Next-generation gene panel testing in adolescents and adults in a medical neuropsychiatric genetics clinic.

Intellectual disability (ID) encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders that may present with psychiatric illness in up to 40% of cases. Despite the evidence for clinical utility of genetic panels in pediatrics, there are no published studies in adolescents/adults with ID or autism spectrum disorder (ASD). This study was approved by our institutional research ethics board. We retrospectively reviewed the medical charts of all patients evaluated between January 2017 and December 2019 in our adult neuropsychiatric genetics clinic at the McGill University Health Centre (MUHC), who had undergone a comprehensive ID/ASD gene panel. Thirty-four patients aged > 16 years, affected by ID/ASD and/or other neuropsychiatric/behavioral disorders, were identified. Pathogenic or likely pathogenic variants were identified in one-third of our cohort (32%): 8 single-nucleotide variants in 8 genes (CASK, SHANK3, IQSEC2, CHD2, ZBTB20, TREX1, SON, and TUBB2A) and 3 copy number variants (17p13.3, 16p13.12p13.11, and 9p24.3p24.1). The presence of psychiatric/behavioral disorders, regardless of the co-occurrence of ID, and, at a borderline level, the presence of ID alone were associated with positive genetic findings (p = 0.024 and p = 0.054, respectively). Moreover, seizures were associated with positive genetic results (p = 0.024). One-third of individuals presenting with psychiatric illness who met our red flags for Mendelian diseases have pathogenic or likely pathogenic variants which can be identified using a comprehensive ID/ASD gene panel (~ 2500 genes) performed on an exome backbone.

[Adaptation and validation of the neurological soft sign's scale of Krebs et al. to children]. / Adaptation et validation d'une échelle des signes neurologiques mineurs chez l'enfant.

BACKGROUND: Neurological soft signs (NSS) include anomalies in motor integration, coordination, sensory integration and lateralization and could be endophenotypic markers in autism spectrum disorders (ASD). Their characterization provides a more precise phenotype of ASD and more homogeneous subtypes to facilitate clinical and genetic research. Few scales for NSS have been adapted and validated in children including children with ASD. Our objective was to perform an adaptation to the child of a scale assessing neurological soft signs and a validation study in both general and clinical populations. METHODS: We have selected the NSS scale of Krebs et al. (2000) already validated in adults. It encompasses 5 dimensions: motor coordination, motor integration, sensory integration, involuntary movement, laterality. After a preliminary study that examined 42 children, several changes have been made to the original version to adapt it to the child and to increase its feasibility, particularly in children with ASD. Then we conducted a validation study by assessing the psychometric properties of this scale in a population of 86 children including 26 children with ASD (DSM 5 Criteria) and 60 typically developing children. Children's ages ranged between 6 and 12 years, and patients and controls were matched for gender, age and intelligence. Patients were assessed using the Autism diagnostic Interview-revised and the Childhood Autism Rating Scale to confirm diagnosis. Typically developing children were assessed using the semi-structured Mini International Neuropsychiatric Interview for Children and Adolescents to eliminate any psychiatric disorder. All children with neurological pathologies (history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma) and obvious physical deformities or sensory deficits that could interfere with neurological assessment were excluded from the study. Both patients and controls were assessed using the Raven Progressive Matrices to exclude intellectual disability, and the adapted Krebs' scale for the assessment of NSS. RESULTS: Adaptation of the scale consisted of a modification in the order of items, in the use of concrete supports for the assessment of laterality and in the elimination of item constructive praxis. The internal consistency was good with a Cronbach alpha of 0.87. Inter-rater reliability was good, kappa coefficient was greater than 0.75 for 16 items, 3 items had a kappa value between 0.74 and 0.60, only 1 item had a kappa coefficient between 0.4 and 0.59. Good inter-rater reliability was also checked for the total score with a value of intra-class correlation coefficient (ICC) of 0.91. Principal component analysis found five factors accounting for 62.96 % of the total variance. About the comparison between patients and controls, significant differences were found for NSS total score (P=0.000) and all subscores. CONCLUSION: The adaptation for children of the Krebs et al.' NSS scale proved to be valid, especially in children with ASD.

[Neurological soft signs in pervasive developmental disorders]. / Signes neurologiques mineurs et troubles envahissants du développement.

BACKGROUND: Many studies have focused on specific motor signs in autism and Asperger's syndrome, but few has been published on the complete range of neurological soft signs (NSS) in children with pervasive developmental disorder (PDD). Scarce are the studies evaluating NSS in children suffering from PDD not otherwise specified (PDDNOS). METHODS: This study compared performance of 11 autistic children (AD) and 10 children with PDDNOS, with controls matched on age, sex and cognitive performance on Krebs et al.'s NSS scale. Because of the duration of the assessments and specific difficulties encountered in managing some items, an adaptation of the scale had to be made during a pilot study with the agreement of the author. To be eligible, patients had to meet the following inclusion criteria: an age range of 6-16 years, a diagnosis of autistic disorder or PDDNOS based on the DSM IV criteria (American Psychiatric Association 1994). The autism diagnostic interview-revised (ADI-R) was used in order to confirm the diagnosis and to evaluate the association of the symptoms to the severity of the NSS. The childhood autism rating scale (CARS) was completed for the patients in order to evaluate symptoms at the time of the NSS examination. Cognitive ability was assessed with Raven's progressive matrices. Were excluded patients with: history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, known genetic syndrome, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma, Asperger's syndrome, obvious physical deformities or sensory deficits that would interfere with neurological assessment, deep mental retardation and recent or chronic substance use or abuse. Healthy controls shared the same exclusion criteria, with no personal history of neurological, psychiatric disorder or substance abuse, no family history of psychiatric disorder and normal or retardation in schooling. All study procedures were approved by the local Ethics Committee (Comité d'éthique, Razi Hospital), according to the declaration of Helsinki. RESULTS: There was no difference between patients and controls with respect to sex, age and cognitive function. All children had an IQ higher than 81. Significant differences were found between AD children and control group in the motor integration function and sensory integration function. Different NSS scores were significantly higher in the PDDNOS group than in controls: the total scores, motor coordination, motor integration function, sensory integration and abnormal movements. Lower performance in motor coordination skills was associated with higher ADI-R communication score in the AD group. No relationship was found between NSS and CARS' total sore. CONCLUSION: This study confirms the impaired neurological functioning in autistic as well as PDDNOS children. The association of motor impairment with autistic symptoms highlights the argument that motor control problems can be part of the autism spectrum disorders. The lack of relationship between NSS and intellectual aptitude in the clinical sample provides new elements for the neurodevelopment model of the autism spectrum.

[Working memory in schizophrenia: a review]. / La mémoire de travail dans la schizophrénie: revue de la littérature.

INTRODUCTION: Working memory refers to a limited capacity system for temporary storage and processing of information that is known to depend on the integrity of the prefrontal cortex. It has been classically described as composed of a "central executive" that performs control, selection and planning functions, and two "slave" systems: on the one hand, the phonological loop that holds verbal, speech-based representations, and on the other hand, the visuospatial sketchpad that manipulates spatial and object visual representations. LITERATURE FINDINGS: Studies in schizophrenia have used different tasks that tap different processes within the working memory. Despite the variety of measures, there is solid neuropsychological evidence that patients with schizophrenia demonstrate deficits in all subsystems of working memory. Several studies have shown no correlations between working memory deficits and age, gender, premorbid IQ, duration of disease or positive syndrome, but a correlation has been found with a low-educational level, and negative and disorganization symptoms. Neuroimaging studies have provided evidence of an involvement of the dorsolateral-prefrontal cortex during working memory performance. Many studies have demonstrated a functional deficit in this area. However, several recent studies have reported either equal or increased activation of the dorsolateral-prefrontal cortex in schizophrenia during working memory performance. Working memory deficits are present early in the course of schizophrenia and they have been shown to be consistently associated with reduced levels of elementary social skills and learning capacity. Unaffected relatives of individuals with schizophrenia and individuals diagnosed with schizotypal personality demonstrate deficits in tasks designed to measure working memory function. Working memory dysfunctions might be suitable candidate markers for vulnerability. Certain executive sub-processes seem to be the most heritable component of the working memory. Working memory deficits in schizophrenia may benefit from specific stimulation of receptors such as the dopaminergic D1 receptor, adrenergic alpha-2A receptor or nicotinic receptors. Few studies on the effect of antipsychotic medication on working memory in schizophrenia have been carried out and their results are highly variable. Atypical antipsychotic drugs, notably risperidone, have appeared to improve performance in working memory tasks. Cognitive exercises can improve working memory with a six-month persistent effect.

[Inhibition of return in schizophrenia: a review]. / Le phénomène de l'inhibition de retour dans la schizophrénie: revue de la littérature.

INTRODUCTION: Most visual environments contain more information than the human brain can process in real time. To overcome this limitation, the attention system acts as a filter by selectively orienting attention to specific regions of the visual field. This ability to orient attention can be reflected in covert shift processes of attention. LITERATURE FINDINGS: In a typical covert orienting task, subjects have to maintain fixation on a central cross and respond as quickly as possible to a target, which appears in a peripheral box following a cue that summons attention to the direction where the target is going to appear (valid cueing) or to the contralateral direction (invalid cueing). When the cues are nonpredictive, the response characteristics critically depend on stimulus-onset asynchrony (SOA). With short SOAs (<300ms), valid cues result in a reaction time advantage over invalid trials, which is due to a reflexive shift of attention towards the source of stimulation. In contrast, with longer SOAs, valid cues result in longer reaction times to the subsequent target. DISCUSSION: This phenomenon is known as the inhibition of return and is mostly thought to reflect an inhibitory mechanism protecting the organism from redirecting attention to previously scanned insignificant locations. Many studies have reported blunted or delayed inhibition of return in patients with schizophrenia. However, some authors reported normal amounts of inhibition of return. This can be partly explained by the use of manipulations of the covert orienting of the attention paradigm that is known to enhance the course of inhibition of return. CONCLUSION: The deficit of inhibition of return seems to be time-stable and to be unrelated to psychopathology or length of illness. The contribution of neuroleptic medication to this deficit cannot be determined. Recent data suggest a deficit of inhibition of return in two human models of psychosis (dimethyltryptamine and ketamine). Further studies should clarify whether blunted inhibition of return might represent a trait marker of schizophrenia.

[Acute postpartum psychoses]. / Les psychoses aiguës du post-partum.

The post-partum is a high risk period for the development of acute psychotic disorders. The frequence of post-partum psychoses is evaluated at 1 to 2 per 1,000 births. Post-partum psychosis include major affective disorders which is the most frequent diagnosis. The clinical pictures have specific characteristics: rapid change of symptomatology, liability of mood, and frequent confusional signs. The short-term prognosis is generally good but the risk of recurrence of the mental disorder, in or outside puerperal context, is high. At clinical, evolutive and genetic levels, the studies do not provide arguments for nosological autonomy of post-partum psychosis. At therapeutic level, the ECT is particularly efficient in this indication.

[Mortality and cause of death in schizophrenia. Review of the literature]. / Mortalité et causes de décès dans la schizophrénie. Revue de la littérature.

Through a review of the literature, the average mortality in schizophrenia is twice higher than among the population. This over mortality is highest among the 20-40 years range of age and added risk tends to disappear after 60 years. All studies stress the unnatural causes of death, suicide or accidental deaths. However several studies found an over mortality caused by natural death. The pathologies most often involved are: infections, lung, gastrointestinal, urogenital and cardiovascular diseases. Cancer mortality in schizophrenic patients is still debated. Some studies point out a reduced mortality compared to the general population whereas other studies find similar or over mortality. Nevertheless mortality ratio is found to be near 1 in the majority of studies. So it can be admitted that schizophrenic patient do really not differ from the general population in regard to cancer mortality. Premature death is highly linked to suicide. The epidemiological indicators that enable us to estimate the importance of suicide mortality are: the rate of suicide per 105 patients per year varies between 150 and 500, the percentage of death by suicide range between 10 and 15 percent. Suicide risk factors are numerous. Some of them are accepted as valid and others are still discussed. The former are: male gender, young and medium age ten first years of the illness course, associated depressive symptoms, past history of suicide attempts, iterative relapses and post hospital discharge period. The latter are: social isolation, celibacy, unemployment, high level of instruction, delusional and hallucinatory activity and familiar rejection.

[Seasons of birth of schizophrenic patients. Retrospective study of a hospitalized population in Tunisia]. / Saisons de naissance des schizophrènes. Etude rétrospective d'une population hospitalière en Tunisie.

Epidemiological research concerning the seasons of births of schizophrenics show for the greatest part that there's an excess of births in winter and in the beginning of spring. Research about the environmental theories of schizophrenia suggest that there would exist one or many seasonal environmental factors affecting the foetus and the neonate, and which would be likely to increase the risk of a subsequent development of schizophrenia. As no research concerning this subject have been published so far in Africa, the writers propose to study the distribution of births of a population of schizophrenics born in Tunisia in comparison to the general population and to compare it to a group of patients hospitalized because of major affective disorders. The results achieved show a significant decrease in the number of schizophrenics births during the third trimester and an excess of births during the month of october, the risk being greater in the case of disorganized schizophrenia. The greater risk for people born in october to develop subsequently schizophrenia is not found in the case of major affective disorders but it is found rather in the case of schizo-affective disorders. More over, we notice a decrease in the number of births during the month of July for the patients presenting major affective disorders and for those presenting schizo-affective disorders. Results seem to demonstrate that there would exist seasonal environmental factors specific to North Africa which are likely to affect the subsequent appearance of schizophrenic disorders. A particular interest should be given to viral infectious to enteroviruses which are responsible for summer diarrhea in Tunisia.(ABSTRACT TRUNCATED AT 250 WORDS)