[Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. / Prise en charge pédopsychiatrique des patients présentant un syndrome microdélétionnel 22q11.2 : du soin à la prévention.

22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research.

PDD-NOS, psychotic features and executive function deficits in a boy with proximal 22q11.2 microduplication: Evolution of the psychiatric symptom profile from childhood to adolescence.

22q11.2 microduplication (22q11.2DupS) is associated with a broad spectrum of phenotypes, including normality. Psychiatric disorders are described in 13% of these patients, including Attention Deficit and Hyperactivity Disorder (ADHD), Intellectual Deficiency (ID), and Autism Spectrum Disorder (ASD), but not schizophrenia. We report changes in the psychiatric symptom profile in the course of development of a young boy with a 22q11.2DupS syndrome, from early childhood to adolescence. The boy's psychiatric presentation was characterized by features of Pervasive Developmental Disorder (PDD), with ADHD in early childhood, a single psychotic episode in mid-infancy, and executive impairment in adolescence. We discuss the importance of an in-depth assessment of cognitive functions in children with22q11.2DupS throughout their development.

[Abnormal electroencephalography results and specific language impairment: towards a theoretical neurodevelopmental model?]. / Anomalies électroencéphalographiques paroxystiques et troubles spécifiques du langage de l'enfant : vers un modèle neurodéveloppemental ?

BACKGROUND: Specific language impairment (SLI) is a primary developmental disorder in which language is significantly more impaired than other developmental domains. Abnormal electroencephalographic recordings without clinical seizures are often observed. The aim of this retrospective study was to characterize the frequency of these abnormalities, to describe them and to analyze their association with anamnestic, clinical, paraclinical and evolution characteristics. METHODS: The cases of 35 children with a diagnosis of SLI, who also underwent electroencephalography and MRI, were systematically reviewed retrospectively. RESULTS: In this population, aged between 4 and 7 years, 49% (n=17) of patients exhibited a specific expressive language disorder and 51% (n=18) a specific receptive disorder. Forty-nine percent of the children featured abnormal electroencephalography results. Abnormalities were essentially localized on the left side of the brain and in two specific regions: the temporo-occipital (60%) and the frontorolandic (30%) regions. The groups with and without abnormalities were compared statistically with each other in terms of clinical, paraclinical and evolution characteristics. Evolution data were available for 24 patients through a telephone interview and for nine patients through a new complete language evaluation. The comparison of the two groups showed significant differences in terms of severity of the phonological disorder, a higher number of delayed acquisition of walking and cleanliness and a higher range of non specific psychomotor difficulties. DISCUSSION: A large proportion of children suffering from SLI present abnormal electroencephalography recordings with no clinical seizures. This rate is much higher than in the general population and the abnormalities are essentially localized on the left side of the brain in regions known for their specific role in language development. These abnormalities are more frequent in children with a severe phonological disorder, suggesting that they may share common pathophysiological features with SLI. CONCLUSION: The presence of EEG abnormalities in a large group of patients suffering from SLI associated with minor neurological abnormalities suggests a possible theoretical neurodevelopmental model. Minor neurodevelopmental abnormalities, genetically transmitted or acquired during the pre- or perinatal period, may create vulnerability towards SLI. This vulnerability, in conjunction with environmental influences such as family environment, linguistic stimuli, exposure to multiple languages, or transitory hearing loss, might take the form of SLI. This hypothesis underlines the importance of prevention and early detection of SLI when identifying vulnerable subjects. Monitoring the family early through parental guidance and early school support would facilitate the acquisition of language.

[Diagnostic investigations for an unexplained developmental disability]. / Stratégie d'exploration d'une déficience intellectuelle inexpliquée.

Developmental disability/mental retardation is a major public health problem and a common cause of consultation in pediatrics, neuropediatrics, and genetics. Etiologies of mental retardation are highly heterogeneous. Diagnostic strategies have been explored in a small number of consensus publications, essentially from English-speaking countries. In these publications, the utility of the conventional karyotype, fragile X screening, metabolic workup, and brain imaging were discussed. Recently, investigations in mental disabilities have been dramatically modified by molecular cytogenetics and the emergence of new metabolic pathologies. Based on the published experiments, the Reference centers for rare disease network "mental deficiencies with rare causes" elaborated an updated protocol for the investigation of nonsyndromal mental disability that takes into account recent innovations in genetics and genomics. Whenever local facilities make it possible, we recommend array CGH investigation as the first step or, when CGH is not available, a combination of classic karyotype with systematic screening of telomeric and interstitial rearrangements by MLPA, fragile X screening in both sexes, and a reorientation of metabolic screening toward certain diseases that have recently been described: congenital disorders of glycosylation (CDG), thyroid hormone carrier deficiency, and creatine metabolism deficiency. We recommend MRI imaging only if head size is abnormal, if neurological examination is abnormal, or regression occurs if walking is not achieved by 2 years, or if development is severely delayed.

[The FAQ self-report is a valid instrument to characterize endophenotypes of the autistic spectrum in parents of children with autism]. / 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-Cohen's 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.

[Clinical features in autism]. / Données actuelles sur la clinique de l'autisme.

Autism is a neurodevelopmental disorder diagnosed on the basis of three behaviorally altered domains: social deficits, impaired language and communication, and stereotyped and repetitive behaviors. The early recognition of the disorder, as early as 2 years, is an important challenge, because early treatments are more efficient in helping children to develop their adaptation skills, allowing their better integration in the society, with less suffering and a lower level of handicap. Therefore, we describe the symptoms that may lead first degree practitioners to suspect autistic disorders as early as possible, and how they can help the children and their parents to be directed to the appropriate services for diagnostic and treatment.

[Investigation of the behavioural phenotype of parents of autistic children through the new FAQ self-report]. / Intérêt de l'autoquestionnaire FAQ dans le repérage d'un endophénotype chez les parents d'enfants autistes.

INTRODUCTION: Autism is characterized by impairments in communication and socialization and by the presence of circumscribed and stereotyped interest. Previous studies have shown that genetic mechanisms may enhance the vulnerability to autism. These mechanisms are complex and may involve the combination of several genes, in interaction with the environment. The genetic mechanism involved in the vulnerability to autism may also concern other disorders and some features, with enhanced prevalence in relatives of autistic patients. It has been shown, for example, that the frequency of language disorders or serial difficulties is increased in the siblings of autistic patients. Characterization and taking into account the presence of such phenotypic traits in the relations may help in understanding the results of genetic studies, in particular association studies in sibling pairs or trios. OBJECTIVE: In this study, we used a new self-report in order to identify endophenotype traits in socialization, communication, rigidity and imagination in parents of autistic children. This self-report is the French adaptation of the previous self-report created by Baron-Cohen et al., aimed at the identification of Asperger profiles in a population of students studying science. METHODOLOGY: Ten autistic children and their parents from a clinical setting were asked to participate in the study. Autistic children were characterized using the ADI-R and various psychometric tests, according to the possibilities of the child (PEP-R, WPPSI-R, WISC3). Twenty parents of normal children were recruited from three different professional settings. There were no differences between the two groups of parents in terms of age or social status. Parents of both groups were asked to fill in the FAQ self-report. RESULTS: We performed a post-hoc analysis comparing the scores of the parents in the two groups. We found a main group, but no sex effect [F (1,37)=5.46; p<0.05]. Scores of autistic parents were higher in all domains compared to the control parents (p<0.05). However, the score on the socialization subscale was the only one that significantly differed from the scores on the imagination, language and rigidity subscales [F (3,111)=20.75, p<0.001]. CONCLUSION: Our results show significant differences between the two groups of parents in the socialization domain. This is of interest both for the interpretation of the presence of allelic variants in the genetic association studies, and for the understanding of the interplay between genotype and phenotype in the development of the autistic disorder.

The neuronal microtubule-associated protein 1B is under homeoprotein transcriptional control.

To identify genes regulated by homeoprotein transcription factors in postnatal neurons, the DNA-binding domain (homeodomain) of Engrailed homeoprotein was internalized into rat cerebellum neurons. The internalized homeodomain (EnHD) acts as a competitive inhibitor of Engrailed and of several homeoproteins (Mainguy et al., 2000). Analysis by differential display revealed that microtubule-associated protein 1B (MAP1B) mRNA is upregulated by EnHD. This upregulation does not require protein synthesis, suggesting a direct effect of the homeodomain on MAP1B transcription. The promoter region of MAP1B was cut into several subdomains, and each subdomain was tested for its ability to bind Engrailed and EnHD and to associate with Engrailed-containing cerebellum nuclear extracts. In addition, the activity, and regulation by Engrailed, of each subdomain and of the entire promoter were evaluated in vivo by electroporation in the chick embryo neural tube. These experiments demonstrate that MAP1B promoter is regulated by Engrailed in vivo. Moreover, they show that one promoter domain that contains all ATTA homeoprotein cognate binding sites common to the rat and human genes is an essential element of this regulation. It is thus proposed that MAP1B, a cytoskeleton protein involved in neuronal growth and regeneration, is under homeoprotein transcriptional regulation.

Dlx-2 homeobox gene controls neuronal differentiation in primary cultures of developing basal ganglia.

Homeodomain-containing genes of the Dlx family are expressed in the developing basal ganglia. To investigate the role of Dlx genes during development, we studied their cellular localization in primary cultures of embryonic basal telencephalon, and examined the changes in cellular phenotypes resulting from blockade of Dlx-2 expression. Cells containing Dlx-1, Dlx-2, and Dlx-5 mRNAs are immature cells of the neuronal lineage expressing the microtubule-associated proteins (MAPs) MAP1B and MAP2, but not glial fibrillary acidic protein (GFAP). Treatment of these cells with antisense oligonucleotides targeted to Dlx-2 caused a specific decrease of Dlx-2 mRNA and protein. This decrease in the Dlx-2 gene product was associated with a decrease in the expression of MAP2, a protein localized in neuronal dendrites, along with a smaller decrease in the 200-kDa neurofilament subunit (NF-H). Proteins expressed preferentially in axons were unchanged. This reduction in MAP2 expression was associated with a decrease in dendrite outgrowth and an increased level of cell proliferation. None of these changes were elicited by antisense oligonucleotides targeted to Dlx-1. We suggest that the Dlx-2 gene product regulates two interrelated aspects of neuronal differentiation: the exit from the mitotic cycle and the capability to grow MAP2-positive dendrites. As such, this gene product may be important for the establishment of neuronal polarity, setting the stage for afferent synaptic connectivity.

Fibroblast growth factor 2 increases Otx2 expression in precursor cells from mammalian telencephalon.

Dissociated primary cultures from rat telencephalon at different developmental stages were used to study the effect of basic fibroblast growth factor (FGF2) on Otx2, Dlx1, and Emx1, three homeobox genes expressed in different regions of the developing mammalian forebrain. At embryonic day (E)13.5. the regional pattern of expression of Otx1, Otx2, Dlx1, Dlx2, Dlx5, and Emx1 is maintained in primary culture, suggesting that cells are already committed to a regional identity at this stage. In these cultures, Otx2 is expressed by precursor cells, whereas Dlx1 and Emx1 are predominantly expressed by postmitotic cells. We found that FGF2 increased Otx2 expression within precursor cells and the total number of Otx2-expressing cells. This effect was gene-specific, dose-dependent, and temporally regulated, with larger effects at earlier stages of development (E11.5). At E13.5, the effect of FGF2 on Otx2 expression was restricted to the basal telencephalon. Our results suggest that a restricted population of neuroblasts respond to FGF2 in a temporally regulated fashion by proliferating and increasing Otx2 expression. This interaction between FGF2 and Otx2 may be important for the regulation of neurogenesis in the forebrain.

Slowly progressive apraxia: two case studies.

Two patients with a slowly progressive and severe motor apraxia are presented. In one case, there was only apraxia; in the other there was moderate memory disturbance and a mild decline of global intellectual ability, suggesting a more widespread cognitive dysfunction. In this second case, recognition of the correct use of objects was also severely impaired, suggesting a disturbance of motor knowledge. In both cases, apraxia was asymmetrical, and associated with a contralateral atrophy of the upper parietal cortex, suggesting a differential involvement of separate action systems for each hand.

Stimulation of protein-tyrosine phosphorylation in rat striatum after lesion of dopamine neurons or chronic neuroleptic treatment.

Even though the short-term actions of dopamine on postsynaptic receptors are well-characterized, the molecular bases for long-term trophic interactions between dopamine neurons and their targets remain unclear. Since protein-tyrosine phosphorylation plays a key role in the action of trophic factors, we have investigated its possible involvement in the interactions between dopamine neurons and their striatal targets. Lesioning rat nigrostriatal dopamine neurons by using 6-hydroxydopamine increased the phosphorylation on tyrosine of several proteins, including a major 180-kDa protein (pp180) in the ipsilateral striatum. Protein-tyrosine kinase activity was also increased in the striatum ipsilateral to the lesion, whereas no change in phosphotyrosine phosphatase activity was detected. The stimulation of pp180 phosphorylation was observed 1, 2, and 8 weeks after 6-hydroxydopamine lesion, was selective for the destruction of dopamine neurons, and was mimicked by chronic blockade of dopamine receptors with neuroleptics. Additional lesion experiments and subcellular fractionation showed that pp180 is located in neuronal postsynaptic densities, suggesting that pp180 is a postsynaptic component of corticostriatal synapses. Our results indicate that lesion of specific afferent fibers can activate tyrosine phosphorylation in central neurons and suggest that tyrosine phosphorylation is involved in the long-term consequences of dopamine deficiency and may play a role in synaptic plasticity.