Bernadette Rogé

Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage–sensitive synaptic pathway that is involved in autism spectrum disorders.

Microcephaly and Macrocephaly in Autism

Data from a series of 126 autistic children ages 2–16 years and referred to an Autism Diagnosis Unit in South-West France were examined. Macrocephaly (head circumference > 97th centile) was observed in 16.7% of the sample, a significantly higher proportion than that expected. Macrocephaly was more frequent among older subjects but was otherwise not associated with gender, developmental level, the presence of epilepsy or of medical disorders, or severity of autistic symptomatology. Microcephaly (head circumference < 3rd centile) was also significantly raised and found in 15.1% of the sample. Microcephaly was significantly associated with the presence of medical disorders. Results support those from recent studies suggesting a raised rate of macrocephaly in autism which, pooling published data, can be estimated to be 20%. It is argued that the raised incidence of microcephaly among low-functioning autistic subjects with medical disorders might have contributed to delay the recognition of an increased head circumference among a minority of subjects with idiopathic autism.

Prevention and treatment of post-partum depression: a controlled randomized study on women at risk

BACKGROUND Research is needed to evaluate the efficacy of prevention and treatment for post-partum depression. METHOD Subjects were screened with the Edinburgh Post-natal Depression Scale (EPDS) at the obstetric clinic. Mothers at risk (N = 258) (EPDS scores > or = 9) were randomly assigned to a prevention/treatment group or a control group. The prevention group received one cognitive-behavioural prevention session during hospitalization. At 4 to 6 weeks post-partum, subjects were screened again with the EPDS, after drop-out rates (refusals plus no return of the second EPDS) of 25.4% (33/130) in the intervention group and 10.9% (14/128) in the control group. Mothers with probable depression (EPDS scores > or = 11) were assessed using the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI). Mothers with major depression continued in the treatment group (N = 18) or in the control group (N = 30). Treated subjects received a cognitive-behavioural programme of between five and eight weekly home-visits. RESULTS Compared with the control group, women in the prevention group had significant reductions in the frequency of probable depression (30.2 % v. 48.2%). Recovery rates based on HDRS scores of < 7 and BDI scores of < 4 were also significantly greater in the treated group than in the control group. CONCLUSIONS The study suggests that this programme for prevention and treatment of post-partum depression is reasonably well-accepted and efficacious.

Visual social attention in autism spectrum disorder: insights from eye tracking studies.

We review different aspects of visual social attention in autism spectrum disorders (ASD) from infancy to adulthood in light of the eye-tracking literature. We first assess the assumption that individuals with ASD demonstrate a deficit in social orienting together with decreased attention to socially relevant stimuli such as faces compared to TD individuals. Results show that social orienting is actually not qualitatively impaired and that decreased attention to faces does not generalized across contexts. We also assess the assumption that individuals with ASD demonstrate excess mouth and diminished eye gaze compared to TD individuals. We find that this assumption receives little support across ages and discuss some factors that might have initially lead to this conjecture. We report that the assessment of the ability to follow the direction of another persons gaze needs to be further examined and that eye-tracking studies add to the evidence that individuals with ASD demonstrate difficulties in interpreting gaze cues. Finally, we highlight innovative data acquisition and analyses that are increasingly shedding light on the more subtle nature of the profound social difficulties experienced by individuals with ASD.

Increased perception of loudness in autism.

Clinical reports on autism describe abnormal responses to auditory stimuli such as intolerance to sounds. The present study assessed subjective perception of loudness in subjects with autism compared to healthy controls, using two psychoacoustic tests. First, the auditory dynamic range was evaluated at six different tone frequencies. Secondly, loudness growth as a function of the intensity level of a 1 kHz tone was estimated. Verbal responses from a group of 11 children and adolescents with autism were compared to responses of 11 age- and gender- matched healthy controls. Smaller auditory dynamic ranges were found in the autistic group than in the control group, as well as increased perception of loudness, indicating hyperacusis in subjects with autism.

Early Processing of Emotional Faces in Children with Autism: An Event-Related Potential Study.

Social deficits are one of the most striking manifestations of autism spectrum disorders (ASDs). Among these social deficits, the recognition and understanding of emotional facial expressions has been widely reported to be affected in ASDs. We investigated emotional face processing in children with and without autism using event-related potentials (ERPs). High-functioning children with autism (n=15, mean age=10.5±3.3 years) completed an implicit emotional task while visual ERPs were recorded. Two groups of typically developing children (chronological age-matched and verbal equivalent age-matched [both ns=15, mean age=7.7±3.8 years]) also participated in this study. The early ERP responses to faces (P1 and N170) were delayed, and the P1 was smaller in children with autism than in typically developing children of the same chronological age, revealing that the first stages of emotional face processing are affected in autism. However, when matched by verbal equivalent age, only P1 amplitude remained affected in autism. Our results suggest that the emotional and facial processing difficulties in autism could start from atypicalities in visual perceptual processes involving rapid feedback to primary visual areas and subsequent holistic processing.

Recognition of emotional and nonemotional facial expressions: A comparison between Williams syndrome and autism

The aim of our study was to compare two neurodevelopmental disorders (Williams syndrome and autism) in terms of the ability to recognize emotional and nonemotional facial expressions. The comparison of these two disorders is particularly relevant to the investigation of face processing and should contribute to a better understanding of social behaviour and social cognition. Twelve participants with WS (from 6;1 to 15 years) and twelve participants with autism (from 4;9 to 8 years) were matched on verbal mental age. Their performances were compared with those of twelve typically developing controls matched on verbal mental age (from 3;1 to 9;2). A set of five tasks assessing different dimensions of emotional and nonemotional facial recognition were administered. Results indicated that recognition of emotional facial expressions is more impaired in Williams syndrome than in autism. Our study comparing Williams syndrome and autism over a small age range highlighted two distinct profiles which call into question the relationships between social behaviour/cognition and emotion perception.

Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients

BackgroundPrader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients.MethodsIn a double-blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment.ResultsPatients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups.ConclusionsThis study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity.Trial registration numberClinicalTrials.gov: NCT01038570

Screening for autism spectrum disorders: state of the art in Europe

A large number of studies have reported on the validity of autism spectrum disorder (ASD) screening procedures. An overall understanding of these studies’ findings cannot be based solely on the level of internal validity of each, since screening instruments might perform differently according to certain factors in different settings. Europe has led the field with the development of the first screening tool and first prospective screening study of autism. This paper seeks to provide an overview of ASD screening studies and ongoing programmes across Europe, and identify variables that have influenced the outcomes of such studies. Results show that, to date, over 70,000 children have been screened in Europe using 18 different screening procedures. Differences among findings across studies have enabled us to identify ten factors that may influence screening results. Although it is impossible to draw firm conclusions as to which screening procedure is most effective, this analysis might facilitate the choice of a screening method that best fits a specific scenario, and this, in turn, may eventually improve early ASD detection procedures.

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism

Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E−09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E−23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E−04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.