Laurence Robel

Autism severity and temporal lobe functional abnormalities

Two independent studies 1 , 2 have described bilateral temporal hypoperfusion in autistic children. Temporal regions are implicated in social perception, language, and “theory‐of‐mind,” abilities that are impaired in autism. We investigated a putative relationship between cerebral blood flow (rCBF) measured at rest and clinical profile of 45 autistic children (Autism Diagnostic Interview–Revised [ADI‐R] scores). A whole‐brain covariance analysis was performed. Significant negative correlation was observed between rCBF and ADI‐R score in the left superior temporal gyrus. The more severe the autistic syndrome, the more rCBF is low in this region, suggesting that left superior temporal hypoperfusion is related to autistic behavior severity. Ann Neurol 2005;58:466–469

MRI Findings in 77 Children with Non-Syndromic Autistic Disorder

Background The clinical relevance of MR scanning in children with autism is still an open question and must be considered in light of the evolution of this technology. MRI was judged to be of insufficient value to be included in the standard clinical evaluation of autism according to the guidelines of the American Academy of Neurology and Child Neurology Society in 2000 [1]. However, this statement was based on results obtained from small samples of patients and, more importantly, included mostly insufficient MRI sequences. Our main objective was to evaluate the prevalence of brain abnormalities in a large group of children with a non-syndromic autistic disorder (AD) using T1, T2 and FLAIR MRI sequences. Methodology MRI inspection of 77 children and adolescents with non-syndromic AD (mean age 7.4±3.6) was performed. All met the DSM-IV and ADI –R criteria for autism. Based on recommended clinical and biological screenings, we excluded patients with infectious, metabolic or genetic diseases, seizures or any other neurological symptoms. Identical MRI inspections of 77 children (mean age 7.0±4.2) without AD, developmental or neurological disorders were also performed. All MRIs were acquired with a 1.5-T Signa GE (3-D T1-FSPGR, T2, FLAIR coronal and axial sequences). Two neuroradiologists independently inspected cortical and sub-cortical regions. MRIs were reported to be normal, abnormal or uninterpretable. Principal Findings MRIs were judged as uninterpretable in 10% (8/77) of the cases. In 48% of the children (33/69 patients), abnormalities were reported. Three predominant abnormalities were observed, including white matter signal abnormalities (19/69), major dilated Virchow–Robin spaces (12/69) and temporal lobe abnormalities (20/69). In all, 52% of the MRIs were interpreted as normal (36/69 patients). Conclusions An unexpectedly high rate of MRI abnormalities was found in the first large series of clinical MRI investigations in non-syndromic autism. These results could contribute to further etiopathogenetic research into autism.

Neurobehavioral Profile and Brain Imaging Study of the 22q13.3 Deletion Syndrome in Childhood

OBJECTIVE. The 22q13.3 deletion syndrome (Online Mendelian Inheritance in Man No. 606232) is a neurodevelopmental disorder that includes hypotonia, severely impaired development of speech and language, autistic-like behavior, and minor dysmorphic features. Although the number of reported cases is increasing, the 22q13.3 deletion remains underdiagnosed because of failure in recognizing the clinical phenotype and detecting the 22qter deletion by routine chromosome analyses. Our goal is to contribute to the description of the neurobehavioral phenotype and brain abnormalities of this microdeletional syndrome. METHODS. We assessed neuromotor, sensory, language, communication, and social development and performed cerebral MRI and study of regional cerebral blood flow measured by positron emission tomography in 8 children carrying the 22q13.3 deletion. RESULTS. Despite variability in expression and severity, the children shared a common developmental profile characterized by hypotonia, sleep disorders, and poor response to their environment in early infancy; expressive language deficit contrasting with emergence of social reciprocity from ages ∼3 to 5 years; sensory processing dysfunction; and neuromotor disorders. Brain MRI findings were normal or showed a thin or morphologically atypical corpus callosum. Positron emission tomography study detected a localized dysfunction of the left temporal polar lobe and amygdala hypoperfusion. CONCLUSIONS. The developmental course of the 22q13.3 deletion syndrome belongs to pervasive developmental disorders but is distinct from autism. An improved description of the natural history of this syndrome should help in recognizing this largely underdiagnosed condition.

Discrimination of face identities and expressions in children with autism: same or different?

Abstract.Autism is a pervasive developmental disorder (PDD) characterized by the association of communication and socialization impairments, and by repetitive stereotyped behaviours. The Minnesota Test of Affective Processing (MNTAP) was used to investigate the discrimination of face identities and face expressions by autistic children. Young children in the 6- to 10-year-old age range suffering from PDD were compared to paired normal children. When the expressions on faces remained neutral, autistic patients had more difficulty in distinguishing different faces than in matching the same facial identities in face pairs: they perceived different faces as being identical. However, recognition errors disappeared when expressions were changed together with face identity. When autistic children were asked to distinguish expressions, they discriminated better identity than difference, just as normal children do. Analysis of face and expression discrimination in terms of identity and difference is a novel approach for the understanding of the clinical features of autism. Autistic children seek sameness and use an atypical strategy to analyse human faces and expressions.

Clinical, Cellular, and Neuropathological Consequences of AP1S2 Mutations: Further Delineation of a Recognizable X-Linked Mental Retardation Syndrome

Mutations in the AP1S2 gene, encoding the σ1B subunit of the clathrin‐associated adaptor protein complex (AP)‐1, have been recently identified in five X‐linked mental retardation (XLMR) families, including the original family with Fried syndrome. Studying four patients in two unrelated families in which AP1S2 nonsense and splice‐site mutations segregated, we found that affected individuals presented, in addition to previously described features, with elevated protein levels in cerebrospinal fluid (CSF). Moreover, computed tomography scans demonstrated that the basal ganglia calcifications associated with AP1S2 mutations appeared during childhood and might be progressive. Based on these observations, we propose that AP1S2 mutations are responsible for a clinically recognizable XLMR and autism syndrome associating hypotonia, delayed walking, speech delay, aggressive behavior, brain calcifications, and elevated CSF protein levels. Using the AP‐2 complex, in which the σ subunit is encoded by one single gene, as a model system, we demonstrated that σ subunits are essential for the stability of human AP complexes. By contrast, no major alteration of the stability, subcellular localization, and function of the AP‐1 complex was observed in fibroblasts derived from a patient carrying an AP1S2 mutation. Similarly, neither macro‐ nor microscopic defects were observed in the brain of an affected fetus. Altogether, these data suggest that the absence of an AP‐1 defect in peripheral tissues is due to functional redundancy among AP‐1 σ subunits (σ1A, σ1B, and σ1C) and that the phenotype observed in our patients results from a subtle and brain‐specific defect of the AP‐1‐dependent intracellular protein traffic. Hum Mutat 29(7), 966–974, 2008.

Polymorphisms of coding trinucleotide repeats of homeogenes in neurodevelopmental psychiatric disorders.

Objectives Autism (MIM♯209850) and schizophrenia (MIM♯181500) are both neurodevelopmental psychiatric disorders characterized by a highly genetic component. Homeogenes and forkhead genes encode transcription factors, which have been involved in brain development and cell differentiation. Thus, they are relevant candidate genes for psychiatric disorders. Genetic studies have reported an association between autism and DLX2, HOXA1, EN2, ARX, and FOXP2 genes whereas only three studies of EN2, OTX2, and FOXP2 were performed on schizophrenia. Interestingly, most of these candidate genes contain trinucleotide repeats coding for polyamino acid stretch in which instability can be the cause of neurodevelopmental disorders. Our goal was to identify variations of coding trinucleotide repeats in schizophrenia, autism, and idiopathic mental retardation. Methods We screened the coding trinucleotide repeats of OTX1, EN1, DLX2, HOXA1, and FOXP2 genes in populations suffering from schizophrenia (247 patients), autism (98 patients), and idiopathic mental retardation (56 patients), and compared them with control populations (112 super controls and 202 healthy controls). Results Novel deletions and insertions of coding trinucleotide repeats were found in the DLX2, HOXA1, and FOXP2 genes. Most of these variations were detected in controls and no difference in their distribution was observed between patient and control groups. Two different polymorphisms in FOXP2 were, however, found only in autistic patients and the functional consequences of these variations of repeats have to be characterized and correlated to particular clinical features. Conclusion This study did not identify specific disease risk variants of trinucleotide repeats in OTX1, EN1, DLX2, HOXA1, and FOXP2 candidate genes in neurodevelopmental psychiatric disorders.

Tracking social motivation systems deficits: the affective neuroscience view of autism.

Abnormal functioning of primary brain systems that express and modulate basic emotional drives are increasingly considered to underlie mental disorders including autism spectrum disorders. We hypothesized that ASD are characterized by disruptions in the primary systems involved in the motivation for social bonding. Twenty adults with ASD were compared to 20 neurotypical participants on the basis of self-reports and clinical assessments, including the Social Anhedonia Scale (SAS) and the Affective Neuroscience Personality Scales (ANPS). ASD diagnosis was related to SAS, as well as to positive (PLAYFULNESS) and negative (FEAR) ANPS-traits. In the overall sample, levels of autistic traits (AQ) were related to SAS and PLAYFULNESS. We argue that PLAYFULNESS could be at the root of social bonding impairments in ASD.

Intérêt de l'autoquestionnaire FAQ dans le repérage d'un endophénotype chez les parents d'enfants autistes

Resume L’autisme est une pathologie du developpement psychoaffectif d’origine polyfactorielle, associant une composante genetique et environnementale. Les facteurs de vulnerabilite genetique impliques dans l’autisme pourraient egalement contribuer aux troubles du langage ou de la socialisation, dont la frequence est accrue chez les apparentes de sujets autistes. Dans cette etude, nous avons construit et teste aupres d’un groupe de 20 parents d’enfants autistes et d’un groupe de 21 parents controles, la pertinence d’un autoquestionnaire visant la caracterisation d’un endophenotype parental, defini par la presence significative de « traits apparentes » aux troubles autistiques, dans les domaines de la socialisation, de la communication, de l’imagination et des interets restreints et stereotypes. Cet autoquestionnaire est apparu comme un outil facile et rapide d’utilisation, permettant de mettre en evidence de facon fine des « particularites endophenotypiques » chez des adultes ne presentant pas de psychopathologie averee, notamment dans le domaine de la socialisation. L’utilisation de cet autoquestionnaire pourrait permettre de prendre en compte la presence d’endophenotypes parentaux dans l’analyse des etudes de liaison genetique.

L’autoquestionnaire FAQ : un outil valide pour le repérage des endophénotypes des parents d’enfants autistes

BACKGROUND We have previously developed the FAQ self-report, an adaptation of the Baron-Cohens Autism Quotient self-report, in order to detect traits of the autistic spectrum in the parents and siblings of children with autism. We have previously shown that parents of children with autism show significant differences in their global scores and in their social functioning scores according to their answers to the FAQ self-report. OBJECTIVE Our aim was to validate the FAQ self-report in a population of control parents, and to confirm our previous results concerning parents of children with autism. METHODOLOGY Hundred and twenty-seven adults (67 female, 60 male), parents of children with normal development were recruited in the general population. They were asked to fulfill the 40 questions of the FAQ self-report at two different times. Sixty-six parents of children with autism were asked to fulfill the FAQ self-report, for group comparisons. Statistical factor analysis and test-retest reliability analysis was performed with the Matlab toolbox(©) software. RESULTS Statistical factor analysis and test-retest reliability show that the FAQ is structured in two main factors, socialization and communication on one hand, rigidity and imagination on the other, with good test-retest reliability. Further comparison between parents of children with autism and control parents shows a significant difference between the two groups for the socialization and communication domain, and for the global score. We show for the first time that scores of the parents of children with autism remain unchanged from infancy to adulthood. CONCLUSION The FAQ is the first French validated self-report focused on the detection of traits of the autistic spectrum in parents and siblings of children with autism. It is structured in two main factors, corresponding to imagination/rigidity, which are negatively correlated, and communication and socialization, which are positively correlated. The FAQ is therefore a reliable instrument to measure endophenotypes associated with the autistic spectrum in parents of children with autism, and may be useful in genetic studies.

Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller’s dementia infantilis, a rare subtype of autism spectrum disorder

BackgroundDeletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD).Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Case presentationHere, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3.The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.ConclusionOur present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years.