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1.
Genet Med ; 25(10): 100924, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37422717

RESUMO

PURPOSE: To date, there is no systematic method to quantify the medical burden of individuals with 22q11.2 deletion syndrome (22q11.2DS). This study aimed to design a Medical Burden Scale for 22q11.2DS to evaluate the effect of medical symptoms severity on quality of life (QoL) and functioning in individuals with this syndrome. METHODS: Individuals with 22q11.2DS (n = 76) were included in the study. A multidisciplinary group of physicians determined the severity of symptoms (on a scale of 0 to 4) of 8 major medical systems affected in 22q11.2DS, as well as the level of cognitive deficits and psychiatric morbidity. Regression models were used to evaluate the impact of medical, cognitive, and psychiatric symptoms' severity on global assessment of functioning (GAF) and QoL. RESULTS: The total Medical Burden Scale score was significantly associated with both QoL and GAF scores, beyond the effect of the psychiatric and cognitive deficits. We also found that QoL and GAF scores were associated with the severity scores of specific medical systems, particularly neurological symptoms, but also cardiovascular, ear-nose-throat, endocrinology, and orthopedics. CONCLUSION: Quantifying the medical burden of 22q11.2DS individuals is feasible and indicates the overall and specific contribution of medical symptoms to QoL and functioning of 22q11.2DS individuals.

2.
Child Psychiatry Hum Dev ; 54(4): 1085-1093, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35083589

RESUMO

This study examined the associations of parents' expressed emotion (EE) and parenting stress, with behavioral problems of children with 22q11.2 deletion syndrome, idiopathic autism (iASD) and typically developing (TD) children. Parents of children aged 3-8 years completed the five-minute-speech-sample (FMSS), parental stress index and children behavioral checklist. Parents' FMSS-EE-criticism was higher among parents of children with 22q11DS and iASD compared to parents of TD children. FMSS-EE scores predicted children's behavioral problems, above and beyond parenting stress. The associations between FMSS-EE, parenting stress and children's behavioral problems were consistent across 22q11DS, iASD and TD children. These findings highlight the need for targeting parents' EE and parenting stress as integral elements in the screening and prevention of behavioral problems of young children with 22q11DS and iASD.


Assuntos
Transtorno do Espectro Autista , Síndrome de DiGeorge , Comportamento Problema , Criança , Humanos , Pré-Escolar , Transtorno do Espectro Autista/genética , Poder Familiar/psicologia , Emoções Manifestas , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Pais
3.
Eur Child Adolesc Psychiatry ; 31(9): 1367-1375, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33871687

RESUMO

This study aimed to retrospectively evaluate an association between stimulant treatment for attention-deficit/hyperactivity disorder (ADHD) in individuals with 22q11.2DS and the development of psychotic disorders, to evaluate long-term effectiveness and safety of stimulant treatment in individuals with 22q11.2DS compared to individuals with idiopathic ADHD, and to explore effects of catechol-O-methyltransferase (COMT) genotype on 22q11.2DS response to stimulants and risk of side effects. Rates of stimulant use and methylphenidate equivalent exposure were compared among individuals with 22q11.2DS, between 51 with psychotic disorders and a control group of 57 22q11.2DS without psychotic disorders, from Tel Aviv and Geneva. In addition, 44 individuals with 22q11.2DS and ADHD from Tel Aviv who initiated stimulants before age 18 years were compared to a control group of 35 age- and sex-matched controls with idiopathic ADHD, for treatment effectiveness (Clinical Global Impression Scale-Improvement), and rates of side effects. Stimulant use history and methylphenidate equivalent exposure did not differ among individuals with 22q11.2DS, between those with and without psychotic disorders. The long-term retrospective follow-up (5.3 ± 4.1 years) of stimulant-treated individuals with 22q11.2DS showed a higher rate of significant clinical improvement of ADHD symptoms, compared to idiopathic ADHD individuals (p = 0.013), and similar side effect rates. There was no effect of the COMT genotype on response to stimulants or on any side effects. This preliminary long-term retrospective analysis suggests that stimulant treatment in 22q11.2DS is apparently safe in terms of psychosis conversion and rates of side effects, and that it is effective in alleviating ADHD symptoms.


Assuntos
Estimulantes do Sistema Nervoso Central , Síndrome de DiGeorge , Metilfenidato , Transtornos Psicóticos , Adolescente , Catecol O-Metiltransferase/genética , Estimulantes do Sistema Nervoso Central/efeitos adversos , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/tratamento farmacológico , Síndrome de DiGeorge/genética , Humanos , Metilfenidato/efeitos adversos , Transtornos Psicóticos/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento
4.
Am J Med Genet A ; 182(3): 461-468, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31837200

RESUMO

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.


Assuntos
Disfunção Cognitiva/genética , Síndrome de DiGeorge/genética , Predisposição Genética para Doença , Transtornos do Sono-Vigília/genética , Adolescente , Adulto , Aracnodactilia/sangue , Aracnodactilia/genética , Aracnodactilia/fisiopatologia , Criança , Cromossomos Humanos Par 22/genética , Disfunção Cognitiva/fisiopatologia , Craniossinostoses/sangue , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Citocinas/sangue , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Interleucina-6/sangue , Masculino , Síndrome de Marfan/sangue , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/fisiopatologia , Inquéritos e Questionários , Adulto Jovem
5.
Am J Med Genet A ; 176(11): 2365-2374, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29171699

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a relatively common genetic disorder. Due to improvement in pediatric care, affected individuals live into adulthood, some of whom marry or have committed relationships, and reproduce. The current study aimed to identify the factors that discriminate between married and unmarried adults with 22q11.2DS. In the presents study, 90 adults with 22q11.2DS (48 men/42 women), aged 29.8 ± 10.3 years, were included in the analysis. Psychiatric comorbidities, IQ score, and adaptive functioning were assessed using gold-standard diagnostic tools. Demographic factors, marital status, and reproductive status were evaluated by self-reports. Of the sample 25 adults (27.7%) were married and 14 (56%) of those had children. Married, as compared to unmarried individuals, were older, had less psychotic comorbidities, showed higher adaptive functioning in all domains of the Vineland Adaptive Behavior Scale, and had higher rates of independent living and sustained employment. Unexpectedly, married individuals showed higher rates of mood disorders and full scale IQ scores did not discriminate between the groups. We propose that multiple factors are associated with marital status among individuals with 22q11.2DS. Identification of key personal, functional, and social characteristics of those who married and reproduced may help counseling health professionals and clinicians in advising affected individuals and their families.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Síndrome de DiGeorge/psicologia , Estado Civil , Adulto , Cognição , Comorbidade , Síndrome de DiGeorge/epidemiologia , Feminino , Humanos , Masculino , Linhagem , Reprodução
6.
Am J Med Genet A ; 173(9): 2461-2466, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28627787

RESUMO

Danon disease (DD) is a rare X-linked disorder caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein. It is characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Whereas the molecular and pathophysiological mechanisms underlying this disorder have been previously reported and continue to be explored, the cognitive deficits and psychiatric comorbidities manifested in DD remain an understudied topic. We systematically assessed cognitive abilities and psychiatric comorbidities in 13 males and females. Most of the participants in our cohort (n = 9; 75%) had an IQ score within the normal range, while only one participant had intellectual disability. Participants' performance on the Cognitive Neuropsychiatric Battery (CNB) showed only mildly impaired cognitive abilities in most modules, except in the executive functioning test, which was low compared to healthy controls. Of note, 69% of the participants met criteria for at least one psychiatric disorder, mainly mood and anxiety disorders, occurring alone or in combination in the same patient. The results of the present study challenge earlier reports suggesting that mental retardation is a core constituent in DD. Of importance, it underscores the need to refer Danon patients to psychiatric assessment.


Assuntos
Cognição , Doença de Depósito de Glicogênio Tipo IIb/genética , Deficiência Intelectual/genética , Proteína 2 de Membrana Associada ao Lisossomo/genética , Adolescente , Adulto , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Doença de Depósito de Glicogênio Tipo IIb/fisiopatologia , Doença de Depósito de Glicogênio Tipo IIb/psicologia , Humanos , Deficiência Intelectual/fisiopatologia , Deficiência Intelectual/psicologia , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
7.
Brain Cogn ; 106: 33-41, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27200494

RESUMO

Increasingly, the effects of copy number variation (CNV) in the genome on brain function and behaviors are recognized as means to elucidate pathophysiology of psychiatric disorders. Such studies require large samples and we characterized the neurocognitive profile of two cohorts of individuals with 22q11.2 deletion syndrome (22q11DS), the most common CNV associated with schizophrenia, in an effort to harmonize phenotyping in multi-site global collaborations. The Penn Computerized Neurocognitive Battery (PCNB) was administered to individuals with 22q11DS in Philadelphia (PHL; n=155, aged 12-40) and Tel Aviv (TLV; n=59, aged 12-36). We examined effect sizes of performance differences between the cohorts and confirmed the factor structure of PCNB performance efficiency in the combined sample based on data from a large comparison community sample. The cohorts performed comparably with notable deficits in executive function, episodic memory and social cognition domains that were previously associated with abnormal neuroimaging findings in 22q11DS. In mixed model analysis, while there was a main effect for site for accuracy (number of correct response) and speed (time to correct response) independently, there were no main site effects for standardized efficiency (average of accuracy and speed). The fit of a structural model was excellent indicating that PCNB tests were related to the targeted cognitive domains. Thus, our results provide preliminary support for the use of the PCNB as an efficient tool for neurocognitive assessment in international 22q11DS collaborations.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Função Executiva/fisiologia , Memória Episódica , Testes Neuropsicológicos , Percepção Social , Adolescente , Adulto , Criança , Estudos de Coortes , Comparação Transcultural , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/normas , Esquizofrenia/genética , Estados Unidos , Adulto Jovem
8.
World J Biol Psychiatry ; 22(1): 46-57, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212948

RESUMO

OBJECTIVES: 22q11.2 deletion syndrome (DS) is the strongest known genetic risk for schizophrenia. Methylome screening was conducted to elucidate possible involvement of epigenetic alterations in the emergence of schizophrenia spectrum disorders (SZ-SD) in 22q11.2DS. METHODS: Sixteen adult men with/without SZ-SD were recruited from a 22q11.2DS cohort and underwent genome-wide DNA methylation profile analysis. Differentially methylated probes (DMPs) and regions (DMRs) were analysed using the ChAMP software. RESULTS: The DMPs (p-value <10-6) and DMRs (p-valueArea <0.01) were enriched in two gene sets, 'imprinting genes' and 'chr6p21', a region overlapping the MHC locus. Most of the identified imprinting genes are involved in neurodevelopment and located in clusters under imprinting control region (ICR) regulation, including PEG10, SGCE (7q21.3), GNAS, GNAS-AS1 (20q13.32) and SNHG14, SNURF-SNRPN, SNORD115 (15q11.2). The differentially methylated genes from the MHC locus included immune HLA-genes and non-immune genes, RNF39, PPP1R18 and NOTCH4, implicated in neurodevelopment and synaptic plasticity. The most significant DMR is located in MHC locus and covered the transcription regulator ZFP57 that is required for control and maintenance of gene imprinting at multiple ICRs. CONCLUSIONS: The differential methylation in imprinting genes and in chr6p21-22 indicate the neurodevelopmental nature of 22q11.2DS-related SZ and the major role of MHC locus in the risk to develop SZ.


Assuntos
Síndrome de DiGeorge , Esquizofrenia , Adulto , Metilação de DNA/genética , Síndrome de DiGeorge/genética , Genoma , Impressão Genômica/genética , Humanos , Masculino , Esquizofrenia/genética
9.
Schizophr Res ; 231: 164-169, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33866261

RESUMO

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at risk for having both psychotic and immune disorders, thus, implying a possible link between the two. The aim of the current study was to evaluate the usefulness of the neutrophiles to leukocytes ratio (NLR), an inflammatory marker, as a bio-marker for overt and prodromal psychotic symptoms in 22q11.2DS. METHODS: Forty-nine individuals with 22q11.2DS (13 with psychotic disorders and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric evaluation using a structured psychiatric interview, the Scale of Prodromal Symptoms (SOPS) and the Global Assessment of Functioning (GAF) scale. Blood samples were collected from all participants on the day of assessment. NLR was calculated, compared among the study groups and correlated with SOPS and GAF scores. The non-psychotic 22q11.2DS group was further divided into high- and low-inflammation groups by NLR values and the analyses were done again. RESULTS: NLR was higher in the psychotic- and the high-inflammation non-psychotic 22q11.2DS groups compared to the low-inflammation non-psychotic 22q11.2DS group and controls. In the high-inflammation non-psychotic 22q11.2DS group NLR increase was associated with an increase of total negative symptoms scores on SOPS and a decrease in GAF scores. CONCLUSION: Our results suggest the potential utility of NLR as a bio-marker for psychotic disorders and subthreshold prodromal symptoms in 22q11.2DS. Furthermore, they imply that a disequilibrium between the innate and adaptive arms of the immune system facilitates the progression of psychosis in at risk populations. Further longitudinal studies are warranted to validate our findings, as this was a cross sectional observation.


Assuntos
Síndrome de DiGeorge , Transtornos Psicóticos , Estudos Transversais , Síndrome de DiGeorge/complicações , Humanos , Linfócitos , Neutrófilos
10.
J Neurodev Disord ; 13(1): 23, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126928

RESUMO

BACKGROUND: Pathways leading to psychosis in 22q11.2 deletion syndrome (22q11.2DS) have been the focus of intensive research during the last two decades. One of the common clinical risk factors for the evolution of psychosis in 22q11.2DS is the presence of positive and negative subthreshold psychotic symptoms. The gold standard for measuring subthreshold symptoms is the Structured Interview for Prodromal Syndromes (SIPS) and its accompanying Scale of Prodromal Symptoms (SOPS) ratings. Although the scale has been used by many centers studying 22q11.2DS, the inter-site reliability of the scale in this population has never been established. METHODS: In the present study, experienced clinical assessors from three large international centers studying 22q11.2DS independently rated video recordings of 18 adolescents and young adults with 22q11.2DS. RESULTS: The intraclass correlations coefficients (ICCs) among three raters for the SOPS total scores, as well as for the positive, negative, and disorganization subscale scores, were good-to-excellent (ICCs range 0.73-0.93). The raters were also able to reliably determine the subjects' subthreshold syndrome status (ICC = 0.71). The reliability of individual items was good-to-excellent for all items, ranging from 0.61 for motor disturbances [G3] to 0.95 for bizarre thinking. CONCLUSIONS: Our results show that trained clinicians can reliably screen for subthreshold psychotic symptoms in individuals with 22q11.2DS. To increase assessment reliability, we suggest specific clarifications and simplifications to the standard SIPS interview for future studies.


Assuntos
Transtorno do Espectro Autista , Síndrome de DiGeorge , Síndrome de Marfan , Transtornos Psicóticos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Adulto Jovem
11.
J Psychiatr Res ; 138: 319-325, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33894539

RESUMO

BACKGROUND: The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations. METHOD: We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures. RESULTS: Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression. CONCLUSION: The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions.


Assuntos
Aracnodactilia , Síndrome de DiGeorge , Síndrome de Marfan , Humanos , Israel , Reprodutibilidade dos Testes
12.
Brain Behav ; 11(8): e2221, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34213087

RESUMO

Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and interpretation, and IQ scores do not translate into insights on implicated brain systems that can link genes to behavior. Individuals with 22q11.2 deletion syndrome (22q11.2DS) often undergo IQ testing to address special needs, but access to testing in resource-limited settings is challenging. The brief Penn Computerized Neurocognitive Battery (CNB) provides measures of cognitive abilities related to brain systems and can screen for cognitive dysfunction. To examine the relation between CNB measures and IQ, we evaluated participants with the 22q11.2DS from Philadelphia and Tel Aviv (N = 117; 52 females; mean age 18.8) who performed both an IQ test and the CNB with a maximum of 5 years between administrations and a subsample (n = 24) who had both IQ and CNB assessments at two time points. We estimated domain-level CNB scores using exploratory factor analysis (including bifactor for overall scores) and related those scores (intraclass correlations (ICCs)) to the IQ scores. We found that the overall CNB accuracy score showed similar correlations between time 1 and time 2 as IQ (0.775 for IQ and 0.721 for CNB accuracy), correlated well with the IQ scores (ICC = 0.565 and 0.593 for time 1 and time 2, respectively), and correlated similarly with adaptive functioning (0.165 and 0.172 for IQ and CNB, respectively). We provide a crosswalk (from linear equating) between standardized CNB and IQ scores. Results suggest that one can substitute the CNB for IQ testing in future genetic studies that aim to probe specific domains of brain-behavior relations beyond IQ.


Assuntos
Aracnodactilia , Síndrome de DiGeorge , Síndrome de Marfan , Adolescente , Feminino , Humanos , Inteligência/genética , Testes de Inteligência
13.
Eur Psychiatry ; 55: 116-121, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30453155

RESUMO

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition characterized by high rates of psychiatric disorders. To our knowledge, this is the first study to assess psychiatric disorders in young children with 22q11DS using a structured psychiatric diagnostic interview, and one of few studies to use the complete gold standard diagnostic evaluation to examine the prevalence of autism spectrum disorder (ASD) in young children with 22q11DS and compare it to a matched control group with iASD. METHODS: We identified the psychiatric disorders and autistic phenotype of young children with 22q11DS (age 3-8 years) and compared them with those of age and sex-matched children with idiopathic autism (iASD). We used the gold standard psychiatric and ASD assessments including the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and a clinical examination by a child psychiatrist. RESULTS: Eighty-four percent of the children with 22q11DS had at least one psychiatric disorder, including anxiety disorders and ADHD, and 16% met strict criteria for ASD. Children with 22q11DS and ASD symptoms had less severe overall ASD symptoms than those with iASD. Children with 22q11DS, regardless of ASD diagnosis, were characterized by repetitive restricted behaviors. CONCLUSIONS: Our results highlight the need to screen for psychiatric disorders in 22q11DS and treat them already in preschool years.


Assuntos
Transtorno Autístico , Síndrome de DiGeorge , Transtornos Mentais , Transtorno Autístico/diagnóstico , Transtorno Autístico/epidemiologia , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/epidemiologia , Síndrome de DiGeorge/psicologia , Feminino , Humanos , Entrevista Psicológica/métodos , Israel/epidemiologia , Masculino , Programas de Rastreamento/métodos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Prevalência , Escalas de Graduação Psiquiátrica , Projetos de Pesquisa
14.
Eur Neuropsychopharmacol ; 26(10): 1610-8, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27524298

RESUMO

The 22q11.2 deletion syndrome (22q11DS) is associated with increased rates of psychotic disorders and cognitive deficits, but large scale studies are needed to elucidate their interaction. The objective of this two-center study was to identify the neurocognitive phenotype of individuals with 22q11DS and psychotic disorders. We hypothesized that psychotic 22q11DS individuals compared to nonpsychotic deleted individuals would have more severe neurocognitive deficits, especially in executive function and social cognition. These deficits would be present when compared to IQ- matched individuals with Williams Syndrome (WS). Three groups were ascertained from the Tel Aviv and Philadelphia centers: 22q11DS individuals with a psychotic disorder (n=31), nonpsychotic 22q11DS (n=86) and typically-developing controls (TD, n=828). In Tel Aviv a group of individuals with WS (n=18) matched in IQ to the 22q11DS psychotic group was also included. The Penn Computerized Neurocognitive Battery (CNB) was used to assess a wide-range of cognitive functions and all patients underwent structured psychiatric evaluations. 22q11DS individuals performed poorly on all CNB domains compared to TD. Participants with 22q11DS and psychosis, compared to nonpsychotic 22q11DS, had more severe deficits in global neurocognitive performance (GNP), executive function, social cognition and episodic memory domains. The primary deficits were also significant when comparing the Tel Aviv 22q11DS psychotic group to IQ-matched individuals with WS. In conclusion, 22q11DS individuals with a psychotic disorder have specific neurocognitive deficits that are reliably identified cross nationality using the CNB. These cognitive dysfunctions should be further studied as potential endophenotypes of psychosis in 22q11DS and as targets for intervention.


Assuntos
Cognição , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/psicologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/psicologia , Adolescente , Adulto , Criança , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Função Executiva , Feminino , Humanos , Testes de Inteligência , Israel , Masculino , Testes Neuropsicológicos , Philadelphia , Comportamento Social , Síndrome de Williams/psicologia , Adulto Jovem
15.
JAMA Psychiatry ; 72(4): 377-85, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25715178

RESUMO

IMPORTANCE: 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. OBJECTIVE: To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. DESIGN, SETTING, AND PARTICIPANTS: 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). MAIN OUTCOMES AND MEASURES: Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.


Assuntos
Transtornos Cognitivos/psicologia , Síndrome de DiGeorge/psicologia , Transtornos Psicóticos/psicologia , Adolescente , Fatores Etários , Criança , Cromossomos Humanos Par 22/genética , Transtornos Cognitivos/complicações , Síndrome de DiGeorge/complicações , Feminino , Humanos , Testes de Inteligência , Masculino , Testes Neuropsicológicos , Estudos Prospectivos , Transtornos Psicóticos/complicações , Fatores de Risco , Adulto Jovem
16.
J Psychiatr Res ; 47(11): 1623-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23910792

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia - P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val(158)Met (rs4680) and PRODH Gln(19)Pro (rs2008720) and Arg(185)Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.


Assuntos
Síndrome da Deleção 22q11/genética , Síndrome da Deleção 22q11/fisiopatologia , Catecol O-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único/genética , Prolina Oxidase/genética , Esquizofrenia/fisiopatologia , Estimulação Acústica , Adolescente , Adulto , Criança , Variação Contingente Negativa/genética , Endofenótipos , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Filtro Sensorial/genética , Adulto Jovem
17.
J Child Adolesc Psychopharmacol ; 21(6): 589-95, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22149470

RESUMO

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Síndrome de DiGeorge/tratamento farmacológico , Síndrome de DiGeorge/psicologia , Metilfenidato/efeitos adversos , Metilfenidato/uso terapêutico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Pressão Sanguínea/efeitos dos fármacos , Catecol O-Metiltransferase/genética , Pré-Escolar , Síndrome de DiGeorge/complicações , Feminino , Frequência Cardíaca/efeitos dos fármacos , Heterozigoto , Humanos , Hipercinese/tratamento farmacológico , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Adulto Jovem
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