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.

Eye tracking and fear recognition deficits in Turner syndrome

Abstract Turner syndrome (TS) is a chromosomal disorder of X-monosomy in females. A minority have impaired social responsiveness, poor discrimination of facial emotions (especially fear), and abnormal amygdala–cortical connectivity. We tested the hypothesis that abnormal gaze fixation, especially with the eye region of faces, would be associated with these features, in a similar pattern to that seen in subjects with autism. Furthermore, since these features tend to be more striking in TS women whose X chromosome is maternal in origin, we also predicted that there may be a difference within the Turners group according to parental origin of the single X. Adults with 45,X karyotype and age and IQ matched 46,XX women were recruited and tested. Facial fear recognition was significantly worse in 45,X females than controls, but there were no group differences according to parental origin of their single X chromosome. Subsequently, we tested 45,X and 46,XX women using a remote eye-tracking device, as they viewed photographs of emotional human faces. Striking differences in scanpaths were found between the TS and controls, and within the TS group, but not according to parental origin of the X chromosome. These findings provide novel evidence for abnormal face processing in some women with TS, and indicate a potential neural mechanism underlying the difficulties in some key aspects of social cognition.

Balance impairment in chronic antiepileptic drug users: A twin and sibling study

Purpose:  Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED‐discordant, twin and sibling matched‐pair approach, and assessed clinically relevant subgroups: AED polytherapy; longer‐duration AED; and falls history.

Genetics of epilepsy The testimony of twins in the molecular era

Objective: Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses. Methods: A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable. Results: Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles. Conclusions: Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the “genetic” syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.

Measuring Social-Cognitive Functions in Children with Somatotropic Axis Dysfunction

Growth hormone (GH) and insulin-like growth factor I (IGF-I) are expressed in specific regions of the central nervous system during early human development. They may consequently influence aspects of cognition, or emotional and behavioural adjustment from childhood to adulthood, in conditions associated with abnormalities of the somatotropic axis. GH receptors are relatively common within hippocampal and perihippocampal regions that are primarily involved in declarative memory for facts and events. They are also located in structures (e.g. the putamen) that are involved in the processing of social perceptions. IGF-I receptors have been discovered in the amygdala and prefrontal cortex, which contribute to the neural circuits known as the ‘social brain’. The evaluation of emotional, social and behavioural adjustment among children who have deficiencies in GH or IGF-I functional integrity requires the objective assessment of their social-cognitive competence. We describe a computerized test battery, the Schedules for the Assessment of Social Intelligence (SASI), which has been shown to possess excellent psychometric properties in terms of reliability and validity. The SASI, which can be used by both children and adults, may provide new evidence for deficits and treatment effects of GH/IGF-I on emotional, behavioural and cognitive functions.