Article

Behavioral and Psychiatric Phenotypes in 22q11.2 Deletion Syndrome

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Abstract

22q11.2 Deletion syndrome (22q11.2DS) is a chromosomal microdeletion that affects approximately 40 to 50 genes and affects various organs and systems throughout the body. Detection is typically achieved by fluorescence in situ hybridization after diagnosis of one of the major features of the deletion or via chromosomal microarray or noninvasive prenatal testing. The physical phenotype can include congenital heart defects, palatal and pharyngeal anomalies, hypocalcemia/hypoparathyroidism, skeletal abnormalities, and cranial/brain anomalies, although prevalence rates of all these features are variable. Cognitive function is impaired to some degree in most individuals, with prevalence rates of greater than 90% for motor/speech delays and learning disabilities. Attention, executive function, working memory, visual-spatial abilities, motor skills, and social cognition/social skills are affected. The deletion is also associated with an increased risk for behavioral disorders and psychiatric illness. The early onset of psychiatric symptoms common to 22q11.2DS disrupts the development and quality of life of individuals with the syndrome and is also a potential risk factor for later development of a psychotic disorder. This review discusses prevalence, phenotypic features, and management of psychiatric disorders commonly diagnosed in children and adolescents with 22q11.2DS, including autism spectrum disorders, attention deficit/hyperactivity disorder, anxiety disorders, mood disorders, and schizophrenia/psychotic disorders. Guidelines for the clinical assessment and management of psychiatric disorders in youth with this syndrome are provided, as are treatment guidelines for the use of psychiatric medications.

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... 4 One should have a high index of suspicion in patients who present with two or more of the following: immunodeficiency, developmental delays, learning disabilities, behavioural disorders, other psychiatric symptoms, cardiac anomalies and hypocalcaemia. 4,5 Research has demonstrated a strong association between DGS and psychiatric disorders such as psychotic disorders, attention-deficit or hyperactivity disorder, mood disorders, anxiety disorders and autistic spectrum disorders (ASD). 3,5 Of the behavioural phenotype of DGS, elevated risk of psychosis, particularly schizophrenia, is the most disturbing feature, accounting for a 30-fold increase compared to the general population. ...
... 4,5 Research has demonstrated a strong association between DGS and psychiatric disorders such as psychotic disorders, attention-deficit or hyperactivity disorder, mood disorders, anxiety disorders and autistic spectrum disorders (ASD). 3,5 Of the behavioural phenotype of DGS, elevated risk of psychosis, particularly schizophrenia, is the most disturbing feature, accounting for a 30-fold increase compared to the general population. 3 A case report of a patient with chromosome 22q11.2 ...
... Earlier literature have suggested the possibility of picking up some predictive symptoms prior to the development of psychosis. 5,12 For example, subthreshold psychotic symptoms such as odd or eccentric symptoms as observed in our index patient are often reported by parents of children with DGS in 30% -50% of cases. 13 Another useful predictor of psychosis in children with DGS is lower verbal IQ, as an average of 10-point decline in verbal IQ from baseline has been linked to later development of psychotic disorders among the patients. ...
Article
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DiGeorge syndrome (DGS) was first described in 1829 by Dr Angelo DiGeorge. DGS is a cluster of symptoms because of a defect in the development of the pharyngeal pouch. Evidence from cytogenetic studies has linked the pathogenesis of DGS with a deletion of a gene located in chromosome 22-band 22q11. In most affected individuals, the deletion is de novo; however, inheritance has been reported in 10% – 25% of patients. DGS commonly presents with a classical triad of conotruncal cardiac anomalies, hypoplastic thymus and hypocalcaemia. DGS may be of focus to a psychiatrist as it is associated with cognitive deficits, high rates of schizophrenia and anxiety disorders. Patients may also present to mental health care workers with learning disabilities, developmental delay and behavioural disorders such as attention-deficit or hyperactivity disorder. Mental health workers therefore play an invaluable role in the diagnosis and timely treatment of the disorder. In a resource-limited area such as Botswana, with scarce mental health professionals, paediatricians and neurologists, DGS may be frequently misdiagnosed with consequent inappropriate interventions that may increase morbidity. Herein, we present a case to raise awareness and demonstrate one of the varied ways the syndrome may present. The multifaceted nature of DGS presentation underscores the need for a multidisciplinary approach to treatment
... 22,67 For example, 22q11.2 deletion syndrome carries one of the highest likelihood ratios of developing some form of psychiatric illness 68 , including a ~30% chance of schizophrenia spectrum disorders, but even for this CNV penetrance for psychiatric disorders seems to be incomplete. 46,68 Cumulatively, CNVs are common in the population, and are not necessarily pathogenic, thus the relevance to the etiology of psychiatric illness of most that can be detected is uncertain. ...
... This knowledge can allow the family to access appropriate help in a timely manner if it is needed, and research shows that early intervention promotes optimal long-term prognosis. [46][47][48][49] When providing consult reports to patients' referring physicians, our practice (developed in consultation with our clinical ethics program) is to indicate that specific probabilities were discussed without documenting the numbers themselves (because they reflect personal information about someone other than the individual to whom the chart relates). 50 ...
Article
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Psychiatric disorders like schizophrenia, bipolar disorder, depression, anxiety, and obsessive compulsive disorder are common disorders with complex etiology. They can exact a heavy toll on the individual with the condition, and can have significant impact on family members too. Accordingly, psychiatric disorders can arise as a concern in the prenatal context - couples may be interested in learning about the chance for their child to develop the illness that manifests in the family, and may be interested in discussing options for prenatal testing. However, the complex nature of these conditions can present challenges for clinicians who seek to help families with these issues. We established the world's first specialist genetic counseling service of its kind in Vancouver, Canada in 2012, and to date, have provided counseling for ~500 families, and have demonstrated increases in patients' empowerment and self efficacy after genetic counseling. We draw on our accumulated clinical experience to outline the process by which we approach prenatal genetic counseling for psychiatric disorders, to assist other clinicians in providing thoughtful, comprehensive support to couples seeking out this service.
... It seems that individuals with 22q11.2DS perform significantly less well in several cognitive domains as compared to patients with SCZ (Goldenberg et al., 2012;Tang, Antshel, Fremont, & Kates, 2015 To be included, participants with 22q11.2DS or SCZ had to have an IQ in the average range, with a standard score ≥7 on the "matri- All patients with psychotic symptoms were treated with typical or atypical psychotics. ...
... This impairment seems to be a core feature of 22q11.2DS, regardless of the presence of SCZ symptoms, and is in line with previous results (Goldenberg et al., 2012;Tang et al., 2015). Actually, significantly lower accuracy in social cognitive domains has already been found in 22q11.2DS ...
Article
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Aim Social cognitive impairments are core features in 22q11.2 deletion syndrome (22q11.2DS) and schizophrenia (SCZ). Indeed, adults with 22q.11.2 DS often have poorer social competence as well as poorer performance on measures of social cognitive skills (emotion recognition and theory of mind, ToM) compared with typically developing people. However, studies comparing specific social cognitive components in 22q11.2DS and SCZ have not yet been widely conducted. Methods In this study we compared performances of 22q11.2DS and SCZ on both facial emotion recognition and ToM. Patients with 22q11.2DS (n = 18) and matched SCZ patients were recruited. After neuropsychological testing, the facial emotion recognition test assessed the patients' ability to recognize six basic, universal emotions (joy, anger, sadness, fear, disgust, and contempt). The Versailles‐situational intentional reading evaluated ToM with six scenes from movies showing characters in complex interactions (involving hints, lies, and indirect speech). Results We show that 22q11.2DS exhibited significantly lower performance in emotion recognition than SCZ patients did, especially for disgust, contempt, and fear. This impairment seems to be a core cognitive phenotype in 22q11.2DS, regardless of the presence of SCZ symptoms. Concerning ToM, our results may highlight the same impairment level in 22q11.2DS and SCZ but require to be replicated in a larger cohort. Conclusion Our results document the existence of threshold social cognitive deficits distinguishing 22q11.2DS from SCZ.
... Second, the presence of autism and mild developmental delay combined with some dysmorphic features had led to referral to clinical genetics and multiple diagnostic Sanger sequencing runs, diverting attention from the obvious infectious phenotype. One patient with AD-HIES and autism has previously been reported [21][22][23][24]. Several PIDs are associated with developmental delay and autism-spectrum disorders, e.g., Di George syndrome, Coronin1A deficiency, and GATA2 deficiency [22][23][24]. ...
... One patient with AD-HIES and autism has previously been reported [21][22][23][24]. Several PIDs are associated with developmental delay and autism-spectrum disorders, e.g., Di George syndrome, Coronin1A deficiency, and GATA2 deficiency [22][23][24]. In light of this especially in children, a diagnosis of autism and presence of dysmorphic features cannot be uncoupled from the infectious phenotype and a genetic diagnosis explaining the entire phenotype should be sought. ...
... Children with 22q11.2DS may begin to experience difficulties only in later elementary school years (3-4th grade), when the educational focus begins to shift from concrete to more abstract thinking such as mathematical reasoning and reading comprehension [11]. Integration and inclusion in mainstream education of children with 22q11.2DS ...
Article
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22q11.2 deletion syndrome (22q11.2DS) is the most common known microdeletion in humans occurring in 1 out of 2000–4000 live births, with increasing numbers of individuals with the microdeletion living into adulthood. The aim of the study was to explore the education and employment trajectories of individuals with 22q11.2DS from childhood to adulthood in a large cohort composed of two significant samples. 260 individuals with 22q11.2DS, 134 male and 126 female, aged 5–59 years (mean age 21.3 ± 10.8 years) were evaluated at two sites, Geneva (GVA) and Tel Aviv (TA). Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold-standard diagnostic tools. Demographic factors, such as data about education, employment, marital status, and living status, were collected. Children entering elementary school (5–12 years) were significantly more likely to attend a mainstream school, while adolescents were significantly more likely to attend special education schools (p < 0.005). Cognitive abilities, and not adaptive functioning, predicted school placement. Among adults with 22q11.2DS (n = 138), 57 (41.3%) were unemployed, 46 (33.3%) were employed in open market employment, and 35 (25.4%) worked in assisted employment. In adulthood, adaptive functioning more than cognitive abilities predicted employment. Surprisingly, psychotic spectrum disorders were not found to be associated with employment. Individuals with 22q11.2DS are characterized by heterogeneity in educational and employment profiles. We found that cognitive abilities and adaptive functioning, and not the presence of psychiatric disorders, are key factors in school placement and employment. These factors should, therefore, be taken into account when planning optimal development of individuals with 22q11.2DS.
... Early onset of psychotic symptoms is common in these patients; few cases of schizophrenia with onset after age 30 in 22q11DS patients have been described. [2][3][4] Case reports and small studies in the literature demonstrate that typical and atypical antipsychotics are often effective in treating schizophrenia in 22q11DS patients. [5][6][7][8][9] However, failure of initial treatment and serious adverse effects (notably, seizure) complicated several of these studies, and none have discussed asenapine or adjunctive benzodiazepines. ...
Article
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22q11.2 deletion syndrome (22q11DS) is a risk factor for psychiatric illnesses, including schizophrenia and anxiety. Small studies have shown that several neuroleptic medications are effective in treating psychosis in this population, but are also associated with an increased risk of adverse effects - particularly, seizures. In this case, we discuss a 34-year-old patient presenting with late onset schizophrenia, which ultimately led to her diagnosis of 22q11DS. Subsequent management of the patient’s psychosis with asenapine was complicated by concurrent anxiety and panic disorder; thus, we examine the role of anxiolytic therapy in conjunction with antipsychotics in this patient population.
... These results are also consistent with studies adopting a genetics-first approach, which have demonstrated that individuals with rare syndromes that are defined by specific rare CNVs (e.g., 22q11.2 deletion syndrome or Williams syndrome) show elevated levels of NPs, that do not always meet clinical diagnostic thresholds (Scerif & Baker, 2015;Tang, Antshel, Fremont, & Kates, 2015). ...
Article
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Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex‐specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare (<1% frequency) CNVs were categorized by size (100–500 kb or > 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex‐specific effects. Medium deletions (OR[CI] = 1.18[1.05–1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19–1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14–3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45–9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex‐specific phenotypic effects.
... Children with 22q11.2DS may begin to experience difficulties only in later elementary school years (3-4th grade), when the educational focus begins to shift from concrete to more abstract thinking such as mathematical reasoning and reading comprehension [11]. Integration and inclusion in mainstream education of children with 22q11.2DS ...
... Due to the complex nature of 22qDS and the number of genes involved, patients present with a wide range of medical abnormalities including congenital heart defects, hypocalcemia, immune deficiencies, palatal abnormalities, speech delay/disorders, intellectual disabilities, and psychiatric features among others (Antshel, Fremont, & Kates, 2008;Chow, Watson, Young, & Bassett, 2006;Greenhalgh et al., 2003;Oskarsdóttir, Persson, Eriksson, & Fasth, 2005;Solot et al., 2000;Sullivan, 2008;Tang, Antshel, Fremont, & Kates, 2015). ...
Article
Palatal involvement occurs commonly in patients with 22q11.2 Deletion Syndrome (22qDS), and includes palatal clefting and velopharyngeal dysfunction in the absence of overt or submucous clefts. The reported incidence and distribution of palatal abnormalities vary in the literature. The aim of this article is to revisit the incidence and presenting features of palatal abnormalities in a large cohort of patients with 22qDS, summarize the surgical treatments performed in this cohort, and provide an overview of surgical treatment protocols and management guidelines for palatal abnormalities in this syndrome. Charts of 1,121 patients seen through the 22q and You Center at the Children's Hospital of Philadelphia were reviewed for palatal status, demographic factors, deletion size, and corrective surgical procedures. Statistical analysis was performed using Pearson's chi‐squared test to identify differences between gender, deletion size, and palatal abnormality. Of the patients with complete evaluations, 67% were found to have a palatal abnormality. The most common finding was velopharyngeal dysfunction in 55.2% of patients, and in 33.3% of patients, this occurred in the absence of palatal clefting. There was no significant difference in the incidence of palatal abnormalities by gender; however, a difference was noted among race (p < 0.01) and deletion sizes (p < 0.01). For example, Caucasian and Asian patients presented with a much higher prevalence of palatal abnormalities, and conversely those with nested deletions presented with a much lower rate of palatal defects. Overall, 26.9% of patients underwent palatal surgery, and the most common indication was velopharyngeal dysfunction. Palatal abnormalities are a hallmark feature of 22q11.2 Deletion Syndrome; understanding the incidence, presenting features, and treatment protocols are essential for practitioners counseling and treating families affected with this disorder.
... region has also been linked to neurological and neuropsychiatric conditions, ranging from epilepsy to schizophrenia. Neurological and neuropsychiatric disorders mainly share the same spectrum of behavior impairments including behavioral disturbances, attention deficit hyperactivity, and intellectual disability [Ben-Sachar et al., 2008;Hu et al., 2009;Alemany et al., 2015;Tang et al., 2015;Jiramongkolchai et al., 2016]. Among the genes related to the 22q11.2 ...
Article
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Juvenile myoclonic epilepsy (JME) is characterized by seizures, severe cognitive abnormalities, and behavior impairments. These features could evolve over time and get worse, especially when the encephalopathy is pharmacoresistant. Thus, genetic studies should provide a better understanding of infantile epilepsy syndromes. Herein, we investigate the genetics of JME in a consanguineous family analyzing the copy number variations detected using over 700 K SNP arrays. We identified a 254-kb deletion in the 22q11.2 region, including only the TOP3B gene, detected in the patient and her father. TOP3B encodes a topoisomerase DNA (III) β protein and has been implicated in several neurological diseases such as schizophrenia and autism. In this study, we discuss the implication of the 22q11.2 region in neurodevelopmental disorders and the association of TOP3B with epilepsy.
... Mean IQ is found to be about 70 and severe and profound ID is uncommon (McDonald-McGinn et al. 2016). Both behavior and social functioning may be affected negatively (Kates et al. 2015). An extremely high frequency of psychosis is found in patients with 22q11.2 ...
Article
Background: People with 22q11.2 deletion syndrome (DS) are assumed to be especially vulnerable to developing mental illness such as psychosis. Aim: The study was established to contribute to knowledge about metyrosine medication in patients with 22q11.2 DS and psychosis. Methods: A case study was established including a woman with intellectual disability, 22q11.2 DS, and psychosis. Metyrosine medication was implemented, as conventional anti-psychotic medication was unsuccessful. Results: Effect of metyrosine medication included both psychotic symptom relief with decreased aggressive behaviour. Adjunctive milieu therapy contributed to complience. Conclusion: For patients with 22q11.2 DS and psychosis, metyrosine medication may prove effective. However, there are significant ethical dilemmas related to metyrosine medication for psychotic symptoms.
... deletion syndrome (22q11DS) (Bassett et al., 2011), which represents the third major risk factor for the development of schizophrenia, after having a monozygotic twin affected or two affected parents (McGuffin et al., 1995;Schneider et al., 2014a). In particular, patients with 22q11DS share the same cognitive deficits, symptoms and brain abnormalities as patients with schizophrenia Maeder et al., 2016;Schneider et al., 2016;Swillen and McDonald-McGinn, 2015;Tang et al., 2015;Vorstman et al., 2015). Thus, the 22q11DS is an ideal condition to test and identify early intervention windows, overcoming the heterogeneity of UHR groups. ...
Article
Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients' genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.
... Early onset of psychotic symptoms is common in these patients; few cases of schizophrenia with onset after age 30 in 22q11DS patients have been described. [2][3][4] Case reports and small studies in the literature demonstrate that typical and atypical antipsychotics are often effective in treating schizophrenia in 22q11DS patients. [5][6][7][8][9] However, failure of initial treatment and serious adverse effects (notably, seizure) complicated several of these studies, and none have discussed asenapine or adjunctive benzodiazepines. ...
Article
Full-text available
22q11.2 deletion syndrome (22q11DS) is a risk factor for psychiatric illnesses, including schizophrenia and anxiety. Small studies have shown that several neuroleptic medications are effective in treating psychosis in this population, but are also associated with an increased risk of adverse effects - particularly, seizures. In this case, we discuss a 34-year-old patient presenting with late onset schizophrenia, which ultimately led to her diagnosis of 22q11DS. Subsequent management of the patient's psychosis with asenapine was complicated by concurrent anxiety and panic disorder; thus, we examine the role of anxiolytic therapy in conjunction with antipsychotics in this patient population.
... Des symptômes psychotiques sont également observés, potentialisant le risque de développer un trouble de type schizophrénie à l'âge adulte (chez 30% des personnes présentant la délétion) (Murphy et al., 1999). De manière générale, quel que soit l'âge et qu'il y ait ou non psychose, des difficultés d'initiation et de maintien des liens sociaux sont observées, pouvant mener à un phénomène d'isolement social (Tang et al., 2015). Ainsi, de manière générale, c'est une forte cause génétique de développement de troubles du spectre autistique et du spectre de la schizophrénie pouvant être mis en lien avec les difficultés de cognition sociale retrouvées dans cette population (Norkett et al., 2017). ...
Thesis
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Cette thèse se propose d’examiner les mécanismes de la perception des expressions faciales émotionnelles et leur développement précoce, grâce à une approche de présentation visuelle périodique rapide (Fast Periodic Visual Presentation : FPVS) couplée à l’électroencéphalographie (EEG). Plus spécifiquement, nous avons cherché à caractériser des réponses cérébrales de discrimination des expressions faciales et à déterminer l’influence d’un contexte olfactif hédonique sur ces réponses, chez l’adulte (Etudes 1 et 2) ainsi que chez le nourrisson à différents stades de développement (Etudes 3 et 4).Nous avons montré que l’adulte présente des réponses cérébrales distinctes selon l’expression faciale cible à discriminer, indiquant une catégorisation spontanée des expressions faciales de base (Étude 1). Par ailleurs, nous avons mis en évidence que la présence d’un contexte olfactif hédonique influence les réponses cérébrales de catégorisation des expressions faciales. Tandis que la réponse à la joie reste inchangée, la réponse au dégoût est moindre en présence d’un contexte olfactif hédonique agréable ou désagréable. L’effet de l’odeur est particulièrement retrouvé pour la réponse à la neutralité, la réponse étant presque absente en contexte désagréable vs. amplifiée en contexte agréable. Les odeurs hédoniques orienteraient ainsi la perception des expressions faciales vers leur propre valence émotionnelle, ou vers la valence de l’odeur pour l’expression neutre émotionnellement ambiguë, entravant ou facilitant leur discrimination des autres expressions, majoritairement négatives (Etude 2). Chez le nourrisson, une première étude a permis d’isoler des réponses cérébrales de discrimination des expressions faciales à 3,5 et 7 mois (Étude 3). Une évolution de la réponse cérébrale à la joie a été observée entre 3,5 et 7 mois (activité fronto-centrale additionnelle), suggérant l’intégration progressive de la signification émotionnelle de cette expression positive. La seconde étude a été initiée chez les nourrissons de 7 mois pour tester l’influence d’un contexte olfactif agréable sur la réponse cérébrale à l’expression de joie (Etude 4, en cours). Elle semble indiquer que la réponse à la joie est amplifiée par un contexte olfactif agréable plutôt que neutre.Ces résultats révèlent que les expressions faciales sont facilement discriminées chez l’adulte, la présence d’un contexte olfactif hédonique orientant la perception vers la valence émotionnelle de l’expression faciale plutôt que vers l’émotion de base associée en tant que telle. La valence émotionnelle des expressions pourrait être acquise précocement au cours du développement, avant 7 mois, âge auquel évolue la discrimination de la joie (positive) par rapport aux autres expressions (majoritairement négatives). En outre, à cet âge, la perception de la joie semble facilitée en présence d’un contexte olfactif agréable. Ainsi, du fait de la maturité fonctionnelle précoce du système olfactif, les odeurs pourraient activement participer à l’acquisition de la signification émotionnelle des expressions faciales au cours du développement, et faciliter la perception des expressions dont la signification émotionnelle est ambiguë chez l’adulte. Dans l’ensemble, nos travaux éclairent le rôle de l’intégration multisensorielle au cours du développement perceptif précoce et ouvrent d’intéressantes perspectives pour investiguer le développement sociocognitif et affectif typique et atypique.
... Half of these patients have some level of cognitive impairment. Behavioral differences include impulsivity, emotional lability, shyness and disinhibition [16][17][18]. ...
... De notar ainda a possibilidade de existência de alguns sintomas prodrómicos de quadros psicóticos, tais como a diminuição da riqueza ideacional, défices a nível da concentração e diminuição da tolerância ao stress. 2,3 Também o declínio cognitivo precoce é considerado um indicador robusto de risco para o desenvolvimento de perturbação psicótica. 1,4 Apesar da elevada frequência de patologia psiquiátrica nos doentes com SDG, apenas 63% destes recebem cuidados de saúde mental ao longo da vida e somente 40% de modo continuado, não existindo guidelines específicas em Coutinho F, et al relação ao tratamento de perturbações psiquiátricas nesta população. ...
Article
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DiGeorge Syndrome is a group of diseases caused by a microdeletion, and some of its most frequent symptoms are those related with development and behavior. We present the case of a female patient with DiGeorge Syndrome and selective mutism since childhood, evaluated for the first time in a psychiatry consultation at the age of 18 for inaugural psychotic symptomatology. We describe the psychopathology, the diagnostic investigation, the treatment, and the clinical evolution. In the future, it will be important to better characterize patients with this syndrome who present psychiatric disease.
... Mostly, nonverbal learning capacities are inadequate, whereas verbal intelligence quotient (IQ) is higher than global IQ (Lajiness-O'Neill et al., 2005;Lepach & Petermann, 2011;Swillen et al., 1997). Psychiatric comorbidity is common: around 20% of children have an autistic spectrum disorder (ASD) (Richards, Jones, Groves, Moss, & Oliver, 2015), attention deficit with hyperactivity disorder (ADHD) (Tang, Antshel, Fremont, & Kates, 2015), anxiety (Swillen & McDonald-McGinn, 2015), or mood disorders (Schneider et al., 2014). ...
Article
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22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol‐O‐methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.
... The 22q11.2 deletion syndrome (22q11.2DS) is a genetic disorder associated with high rates of psychiatric comorbidity including psychosis, depression, and attention-deficit/ hyperactivity disorder. 123 Individuals with this syndrome are missing 1 copy of the COMT gene. The ability of SAMe to increase COMT enzymatic activity has been proposed as a potential therapeutic mechanism for alleviating psychiatric symptoms in this patient population. ...
Article
Objective: A systematic review on S-adenosylmethionine (SAMe) for treatment of neuropsychiatric conditions and comorbid medical conditions. Data sources: Searches were conducted in PubMed, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Google Scholar databases between July 15, 2015, and September 28, 2016, by combining search terms for SAMe (s-adenosyl methionine or s-adenosyl-l-methionine) with terms for relevant disease states (major depressive disorder, MDD, depression, perinatal depression, human immunodeficiency virus, HIV, Parkinson's, Alzheimer's, dementia, anxiety, schizophrenia, psychotic, 22q11.2, substance abuse, fibromyalgia, osteoarthritis, hepatitis, or cirrhosis). Additional studies were identified from prior literature. Ongoing clinical trials were identified through clinical trial registries. Study selection: Of the 174 records retrieved, 21 were excluded, as they were not original investigations. An additional 21 records were excluded for falling outside the scope of this review. Of the 132 studies included in this review, 115 were clinical trials and 17 were preclinical studies. Data extraction: A wide range of studies was included in this review to capture information that would be of interest to psychiatrists in clinical practice. Results: This review of SAMe in the treatment of major depressive disorder found promising but limited evidence of efficacy and safety to support its use as a monotherapy and as an augmentation for other antidepressants. Additionally, preliminary evidence suggests that SAMe may ameliorate symptoms in certain neurocognitive, substance use, and psychotic disorders and comorbid medical conditions. Conclusions: S-adenosylmethionine holds promise as a treatment for multiple neuropsychiatric conditions, but the body of evidence has limitations. The encouraging findings support further study of SAMe in both psychiatric and comorbid medical illnesses.
... Psychiatric disorders seen in children and adolescents with 22q11DS include attentiondeficit hyperactivity disorder (ADHD; 35-46%) (Niarchou 2015), oppositional defiant disorder (16-43%), specific and social phobias (23-61%), generalised anxiety disorder (GAD; 17-29%), separation anxiety disorder (16-21%), obsessivecompulsive disorder (OCD; 4-33%), major depressive disorder and dysthymia (10-20%) and autism spectrum disorders (14-45%) (Tang 2015). By late adolescence and adulthood, up to one-third of patients with 22q11DS develop psychotic disorders resembling schizophrenia and schizoaffective disorders (Gothelf 2009). ...
Article
Microdeletion syndrome is an important topic in intellectual disability, associated with various psychiatric symptoms, such as autism, attention deficit, hyperactivity, obsession and compulsion, and psychosis. In this article, we provide a clinical update on the following syndromes and their associated psychiatric disorders: Prader–Willi syndrome, Angelman syndrome, Williams syndrome, Wolf–Hirschhorn syndrome, cri du chat syndrome, DiGeorge syndrome and Rubinstein–Taybi syndrome. LEARNING OBJECTIVES • Gain an up-to-date understanding of the microdeletion syndromes commonly seen in daily practice • Appreciate the association between underlying chromosomal abnormalities and the resultant intellectual disabilities in microdeletion syndromes • Gain up-to-date knowledge about the treatment options for the various microdeletion syndromes commonly seen in daily practice
... The phenotype associated with 22q11DS is highly variable, even within families, involves multiple organ systems, and ranges from life-threatening conditions to only a few characteristics of the syndrome. In addition to physical, metabolic, and endocrine features, individuals with 22q11DS are at increased risk for psychiatric disorders throughout development, especially autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), anxiety and affective disorders, and schizophrenia spectrum disorders and psychosis (Tang et al., 2015). This review focuses on the psychiatric phenotypes of 22q11DS, with specific attention given to the social cognitive domain and its relevance to both 22q11DS and psychosis. ...
Article
Individuals with 22q11.2 deletion syndrome (22q11DS) exhibit a broad array of physical and psychiatric features, of which impaired social cognition and poor social functioning are common. This review seeks to (1) characterize the current understanding of impairment across social cognitive domains in the context of 22q11DS, and (2) synthesize the relevant literature on social cognition and psychosis, given that the prevalence of psychosis in 22q11DS is especially high compared to the general population. A total of 16 papers examining social cognition in 22q11DS were identified through a comprehensive literature search conducted using electronic databases such as PubMed and PSYCInfo. Results suggest that individuals with 22q11DS exhibit impaired emotion processing and complex theory of mind relative to their typically developing peers, though some findings were accounted for by neurocognitive and intellectual abilities. Further, no studies have examined the domains of attribution bias or social perception in 22q11DS, highlighting a critical gap in the extant literature. More research is needed to better elucidate the trajectory of how and why social cognitive impairment develops in 22q11DS, and to explore possible relationships to psychiatric comorbidities like psychosis. Treatment implications and future steps are considered.
... The fourth patient had the 22q11 deletion syndrome, which has a known association not only with PD but also with congenital cardiac disease and often requires cardiac surgery. 9 As expected, the mean clozapine dose was considerably lower in patients who had PD compared with psychotic patients (45.8 vs. 360 mg, respectively). All patients with PD and the vast majority of psychotic patients were men. ...
Article
Cardiomyopathy is a potentially fatal adverse drug reaction (ADR) associated with clozapine in psychotic patients but considered to be a very rare1. Yet, one recent study has reported an incidence of echocardiographic evidence of clozapine-induced cardiomyopathy of 4.65%. This suggests that the real incidence of this reaction might be greatly underestimated.2 This article is protected by copyright. All rights reserved.
... 20 An abundance of evidence suggests that environmental factors influence the behavioral phenotype of 22q11DS and that these variables could significantly impact the trajectory of the development and maintenance of behavioral problems. 11,21 In their treatment guidelines for 22q11DS, Tang and colleagues 15 noted that interventions for severe behavior problems have focused primarily on psychopharmacologic intervention (see also ref. 16). However, few studies have evaluated the effectiveness and safety of psychotropic medication as an intervention for behavior problems. ...
Article
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22q11.2-deletion syndrome is a genetic disorder caused by a small deletion of chromosome 22. This deletion often results in developmental delays, learning disabilities, medical conditions, and comorbid psychiatric conditions. Patients with 22q11.2DS may present with a variety of behavioral phenotypes including obsessiveness and rigidity, poor social skills, and anxiety. In some cases, the phenotype can consist of destructive and inappropriate behavior including harming self and others. Behavioral difficulties are reported as one of the most challenging aspects of 22q11.2-deletion syndrome for families of patients, however, few studies have examined behavioral interventions as a possible therapeutic treatment for this population. Using principles derived from operant-behavioral psychology, we conducted functional assessments to determine the environmental correlates of destructive and inappropriate behaviors in two adult men with 22q11.2-deletion syndrome. Subsequently, behavioral interventions based on differential reinforcement were incorporated into each participant’s natural environment to eliminate these behaviors. Significant reductions in destructive and inappropriate behavior were observed with both participants and therapeutic gains were maintained at follow-up. We discuss the role of behavioral interventions in combination with appropriate psychotropic medication when addressing challenging behaviors in this population.
... Thus, negative symptoms appear to be one of the clinical characteristic of 22q11DS since they are present in roughly a third of patients in the absence of positive symptoms (Schneider et al., 2014b). Additionally, negative symptoms are more severe in patients with 22q11DS at risk for developing psychosis compared to at-risk subjects without the microdeletion (Armando et al., 2012;Tang et al., 2015). ...
Article
Approximately 30% of individuals with 22q11.2 Deletion Syndrome (22q11DS) develop schizophrenia during adolescence/early adulthood, making this syndrome a model for the disorder. Furthermore, negative symptoms exist in up to 80% of patients diagnosed with 22q11DS. The present study aims to uncover morphological brain alterations associated with negative symptoms in a cohort of patients with 22q11DS who are at-risk for developing schizophrenia. A total of 71 patients with 22q11DS aged 12 to 35 (54% females) with no past or present diagnosis of a schizophrenia were included in the study. Psychotic symptom scores were used to divide patients into subgroups by means of a cluster analysis. Three major subgroups were evident: patients with low negative and positive symptoms; patients with high negative symptoms and low positive symptoms; and patients with high negative and positive symptoms. Cortical volume, thickness and gyrification were compared between subgroups using FreeSurfer software. Results showed that patients with high negative symptoms, compared to those with low negative symptoms, have decreased gyrification in the medial occipito-temporal (MOT) and lateral temporo-parietal (LTP) cortices of the left hemisphere, and in the medial temporal (MT)/posterior cingulate (PCC) cortices of the right hemisphere. These findings suggest that high negative symptoms are associated with gyrification reductions predominantly in medial occipital and temporal regions, which are areas implicated in social cognition and early visual processing. Furthermore, as cortical folding develops in utero and during the first years of life, reduced gyrification may represent an early biomarker predicting the development of negative symptoms.
... Given the previously reported high rates of neuropsychiatric disorders in 22q-del and 22q-dup [11,12,[47][48][49], we collected extensive clinical and cognitive data for the present study. We utilized the Structured Clinical Interview for DSM V (SCID-I) and the Brief Psychiatric Rating Scale-Expanded Version (BPRS) [50][51][52] to assess neuropsychiatric diagnosis and symptoms. ...
Article
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Deletions and duplications at the 22q11.2 locus are associated with significant neurodevelopmental and psychiatric morbidity. Previous diffusion-weighted magnetic resonance imaging (MRI) studies in 22q11.2 deletion carriers (22q-del) found nonspecific white matter (WM) abnormalities, characterized by higher fractional anisotropy. Here, utilizing novel imaging and processing methods that allow separation of signal contribution from different tissue properties, we investigate whether higher anisotropy is driven by (1) extracellular changes, (2) selective degeneration of secondary fibers, or (3) volumetric differences. We further, for the first time, investigate WM microstructure in 22q11.2 duplication carriers (22q-dup). Multi-shell diffusion-weighted images were acquired from 26 22q-del, 19 22q-dup, and 18 healthy individuals (HC). Images were fitted with the free-water model to estimate anisotropy following extracellular free-water elimination and with the novel BedpostX model to estimate fractional volumes of primary and secondary fiber populations. Outcome measures were compared between groups, with and without correction for WM and cerebrospinal fluid (CSF) volumes. In 22q-del, anisotropy following free-water elimination remained significantly higher compared with controls. BedpostX did not identify selective secondary fiber degeneration. Higher anisotropy diminished when correcting for the higher CSF and lower WM volumes. In contrast, 22q-dup had lower anisotropy and greater extracellular space than HC, not influenced by macrostructural volumes. Our findings demonstrate opposing effects of reciprocal 22q11.2 copy-number variation on WM, which may arise from distinct pathologies. In 22q-del, microstructural abnormalities may be secondary to enlarged CSF space and more densely packed WM. In 22q-dup, we see evidence for demyelination similar to what is commonly observed in neuropsychiatric disorders.
... However polarized results have been shown where bipolar disorders were seen in children in rates over 60% in one study (22) and no increased incidence in another (23). It is noteworthy however that these children have a higher prevalence of intellectual difficulties, autism spectrum disorder and anxiety (24). ...
Poster
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Established in 2015, the Sri Lanka College of Child & Adolescent Psychiatrists have continued to make positive strides towards the goal of enhancing child mental health and child psychiatry services in Sri Lanka. During the years 2020-2021, the Sri Lanka College of Child & Adolescent Psychiatrists have been involved in academic activities, peer group activities to promote continuing professional development, activities to enhance public awareness, service development and activities in collaboration with educational, legal and child protection sectors. In 2020, the Sri Lanka College of Child & Adolescent Psychiatrists became a member of the International Association for Child and Adolescent Psychiatry and Allied Professions (IACAPAP), an international organization that advocates for the promotion of mental health and development of children and adolescents through policy, practice and research. For the biennial scientific conference of the college, the theme of “Child Mental Health and Education in a Pandemic” has been chosen to address a timely concern.
... deletion syndrome (22q11DS), a neurogenetic condition affecting 1:2000-4000 live births that is associated with a broad phenotype of clinical and behavioral characteristics (McDonald-McGinn et al., 2017;Olsen et al., 2018), and Autism Spectrum Disorders (ASD). Individuals with 22q11DS present social functioning impairments in terms of adaptive behavior, social inhibition and isolation from peers (Schneider et al., 2014;Schonherz et al., 2014;Swillen, et al., 1997aSwillen, et al., , 1997b) that tend to become more pronounced during adolescence (Kates et al., 2015). In ASD, altered social interactions appear very early on and remain relatively stable or improve with age (e.g. ...
Article
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Social impairments are common features of 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). The Ecological Momentary Assessment (EMA) allowed access to daily-life information in order to explore the phenomenology of social interactions. 32 individuals with 22q11DS, 26 individuals with ASD and 44 typically developing peers (TD) aged 12–30 were assessed during 6 days 8 times a day using a mobile app. Participants with 22q11DS and ASD did not spend more time alone but showed distinct implication in the social sphere than TD. Distinct profiles emerged between the two conditions regarding the subjective experience of aloneness and the subjective experience of social interactions. This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD that points towards different therapeutic targets.
... In contrast, participants with 22q11DS displayed less socially inadequate behaviors. This may be considered in light of the shyness that is characteristic of the 22q11DS phenotype: children but also adolescents and adults with 22q11DS are typically described as socially withdrawn and lacking initiative (Kates et al., 2015;Shprintzen, 2000). Incidentally, the other distinction between the two clinical groups appeared in assertiveness (persistence/submission scale): participants with 22q11DS were less assertive than those with ASD. ...
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Backgrounds: Social skills are frequently impaired in neurodevelopmental disorders, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with questionnaires, direct assessment provides a more valid estimate of the constructs. Role-plays (i.e., simulates situational settings) therefore appear to be an appropriate indicator of social skills in daily life, as they allow for systematic and direct observations of behaviors. Methods: 53 individuals with 22q11DS, 34 individuals with ASD, and 64 typically developing (TD) peers aged 12-30 years were assessed with role-plays as well as hetero-reported questionnaires and clinical interviews on social skills, functioning and anxiety. Results: Both clinical groups showed impaired social skills compared to TD, but distinct social profiles emerged between the groups. Individuals with ASD exhibited high social inadequacy, whereas individuals with 22q11DS were characterized by a lack of assertiveness. No association was found between social skills measured by direct observation and caregiver reports. Social anxiety, although greater in clinical groups than in TD, was not associated with social skills. Conclusions: This study highlights the need to train social skills through tailored interventions to target the specific difficulties of each clinical population. It also highlights the importance of combining measures as they do not necessarily provide the same outcome.
Article
Background Patients with 22q11.2 deletion syndrome (22q11DS) present a high risk of developing psychosis. While clinical and cognitive predictors for the conversion towards a full-blown psychotic disorder are well defined and largely used in practice, neural biomarkers do not yet exist. However, a number of investigations indicated an association between abnormalities in cortical morphology and higher symptoms severities in patients with 22q11DS. Nevertheless, few studies included homogeneous groups of patients differing in their psychotic symptoms profile. Methods In this study, we included 22 patients meeting the criteria for an ultra-high-risk (UHR) psychotic state and 22 age-, gender- and IQ-matched non-UHR patients. Measures of cortical morphology, including cortical thickness, volume, surface area and gyrification, were compared between the two groups using mass-univariate and multivariate comparisons. Furthermore, the development of these measures was tested in the two groups using a mixed-model approach. Results Our results showed differences in cortical volume and surface area in UHR patients compared with non-UHR. In particular, we found a positive association between surface area and the rate of change of global functioning, suggesting that higher surface area is predictive of improved functioning with age. We also observed accelerated cortical thinning during adolescence in UHR patients with 22q11DS. Conclusions These results, although preliminary, suggest that alterations in cortical volume and surface area as well as altered development of cortical thickness may be associated to a greater probability to develop psychosis in 22q11DS.
Chapter
Autism spectrum disorder is a neurobiological disease with onset in early development and characterized by impaired social communication and interaction as well as restricted and repetitive behaviors. Early screen and diagnosis are important for individuals to benefit from evidence-based interventions, and as part of that early diagnosis, careful consideration of a broad differential is important. This differential includes language disorders, cognitive delays, and genetic variants, as well as comorbid medical and psychiatric conditions, all of which could have a significant impact on development and outcome.
Article
22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.
Article
El Síndrome de Deleción 22q11.2 o Síndrome de DiGeorge es una entidad genética caracterizada por la triada clínica de anomalías cardiacas conotruncales, hipoplasia tímica e hipocalcemia. No obstante, el fenotipo 22q11.2 es bastante variable, incluyendo anomalías físicas, metabólicas, endocrinológicas y a nivel conductual y del desarrollo. Incluye asociación piscopatológica con distintos síndromes psiquiátricos. Describimos el caso de un varón de 16 años con criterios diagnósticos de Trastorno del Espectro Autista enmarcado en un Síndrome de Deleción 22q11.2.
Article
The last decade has provided new insights into the genetic architecture of schizophrenia. For the first time researchers have identified genetic factors conferring risk that can be mapped to tissue and cell specific perturbations of the molecular machinery underlying disease processes. However, it has also become clear that attempts to gain mechanistic insights into disease processes that span multiple levels of biological complexity, from genes to cells to circuits to behaviors, are inherently difficult and will require interdisciplinary efforts. Here we discuss the opportunities and pitfalls of developing causal models of SCZ that will lead to novel treatments and prevention strategies. We make the case that integrated large-scale Team Science efforts will be necessary to achieve this goal and that a systems level approach that includes genetics and integrative modelling is needed.
Article
Purpose This article reviews the psychosocial risks associated with 22q11.2 deletion syndrome, a relatively common genetic condition associated with a range of physical and psychiatric problems. Risks associated with developmental stages from infancy through adolescence and early adulthood are described, including developmental, learning, and intellectual disabilities as well as psychiatric disorders including anxiety, mood, and psychotic disorders. Other risks related to coping with health problems and related treatments are also detailed for both affected individuals and their families. Conclusion The article ends with strategies for addressing psychosocial risks including provision of condition-specific education, enhancement of social support, routine assessment of cognitive abilities, regular mental health screening, and referrals for empirically supported psychiatric and psychological treatments.
Article
22q11.2 deletion is one of the most well‐known copy number variants (CNVs) associated with developing a psychiatric condition (e.g. schizophrenia), but there is a growing list of other CNVs which also confer substantial risk for developing psychiatric conditions. With increased use of chromosome microarray and exome sequencing, the frequency with which these CNVs are detected is increasing. While individuals with such CNVs often receive genetic counseling, research shows that associated psychiatric conditions are less often addressed ‐ clinicians tend to focus on the non‐psychiatric manifestations of the CNV. This represents an important service gap for people with these CNVs and their families, as research shows that genetic counseling about psychiatric illness can produce meaningful positive outcomes for people, including increases in empowerment, and self‐efficacy. Therefore, there is a need to ensure that individuals with psychiatric condition‐associated CNVs are being counseled about these manifestations of their condition in a way that can promote best outcomes. In this paper we describe the process of providing genetic counseling in two clinical scenarios in which a psychiatric susceptibility CNV is identified: 1) in an individual who has not been diagnosed with a psychiatric condition and 2) in an individual with an established psychiatric condition.
Article
Restricted and repetitive behaviors (RRB) are common in individuals with 22q11.2 microdeletion syndrome (22q11.2DS), yet the underlying mechanisms of these behaviors remain poorly characterized. In the present pilot investigation, we aimed to further our understanding of RRB in 22q11.2DS by exploring their relationship with cognitive control and anxiety as well as with sex, chronological age, and full‐scale IQ. Parents of 38 children with 22q11.2DS (17 females; Mage = 11.15 years, SD = 2.46) completed the Social Communication Questionnaire as a measure of RRB and social and communication (SC) problems and the Behavioral Assessment System for Children‐2 as a measure of anxiety and cognitive control. Higher RRB scores were significantly associated with higher anxiety levels (r = 0.44, P = 0.006), more impairments in cognitive control (r = 0.56, P < 0.001), and higher SC scores (r = 0.43, P = 0.011). In the first step of the hierarchical regression model, anxiety accounted for 24.5% of variance (F = 10.05, P = 0.003); cognitive control accounted for an additional 18.1% of variance (Fchange = 11.15, P < 0.001) in the second step; SC score accounted for only 0.8% of additional variance in the third step (Fchange = 0.40, P = 0.53). The final model explained 43.4% of variance (F = 7.42, P = 0.001), with cognitive control as a unique independent predictor of RRB score (t = 2.52, P = 0.01). The current study provides the first exploration of the cognitive control—anxiety—RRB link in individuals with 22q11.2DS and points to cognitive control as a potentially viable target for treatments aimed at reducing RRB. Autism Res 2019, 12: 1737–1744. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with 22q11.2 deletion syndrome show high levels of repetitive behaviors, however, the previous research has not explored why people with this syndrome exhibit high rates of repetitive behaviors. Understanding the reasons for the high levels of repetitive behaviors is important given that these behaviors can be highly impairing. Our study found that repetitive behaviors were associated with impaired ability to self‐regulate and high levels of anxiety. These findings need to be further replicated; however, they are important as they suggest potentially promising ways of reducing these behaviors.
Article
22q11.2 deletion syndrome (DS) is considered to be the most robust genetic model of psychosis. In the last decade, there has been increased interest in the brain abnormalities associated with these genetic changes. Most imaging findings in this population come from small samples. This increases the risk of reporting spurious effects that reflect the idiosyncrasies of each study. Thus, the current work is aimed at identifying whether there are spatially consistent structural and functional brain abnormalities in individuals with 22q11.2 DS through (i) a comprehensive label-based systematic review and (ii) a coordinate-based meta-analysis of magnetic resonance imaging studies. The systematic review identified the frontal middle gyri, posterior cingulum, right cuneus and bilateral precuneus as the most affected regions. The meta-analysis revealed consistent abnormalities in the bilateral inferior parietal lobe, right precuneus, right superior temporal gyrus and posterior cingulate cortex. This study provides an important starting point for future research as it sheds light on possible genetically determined psychosis susceptibility regions.
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Background The 22q11.2 deletion syndrome (22q11DS) is a genetic syndrome that results in a highly variable profile of affected individuals of which impairments in the social domain and increased psychopathology are the most prominent. Notably, 25–30% of affected individuals eventually develop schizophrenia/psychosis, predisposing persons with the syndrome to increased risk for this disorder. Because social cognition is considered to underlie social behavior and to be related to psychopathology, this systematic review investigated social cognition in individuals with 22q11DS and examined reported links across its domains with psychopathology and social outcomes. This can provide the basis for a closer understanding of the path from risk to disorder and will inform on the specific domains that can be targeted with preventive intervention strategies. Method Systematic literature review of studies that reported the links between social cognitive domains and psychopathology and/or social outcomes in individuals with 22q11DS. Electronic databases searched were PubMed and PsycINFO. Results Defined eligibility criteria identified a total of ten studies to be included in the present review. Selected studies investigated links between two domains of social cognition (emotion processing and theory of mind (ToM)) and psychopathology and/or social outcomes. With respect to the links to psychopathology, two aspects of social cognition were related primarily to negative symptoms. Results regarding the associations to positive and emotional symptoms (anxiety/depression) are limited and require further investigation. Even though both aspects of social cognition were associated with social outcomes, several studies also found no links between these two domains. Both reports invite for an additional examination of reported results and specific considerations regarding chosen constructs. Conclusion Although equivocal, results of the present review provide sufficient evidence that social cognition is a useful domain for the closer elucidation of clinical outcomes and social difficulties in this population. At the same time, longitudinal studies and consideration of other variables are also necessary for a timely understanding of affected persons in this respect.
Article
Objective: 22q11.2 deletion syndrome (22q11DS) is a common genetic deletion syndrome associated with psychiatric disorders and developmental delays. A significant amount of 22q11DS research literature is published annually; here, we focus exclusively on longitudinal data that have been published in the past 5 years regarding psychiatric disorders and/or cognitive and social development. After a review, areas for future research consideration and clinical recommendations are presented. Methods: Articles were reviewed and organized in adherence with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for conducting systematic reviews. The literature search identified 852 studies, and 22 studies met inclusion criteria. Results: Longitudinal study findings indicate that developmental considerations for youth with 22q11DS should focus on the primacy and enduring nature of social and executive functioning deficits, attention-deficit/hyperactivity disorder, anxiety, and negative symptoms of psychosis. Conclusion: From the diathesis of physiological conditions and genetic variance, 22q11DS and its associated phenotype of persistent cognitive deficits, comorbid psychiatric disorders, and social impairments likely conspire to increase the risk for stress in adolescence. The diathesis-stress framework, along with chronic stress, increases psychosis risk in individuals with 22q11DS. The existing literature has a heavy focus on the impact of the deletion on individual skills and attributes, such as cognition, but lacks information on the impact of the environment. Future 22q11DS research should consider specific aspects of social functioning, including interactions with parenting styles and family communication, as well as high demands in educational settings, as possible risk factors for psychosis.
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Background: Social impairments are common features of several neurodevelopmental conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). However, little is known about social interactions in daily-life. The Ecological Momentary Assessment (EMA) was used to have access to daily-life information and to distinguish the phenomenology of social interactions between the two conditions, often considered as presenting a similar profile of social impairments. Methods: 32 individuals with 22q11DS, 26 individuals with ASD and 44 healthy controls (HC) aged 12-30 were recruited. All participants were assessed during 6 days 8 times a day using a mobile app. The EMA protocol assessed positive and negative affect, social context (alone versus in company) and the subjective experience of aloneness and social interactions. Results: Participants with 22q11DS and ASD did not spend more time alone, but spent less time with familiar individuals such as friends, and more time with people they live with, compared to HC. However, distinct profiles emerged between the two conditions regarding the subjective experience of aloneness, with more intense feelings of exclusion in participants with ASD compared to participants with 22q11DS and HC. The subjective appreciation of interactions revealed that individuals with ASD felt more judged and more nervous than both 22q11DS and HC. Nevertheless, both conditions expressed a higher desire to be alone when in company of other people than HC. Conclusions: This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD, giving new intel regarding the social phenotype in these conditions, and pointing towards different therapeutic targets.
Article
22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder caused by a microdeletion on the long arm of chromosome 22. Sleep problems have been reported in this population, and psychiatric disorders and affect dysregulation are common to the behavioral phenotype of 22q11DS. Sleep and affect have been consistently linked across multiple studies, yet despite this very little research has investigated sleep problems in 22q11DS, or the link between sleep and affect in this population. The Experience Sampling Method was used to track daily reports of sleep quality and affect in a total of 29 individuals with 22q11DS and 21 control subjects. Measurements were recorded during a 6-day period using an electronic device that prompted daily response with audio cues. Participants with 22q11DS were found to experience a longer sleep onset latency and a greater amount, and duration, of night wakings compared with control subjects. Despite this, no significant between-group difference was found for subjective sleep quality. 22q11DS participants reported more experiences of negative affect and less positive affect than control subjects. A bidirectional relationship was found between sleep measures and affect. Sleep problems can cause a wide range of negative health effects, and individuals with 22q11DS are particularly vulnerable to deficits of sleep. To ensure high standards of care, healthcare providers should be aware of the possibility and impact of sleep problems in this population.
Chapter
22q11.2 deletions syndrome represents the most common microdeletion syndrome. A large phenotypic variance exists among patients with 2211.2 deletion syndrome. Given the multitude of head and neck manifestations associated with the syndrome, otolaryngologists play a key role in its diagnosis and management. The medical complexity of patients with 22q11.2 deletion syndrome is best addressed by a multidisciplinary approach in order to provide efficient, coordinated care.
Article
Objective Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families. Method We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided. Results There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups. Conclusions Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification.
Article
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Mutations are genetic sequence changes, and they are the principal cause of organism diversity. These changes occur at many different levels and can have far-reaching different consequences. These alterations occur due to genetic or epigenetic factors. These changes possibly cause phenotypic change in human which develop a disorder or evolution. Notably, our genetics can repair undesirable mutations during replication in most of the time. The types of mutations will be reviewed and discussed in this report.
Article
Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur. With the DSM-5, clinicians are permitted to make an ASD diagnosis in the context of ADHD. In earlier versions of the DSM, this was not acceptable. Both ASD and ADHD are reported to have had substantial increases in prevalence within the past 10 years. As a function of both the increased prevalence of both disorders as well as the ability to make an ASD diagnosis in ADHD, there has been a significant amount of research focusing on the comorbidity between ADHD and ASD in the past few years. Here, we provide an update on the biological, cognitive and behavioral overlap/distinctiveness between the two neurodevelopmental disorders with a focus on data published in the last four years. Treatment strategies for the comorbid condition as well as future areas of research and clinical need are discussed.
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The purpose of this study was to evaluate the effectiveness and safety of antipsychotic and antidepressant medications in individuals with 22q11.2 deletion syndrome (22q11.2 DS) and psychiatric comorbidity. We used a record review, structured clinical interviews, and the Clinical Global Impressions (CGI) scale to retrospectively assess the effectiveness and safety of antipsychotic medications for schizophrenia spectrum disorders and of antidepressant medications for depressive and anxiety disorders in 40 individuals with 22q11.2DS. We observed significant improvement in CGI-Severity scores in individuals with 22q11.2DS treated with antipsychotic or antidepressant medications, and a ∼50% response rate based on the CGI-Improvement score. Adverse events were similar in types and rates to those reported in non-22q11.2 individuals treated with antipsychotics or antidepressants. Our data show that treatment with antipsychotics and antidepressants may be effective while being relatively safe in individuals with 22q11.2DS. Antipsychotic and antidepressant medications should be considered in any individual with 22q11.2DS who has a psychiatric morbidity, such as psychosis or mood or anxiety disorders. Although the psychotropic medications were generally well tolerated in our sample, more rigorous metabolic and cardiovascular measures are required in future studies to conclusively verify the safety of these medications.
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The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs-on-Beads™ (PNBoBs™) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBs™ under different prenatal indications. A total of 9648 prenatal samples were prospectively analyzed by karyotyping plus PNBoBs™ and classified by prenatal indication. The frequencies of the genomic defects and their 95%CIs were calculated for each indication. The overall incidence of cryptic imbalances was 0.7%. The majority involved the DiGeorge syndrome critical region (DGS). The additional diagnostic yield of PNBoBs™ in the population with a low a priori risk was 1/298. The prevalences of DGS microdeletion and microduplication in the low-risk population were 1/992 and 1/850, respectively. The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell-free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.
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Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD) were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT), a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ). When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures.
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Background: The primary objective of the current study was to examine the childhood predictors of adolescent reading comprehension in velo-cardio-facial syndrome (VCFS). Although much research has focused on mathematics skills among individuals with VCFS, no studies have examined predictors of reading comprehension. Methods: 69 late adolescents with VCFS, 23 siblings of youth with VCFS and 30 community controls participated in a longitudinal research project and had repeat neuropsychological test batteries and psychiatric evaluations every 3 years. The Wechsler Individual Achievement Test-2nd edition (WIAT-II) Reading Comprehension subtest served as our primary outcome variable. Results: Consistent with previous research, children and adolescents with VCFS had mean reading comprehension scores on the WIAT-II, that were approximately two standard deviations below the mean and word reading scores approximately one standard deviation below the mean. A more novel finding is that relative to both control groups, individuals with VCFS demonstrated a longitudinal decline in reading comprehension abilities yet a slight increase in word reading abilities. In the combined control sample, WISC-III FSIQ, WIAT-II Word Reading, WISC-III Vocabulary and CVLT-C List A Trial 1 accounted for 75% of the variance in Time 3 WIAT-II Reading Comprehension scores. In the VCFS sample, WISC-III FSIQ, BASC-Teacher Aggression, CVLT-C Intrusions, Tower of London, Visual Span Backwards, WCST Non-perseverative Errors, WIAT-II Word Reading and WISC-III Freedom from Distractibility index accounted for 85% of the variance in Time 3 WIAT-II Reading Comprehension scores. A principal component analysis with promax rotation computed on the statistically significant Time 1 predictor variables in the VCFS sample resulted in three factors: Word reading decoding/Interference control, Self-Control/Self-Monitoring and Working Memory. Conclusions: Childhood predictors of late adolescent reading comprehension in VCFS differ in some meaningful ways from predictors in the non-VCFS population. These results offer some guidance for how best to consider intervention efforts to improve reading comprehension in the VCFS population.
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Abstract Individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS) have been shown to have impairments in processing spatiotemporal information. The authors examined whether children with 22q11.2DS exhibit impairments in spatial working memory performance due to these weaknesses, even when controlling for maintenance of attention. Children with 22q11.2DS (n = 47) and typically developing controls (n = 49) ages 6-15 years saw images within a grid and after a delay, then indicated the positions of the images in the correct temporal order. Children with 22q11.2DS made more spatial and temporal errors than controls. Females with 22q11.2DS made more spatial and temporal errors than males. These results extend findings of impaired spatiotemporal processing into the memory domain in 22q11.2DS by documenting their influence on working memory performance.
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Autism spectrum disorder is characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills that arise in the first years of life. Although frequently associated with intellectual disability, this condition is distinctive in its course, impact, and treatment. Autism spectrum disorder has a wide range of syndrome expression and its management presents particular challenges for clinicians. Individuals with an autism spectrum disorder can present for clinical care at any point in development. The multiple developmental and behavioral problems associated with this condition necessitate multidisciplinary care, coordination of services, and advocacy for individuals and their families. Early, sustained intervention and the use of multiple treatment modalities are indicated.
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Background Clinically elevated anxiety is a common, impairing feature of autism spectrum disorders (ASD). A modular CBT program designed for preteens with ASD, Behavioral Interventions for Anxiety in Children with Autism (BIACA; Wood et al., 2009), was enhanced and modified to address the developmental needs of early adolescents with ASD and clinical anxiety. Method Thirty-three adolescents (11–15 years old) were randomly assigned to 16 sessions of CBT or an equivalent waitlist period. The CBT model emphasized exposure, challenging irrational beliefs, and behavioral supports provided by caregivers, as well as numerous ASD-specific treatment elements. Independent evaluators, parents, and adolescents rated symptom severity at baseline and post-treatment/post-waitlist. Results In intent-to-treat analyses, the CBT group outperformed the waitlist group on independent evaluators’ ratings of anxiety severity on the Pediatric Anxiety Rating Scale (PARS) and 79% of the CBT group met Clinical Global Impressions-Improvement scale criteria for positive treatment response at posttreatment, as compared to only 28.6% of the waitlist group. Group differences were not found for diagnostic remission or questionnaire measures of anxiety. However, parent-report data indicated that there was a positive treatment effect of CBT on autism symptom severity. Conclusions The CBT manual under investigation, enhanced for early adolescents with ASD, yielded meaningful treatment effects on the primary outcome measure (PARS), although additional developmental modifications to the manual are likely warranted. Future studies examining this protocol relative to an active control are needed. Clinicaltrials.gov trial reference number: NCT01177969. Internet links: http://clinicaltrials.gov/ct2/show/NCT01177969
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High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD.
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Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with cognitive impairments and significantly elevated risk for developing schizophrenia. While impairments in response inhibition are central to executive dysfunction in schizophrenia, the nature and development of such impairments in children with 22q11.2DS, a group at high risk for the disorder, are not clear. Here we used a classic Go/No-Go paradigm to quantify proactive (anticipatory stopping) and reactive (actual stopping) response inhibition in 47 children with 22q11.2DS and 36 typically developing (TD) children, all ages 7-14. A cross-sectional design was used to examine age-related associations with response inhibition. When compared with TD individuals, children with 22q11.2DS demonstrated typical proactive response inhibition at all ages. By contrast, reactive response inhibition was impaired in children with 22q11.2DS relative to TD children. While older age predicted better reactive response inhibition in TD children, there was no age-related association with reactive response inhibition in children with 22q11.2DS. Closer examination of individual performance data revealed a wide range of performance abilities in older children with 22q11.2DS; some typical and others highly impaired. The results of this cross-sectional analysis suggest an impaired developmental trajectory of reactive response inhibition in some children with 22q11.2DS that might be related to atypical development of neuroanatomical systems underlying this cognitive process. As part of a larger study, this investigation might help identify risk factors for conversion to schizophrenia and lead to early diagnosis and preventive intervention.
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Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and as up to one third of the participants with VCFS develop schizophrenia-like psychotic disorder, the syndrome is the most commonly known genetic risk factor to schizophrenia. Identifying the genetic, cognitive, and psychiatric risk factors for VCFS-schizophrenia is under the focus of intensive research.
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Chromosome 22q11.2 deletion syndrome (22q11.2DS) results from a 1.5- to 3-megabase deletion on the long arm of chromosome 22 and occurs in approximately 1 in 4000 live births. Previous studies indicate that children with 22q11.2DS are impaired on tasks involving spatial attention. However, the degree to which these impairments are due to volitionally generated (endogenous) or reflexive (exogenous) orienting of attention is unclear. Additionally, the efficacy of these component attention processes throughout child development in 22q11.2DS has yet to be examined. Here we compared the performance of a wide age range (7 to 14 years) of children with 22q11.2DS to typically developing (TD) children on a comprehensive visual cueing paradigm to dissociate the contributions of endogenous and exogenous attentional impairments. Paired and two-sample t-tests were used to compare outcome measures within a group or between groups. Additionally, repeated measures regression models were fit to the data in order to examine effects of age on performance. We found that children with 22q11.2DS were impaired on a cueing task with an endogenous cue, but not on the same task with an exogenous cue. Additionally, it was younger children exclusively who were impaired on endogenous cueing when compared to age-matched TD children. Older children with 22q11.2DS performed comparably to age-matched TD peers on the endogenous cueing task. These results suggest that endogenous but not exogenous orienting of attention is selectively impaired in children with 22q11.2DS. Additionally, the age effect on cueing in children with 22q11.2DS suggests a possible altered developmental trajectory of endogenous cueing.
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Autism, a severe disorder of development, is difficult to detect in very young children. However, children who receive early intervention have improved long-term prognoses. The Modified Checklist for Autism in Toddlers (M-CHAT), consisting of 23 yes/no items, was used to screen 1,293 children. Of the 58 children given a diagnostic/developmental evaluation, 39 were diagnosed with a disorder on the autism spectrum. Six items pertaining to social relatedness and communication were found to have the best discriminability between children diagnosed with and without autism/PDD. Cutoff scores were created for the best items and the total checklist. Results indicate that the M-CHAT is a promising instrument for the early detection of autism.
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Velo-cardio-facial syndrome (VCFS) is characterized by a high prevalence of depression and anxiety disorders in childhood and adolescence. These disorders are a source of great impairment in everyday functioning, as well as important risk factors for the emergence of later psychotic disorders. Impairment in daily and social functioning as well as loss of IQ throughout growth are also are well-established correlates of the VCFS. This study aimed to confirm the high prevalence of depression and anxiety disorders. The second objective was to ascertain the correlation between anxious and depressive symptoms and the decline in adaptive and cognitive functioning. A total of 73 children and adolescents with VCFS (mean age 11.9 years) underwent psychiatric evaluation. Subjects were further divided into four age groups: ages 6-9, 9-12, 12-15 and 15-18 years. Assessments measuring intelligence, anxious and depressive symptoms, and adaptation skills reported by parents were submitted to a subsample of 62 children (mean age 12.2 years); 62.2 % of the sample showed an anxiety disorder, specific phobia being the most represented at all ages. Lifetime depression concerned 27 % of the sample, peaking at age 12-15 years. Anxious and depressive symptoms and low IQ were significantly associated with low adaptive functioning. Anxiety and depression are common disorders in children and adolescents with VCFS and have a great impact on adaptive functioning. Clinicians should pay great attention to diagnosis and treatment.
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Methylphenidate (MPH) is commonly used to treat attention-deficit/hyperactivity disorder (ADHD) in all children, including those with velocardiofacial syndrome (VCFS). Yet concerns have been raised regarding its safety and efficacy in VCFS. The goal of this study was to examine the safety and efficacy of MPH in children with VCFS. Thirty-four children and adolescents with VCFS and ADHD participated in a randomized, controlled trial with a 2:1 ratio of MPH versus placebo. All subjects underwent a cardiological evaluation before and after MPH administration. The primary outcome measure was prefrontal cognitive performance following a single dose of MPH or placebo. A follow-up assessment was conducted after a 6-month treatment with MPH. Compared with placebo, single MPH administration was associated with a more robust improvement in prefrontal cognitive performance, including achievements in the Hearts and Flowers executive function task and the visual continuous performance task. After 6 months of treatment, a 40% reduction in severity of ADHD symptoms was reported by parents on the Revised Conners Rating Scale. All subjects treated with MPH reported at least one side effect, but it did not necessitate discontinuation of treatment. MPH induced an increase in heart rate and blood pressure that was usually minor, but was clinically significant in two cases. No differences in response to MPH were observed between catechol-O-methyltransferase Met versus Val carriers. The use of MPH in children with VCFS appears to be effective and relatively safe. A comprehensive cardiovascular evaluation for children with VCFS before and during stimulant treatment is recommended.
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The International 22q11.2 Deletion Syndrome Consortium** A 12-year-old boy currently is followed by multiple sub-specialists for problems caused by the chromosome 22q11.2 deletion syndrome (22q11DS) (Figure). He was born via spontaneous vaginal delivery, weighing 3033 g, to a 31-year-old G3P3 mother after a full-term pregnancy complicated only by mild polyhydramnios. Family history was non-contributory. Apgar scores were 8 at 1 minute and 9 at 5 minutes. With the exception of a weak cry, the results of the infant's initial examination were unremarkable, and he was moved to the well-baby nursery. Shortly thereafter, a cardiac murmur was noted, the cardiology department was consulted, and the child was transferred to a local tertiary care facility with a diagnosis of tetralogy of Fallot. Stable, he was discharged home at 3 days of life. At 5 days of life, he had jerky movements. On presentation to the local emergency department, his total calcium level was 4.7 mg/dL, and later partial hypoparathyroidism was diagnosed. At that time, a consulting geneticist suggested the diagnosis of chromosome 22q11DS. Weeks later, the family received a telephone call confirming the diagnosis with fluorescence in situ hybridization (FISH). No additional information about the diagnosis, prognosis, etiology, or recurrence risk was pro-vided until the child was 5 months of age, when he underwent cardiac repair at a third hospital, where a comprehensive 22q11DS program was in operation. In the interim, the child had feeding difficulties requiring supplemental nasogastric tube feeds, nasal regurgitation, and gastroesophageal reflux, while the parents searched the internet for reliable information about their son's diagnosis. Subsequent notable abnormalities and interventions included: recurrent otitis media with bilateral myringotomy tube placement at 6 months; angioplasty with left pulmonary artery stent placement after the identification of pulmonary artery stenosis with bilateral pleural effusions at age 6 years; chronic upper respiratory infections with significant T cell dysfunction requiring live viral vaccines to be held until age 7 years; velopharyngeal incompetence necessitating posterior pharyngeal flap surgery at 7 years; enamel hypoplasia and numerous caries resulting in 3 separate dental procedures under general cardiac anesthesia beginning at age 7 years; multiple cervical and thoracic vertebral anomalies with tho-racic levoconvex scoliosis and upper lumbar dextroscoliosis requiring growing rod placement at age 11 years with subse-quent rod extension at ages 11.5 and 12 years; postoperative hypocalcemia; short stature; constipation; and persistent idiopathic thrombocytopenia. Pertinent negative test results included normal renal ultrasound scanning and parental 22q11.2 deletion studies. On physical examination, the boy's height and weight have consistently tracked just below the fifth percentile, with no evidence of growth hormone deficiency. His head circumfer-ence is within reference range at the 25th percentile. Dysmor-phic features include: a low anterior hairline; hooded eyelids; malar flatness; normally formed but protuberant ears with attached lobes; a mildly deviated nose with a bulbous nasal tip and hypoplastic alae nasi; asymmetric crying facies with a thin upper lip; mild micrognathia; a sacral dimple; and soft tissue syndactyly of the second and third toes. Developmentally, the boy had mild delays in achieving mo-tor milestones, sitting at 11 months and walking at 18 months. However, he exhibited significant delays in the emergence of language: he never babbled, spoke his first words at age 3 years, and only achieved full conversational speech at 7 years. However, he had relative strengths in receptive language and communicated appropriately by the use of sign language. Now quite conversant, he is mainstreamed in the seventh grade with resource room supports. Moreover, he is affable, but exhibits anxiety and perseverations. Lastly, despite numerous medical, academic, and social challenges, he
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Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue × flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS.
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Velo-cardio-facial syndrome or 22q11.2 deletion syndrome (22q11DS) is the most common known microdeletion syndrome. One of the genes in the deleted region is the catechol-O-methyltransferase (COMT) gene, which is thought to have significant effects on cognition through its influence on dopamine metabolism. The aim of the present study was to better characterize the cognitive phenotype in a large cohort children with 22q11DS compared with sibling controls and to investigate if the cognitive deficits in 22q11DS were modulated by COMT expression. The memory, executive function and attentional abilities of children with 22q11DS (n = 50) compared to sibling controls (n = 31), were measured. Also, within children with 22q11DS, a preliminary exploration was carried out of the relationship between cognitive ability and COMT genotype. Overall, the 22q11DS group had significantly reduced scores on tests of memory (especially in visual memory) and executive function (particularly in planning, working memory, and motor organization) compared with sibling controls. No association, however, was identified between COMT genotype and cognitive function. Although 22q11DS children have specific cognitive deficits, differences in COMT do not account for these findings.
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Velocardiofacial syndrome (VCFS) also known as DiGeorge, conotruncal anomaly face and Cayler syndromes is caused by a microdeletion in the long arm of chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and as up to one third of the subjects with VCFS develop schizophrenia like psychotic disorder the syndrome is the most commonly known genetic risk factor to schizophrenia. Identifying the genetic, cognitive and psychiatric risk factors for VCFS-schizophrenia is under the focus of intensive research.
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Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample. Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests. The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects. Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.
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We have confirmed a proposed association between schizophrenia and the 22q11 deletion syndrome (22qDS) by identifying patients with 22qDS in a schizophrenia population. It is unclear, however, whether the psychiatric symptom pattern is different in this subtype of schizophrenia. Objective: To determine how major psychiatric symptoms in patients with 22qDS-schizophrenia compare with patients with schizophrenia but no 22qDS. Methods: All subjects had DSM-IV schizophrenia or schizoaffective disorder (SZ), 22DS subjects (n=9) had deletions in the 22q11 region determined using standard FISH methods (probe N25. Vysor). The comparison group of age and sex-matched non-deleted subjects (n=36) were drawn from a well characterised familial SZ sample. All subjects had a standard assessment of severity of symptoms common in SZ. the 30-item Positive and Negative Syndrome Scale (PA.NSS). and Global Assessment of Functioning (GAK) to assess functioning level. Results: Age at onset of SZ was significantly younger in the 22qDS group (18.3. SD 3.0 vs =26.8 SD 10.8, t=-3.96.p=0003). There was no significant difference in GAF score, severity of psychotic features (e.g. hallucinations and delusions), negative (e.g. blunting of emotional expression, decreased spontaneous speech), cognitive (e.g. orientation, attention), or anxiety/depression symptom groups. Only severity of the excitement symptom group (e.g. hostility, poor impulse control) was greater in the 22qDS group (p=.004). Conclusions: Adult patients with a 22qDS subtype of schizophrenia had similar symptom patterns and functioning as patients with familial schizophrenia in most of the major SZ symptom groups. However, a symptom group which would include emotional lability and impulsive behaviour was more severe, as would be expected from previous reports of paediatric 22qDS samples.
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Objective: The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period. Method: The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Children's Depression Rating Scale-Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure. Results: Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality. Conclusions: In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.
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Errors in Byline, Author Affiliations, and Acknowledgment. In the Original Article titled “Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication,” published in the June issue of the ARCHIVES (2005;62:593-602), an author’s name was inadvertently omitted from the byline and author affiliations footnote on page 592, and another author’s affiliation was listed incorrectly. The byline should have appeared as follows: “Ronald C. Kessler, PhD; Patricia Berglund, MBA; Olga Demler, MA, MS; Robert Jin, MA; Kathleen R. Merikangas, PhD; Ellen E. Walters, MS.” The author affiliations footnote should have appeared as follows: “Author Affiliations: Department of Health Care Policy, Harvard Medical School, Boston, Mass (Dr Kessler; Mss Demler and Walters; and Mr Jin); Institute for Social Research, University of Michigan, Ann Arbor (Ms Berglund); and Section on Developmental Genetic Epidemiology, National Institute of Mental Health, Rockville, Md (Dr Merikangas).” On page 601, the first sentence of the acknowledgment should have appeared as follows: “The authors appreciate the helpful comments of William Eaton, PhD, and Michael Von Korff, ScD.” Online versions of this article on the Archives of General Psychiatry Web site were corrected on June 10, 2005.
Article
22q11DS is a multiple anomaly syndrome involving intellectual and behavioral deficits, and increased risk for schizophrenia. As cognitive remediation (CR) has recently been found to improve cognition in younger patients with schizophrenia, we investigated the efficacy, feasibility, and fidelity of a remote, hybrid strategy, computerized CR program in youth with 22q11DS. A longitudinal design was implemented in which 21 participants served as their own controls. Following an eight month baseline period in which no interventions were provided, cognitive coaches met with participants remotely for CR via video conferencing three times a week over a targeted 8month timeframe and facilitated their progress through the intervention, offering task-specific strategies. A subset of strategies were examined for fidelity. Outcomes were evaluated using a neurocognitive test battery at baseline, pre-treatment and post-treatment. All participants adhered to the intervention. The mean length of the treatment phase was 7.96months. A moderately high correlation (intraclass correlation coefficient, 0.73) was found for amount and type of strategies offered by coaches. Participants exhibited significant improvements (ES=.36-.55, p≤.009) in working memory, shifting attention and cognitive flexibility. All significant models were driven by improvements in pre to post-treatment scores. Based on our preliminary investigation, a remote, hybrid strategy, computerized CR program can be implemented with 22q11DS youth despite geographic location, health, and cognitive deficits. It appears effective in enhancing cognitive skills during the developmental period of adolescence, making this type of CR delivery useful for youth with 22q11DS transitioning into post-school environments. Copyright © 2015 Elsevier B.V. All rights reserved.
Article
Objectives To determine the psychometric properties of the Vanderbilt Attention Deficit/Hyperactivity Disorder Parent Rating Scale (VADPRS), which utilizes information based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV). The VADPRS was created to collect uniform patient data and minimize the time burden of lengthy interviews. Methods Participant data (N = 243) was used from the first 2 years of a longitudinal study on communication among physicians, teachers, and parents in diagnosing, treating, and managing children with attention deficit/hyperactivity disorder (ADHD). The reliability, factor structure, and concurrent validity of the VADPRS were evaluated and compared with ratings of children in clinical and nonclinical samples on the Vanderbilt ADHD Teacher Rating Scale and the Computerized Diagnostic Interview Schedule for Children–IV, Parent version. Results The internal consistency and factor structure of the VADPRS are acceptable and consistent with DSM-IV and other accepted measures of ADHD. Conclusion The VADPRS is a reliable, cost-effective assessment for ADHD in clinical and research settings.
Article
Background Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. Aims To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia. Method We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group). Results Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine. Conclusions Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia. Royal College of Psychiatrists.