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1.
J Clin Psychiatry ; 81(2)2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32237299

RESUMO

OBJECTIVE: To present a striking case of new-onset psychosis in a middle-aged woman subsequently diagnosed with behavioral variant frontotemporal dementia (bvFTD). To review the data regarding key red-flag features that may suggest a diagnosis of a neurodegenerative process, and specifically bvFTD, rather than a primary psychotic disorder. To examine the role of genetics, especially mutations of the microtubule-associated protein tau (MAPT) gene, in familial cases of frontotemporal dementia (FTD). DATA SOURCES: The pertinent literature was searched online (PubMed, Google Scholar) using the following search terms: frontotemporal dementia (FTD), Pick's disease, behavioral variant FTD (bvFTD), psychosis, delusions, MAPT, and genetics. No date or language limit was applied. STUDY SELECTION: The case report was generated through detailed assessment of clinical notes, imaging studies, and laboratory results. The brain autopsy was carried out and summarized by our neuropathology team. Previously published literature was selected for inclusion in the review section based on relevance to the topic. RESULTS: A neurodegenerative etiology for psychosis (and specifically bvFTD) should be suspected in patients with progressive deficits in executive function, language, or memory. Other key warning features include the presence of a strong family history of a late-life psychotic disorder (or institutional placement or suicide), loss of empathy, impaired recognition of facial expression, or the development of emotional blunting and apathy, abnormal movements, or seizures. CONCLUSIONS: Neurodegenerative disease should be on the differential diagnosis for any patient presenting with new-onset psychosis and behavioral changes in mid to late adulthood. Should red-flag features be present, early referral to a clinic specializing in dementia is recommended for further evaluation. This case highlights that MAPT mutations can be associated with psychosis in FTD and should be considered in the genetic workup. Ongoing research into the cellular and neural circuit mechanisms of psychosis in neurodegenerative disease may shed light on pathologic processes underlying psychosis in primary psychiatric disorders.


Assuntos
Delusões/diagnóstico , Demência Frontotemporal/diagnóstico , Transtornos Psicóticos/diagnóstico , Delusões/etiologia , Delusões/genética , Evolução Fatal , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Humanos , Pessoa de Meia-Idade , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/genética , Proteínas tau/genética
2.
BMC Psychiatry ; 20(1): 184, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321479

RESUMO

BACKGROUND: 3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family. CASE PRESENTATION: Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range. CONCLUSIONS: This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.


Assuntos
Deficiência Intelectual/genética , Transtornos Mentais/genética , Linhagem , Transtornos Psicóticos/genética , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/psicologia , Masculino , Transtornos Mentais/fisiopatologia , Fenótipo , Transtornos Psicóticos/diagnóstico , Qualidade de Vida , Síndrome
4.
PLoS One ; 15(3): e0230102, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160235

RESUMO

As emotion regulation deficits have been implicated in psychotic disorders, it is imperative to investigate not only the effect of regulation strategies but also how they are used. One such strategy is expressive suppression, the inhibition of emotion-expressive behavior, which may be influenced by social context. Therefore, this study aimed to investigate whether the use of expressive suppression was associated with social context and affect in daily life and if this differed between patients with psychosis and controls. Multilevel models using experience sampling method (ESM) data of 34 patients with psychotic disorders and 53 controls from the Genetic Risk and Outcome in Psychosis (GROUP) project were conducted. Expressive suppression and social context were assessed once a day for six days and daily affect was averaged per participant per day. Social context was significantly associated with the use of expressive suppression in daily life, so that the use of expressive suppression differed when in the presence of familiar versus non-familiar company when receiving negative feedback. This finding did not differ between patients and controls. This demonstrates that taking the situation into account when studying expressive suppression, and emotion regulation in general, may improve our understanding of how regulation takes place.


Assuntos
Transtornos Psicóticos/patologia , Meio Social , Adulto , Estudos de Casos e Controles , Emoções , Função Executiva , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo
5.
Neurobiol Aging ; 89: 83-88, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32007278

RESUMO

Psychotic symptoms are a common and debilitating feature of Alzheimer's disease (AD) and are associated with a more rapid course of decline. Current evidence from postmortem and neuroimaging studies implicates frontal, temporal, and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in 3 key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex, and superior temporal gyrus) in postmortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in the AS3MT gene-previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across 4 neighboring CpG sites in the ASM3T gene. Finally, our regional analysis nominated multiple CpG sites in TBX15 and WT1, which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Metilação de DNA/genética , Transtornos Psicóticos/genética , Doença de Alzheimer/complicações , Monoaminas Biogênicas/metabolismo , Ilhas de CpG/genética , Epigênese Genética , Variação Genética/genética , Humanos , Metiltransferases/genética , Transtornos Psicóticos/etiologia , Esquizofrenia/etiologia , Esquizofrenia/genética , Proteínas com Domínio T/genética , Proteínas WT1/genética
6.
Psychiatr Genet ; 30(2): 60-63, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32106127

RESUMO

Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.


Assuntos
Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Carnitina O-Palmitoiltransferase/genética , Estudos de Casos e Controles , Fator de Especificidade de Clivagem e Poliadenilação/genética , Variações do Número de Cópias de DNA/genética , Exoma , Feminino , Seguimentos , Predisposição Genética para Doença/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA , Irmãos , Gêmeos Monozigóticos/genética , Ubiquitina-Proteína Ligases/genética , Sequenciamento Completo do Exoma/métodos
8.
Am J Psychiatry ; 177(2): 155-163, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711302

RESUMO

OBJECTIVE: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. METHODS: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. RESULTS: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. CONCLUSIONS: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.


Assuntos
Predisposição Genética para Doença , Herança Multifatorial/genética , Transtornos Psicóticos/genética , Adolescente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Valor Preditivo dos Testes , Sintomas Prodrômicos , Fatores de Risco , Adulto Jovem
9.
Transl Psychiatry ; 9(1): 230, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530798

RESUMO

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Ventrículos Laterais/diagnóstico por imagem , Moléculas de Adesão de Célula Nervosa/genética , Transtornos Psicóticos/genética , Adulto , Alelos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/diagnóstico por imagem , Adulto Jovem
10.
Mutat Res ; 843: 73-80, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31421742

RESUMO

Intake of folate (vitamin B9) is strongly inversely linked with human cancer risk, particularly colon cancer. In general, people with the highest dietary intake of folate or with high blood folate levels are at a reduced risk (approx. 25%) of developing colon cancer. Folate acts in normal cellular metabolism to maintain genomic stability through the provision of nucleotides for DNA replication and DNA repair and by regulating DNA methylation and gene expression. Folate deficiency can accelerate carcinogenesis by inducing misincorporation of uracil into DNA, by increasing DNA strand breakage, by inhibiting DNA base excision repair capacity and by inducing DNA hypomethylation and consequently aberrant gene and protein expression. Conversely, increasing folate intake may improve genomic stability. This review describes key applications of single cell gel electrophoresis (the comet assay) in assessing genomic instability (misincorporated uracil, DNA single strand breakage and DNA repair capacity) in response to folate status (deficient or supplemented) in human cells in vitro, in rodent models and in human case-control and intervention studies. It highlights an adaptation of the SCGE comet assay for measuring genome-wide and gene-specific DNA methylation in human cells and colon tissue.


Assuntos
Monitoramento Biológico/métodos , Neoplasias do Colo/genética , Ensaio Cometa/métodos , Ácido Fólico/farmacologia , Instabilidade Genômica , Análise de Célula Única/métodos , Linhagem Celular , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/prevenção & controle , Quebras de DNA , Metilação de DNA , Reparo do DNA , Replicação do DNA , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/genética , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/genética , Genótipo , Homocistinúria/sangue , Homocistinúria/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Espasticidade Muscular/sangue , Espasticidade Muscular/genética , Transtornos Psicóticos/sangue , Transtornos Psicóticos/genética , Risco , Uracila/metabolismo
11.
Psychiatr Genet ; 29(5): 132-141, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31464994

RESUMO

Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.


Assuntos
Fatores de Transcrição Kruppel-Like/genética , Transtornos Psicóticos/genética , Psicotrópicos/efeitos adversos , Dedos de Zinco/genética , Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Polimorfismo de Nucleotídeo Único , Psicotrópicos/uso terapêutico , Esquizofrenia/genética
12.
Pharmacogenomics ; 20(11): 781-789, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31393222

RESUMO

Aim: Describe the characteristics of providers ordering, patients receiving, and clinical impact of a psychotropic pharmacogenetic test on veteran care. Patients & methods: Observational cohort study linking veterans' laboratory results to electronic health record data. Changes in psychotropic medication prescribing were measured as a function of test results. Results: A total of 38 providers tested 181 veterans between 10/6/2014 and 2/1/2018. Prescriptions for medications with severe gene-drug interactions decreased; however, 11 such medications were used after testing. For 43 patients, documentation of the results was missing. Conclusion: Most prescribing decisions were congruent with test results, but in a nontrivial number of cases, prescribers appeared not to act on the results. Poor result documentation impeded the potential of results to inform clinical care.


Assuntos
Farmacogenética , Testes Farmacogenômicos , Transtornos Psicóticos/tratamento farmacológico , Psicotrópicos/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Interações Medicamentosas , Prescrições de Medicamentos , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/genética , Psicotrópicos/efeitos adversos , Veteranos
13.
Genes Brain Behav ; 18(8): e12602, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31385409

RESUMO

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.


Assuntos
Estudo de Associação Genômica Ampla , Inteligência/genética , Transtornos Psicóticos/genética , Adulto , Cognição , Proteína Inibidora do Complemento C1/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
14.
Psychiatr Danub ; 31(2): 162-171, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291220

RESUMO

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.


Assuntos
Biomarcadores/análise , Transtornos Psicóticos/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Hidrocortisona/análise , Masculino , Farmacogenética , Estudos Prospectivos , Transtornos Psicóticos/complicações , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Saliva/química , Esquizofrenia/complicações
15.
Bipolar Disord ; 21(7): 650-659, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31343802

RESUMO

The evidence for efficacy of many currently available treatments for bipolar disorder is based on studies of nonrefractory patients with bipolar disorder. Therefore, not surprisingly, most treatment recommendations and guidelines for the treatment of bipolar disorder and its many comorbidities depend heavily on data from placebo controlled randomized clinical trials (RCTs), but these RCTs provide little direction for the clinician as to what next steps might be optimal in non- or partial-responders and in those with ongoing medical and psychiatric comorbidities. Given this and the paucity of RCTs at later treatment junctures, we thought it appropriate to begin a discussion of the quality of the data that some experts in the field might consider using in choosing and sequencing drugs and their combination. We acknowledge that many other clinical investigators may prefer very different sequences, but thought the suggestions offered here might be useful to some clinicians in the field, might start discussions of other options in the literature, and, at the same time, provide a preliminary outline for a new round of much-needed clinical trials to better inform clinical practice. Given the very wide range of the quality of the data and clinical principles on which the current suggestions are based, only minimal references are included and a comprehensive review of the literature supporting each option would be outside the scope of this manuscript.


Assuntos
Anticonvulsivantes/uso terapêutico , Antimaníacos/uso terapêutico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/terapia , Psicoterapia , Anquirinas/genética , Transtornos de Ansiedade/terapia , Canais de Cálcio Tipo L/genética , Doenças Cardiovasculares , Tomada de Decisão Clínica , Comorbidade , Monitoramento de Medicamentos , Quimioterapia Combinada , Eletroconvulsoterapia , Medicina Baseada em Evidências , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Testes Genéticos , Homocistinúria/genética , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/genética , Guias de Prática Clínica como Assunto , Transtornos Psicóticos/genética , Prevenção Secundária , Abandono do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias/terapia , Estimulação Magnética Transcraniana
16.
Tijdschr Psychiatr ; 61(6): 421-425, 2019.
Artigo em Holandês | MEDLINE | ID: mdl-31243752

RESUMO

Genetic factors play an important role in the development of psychotic disorders. With increasing evidence, several rare copy number variants (cnvs) have been identified as risk factors. We describe a patient who had two psychotic episodes during his adolescence. In this patient, a 16p11.2 duplication was detected. This duplication is a recurrent cnv associated with various somatic and psychiatric phenotypes including psychosis and schizophrenia. The potential clinical relevance of this finding is discussed.


Assuntos
Transtornos Psicóticos/genética , Adolescente , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Transtornos Psicóticos/diagnóstico , Adulto Jovem
17.
Eur J Med Genet ; 62(8): 103705, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31229682

RESUMO

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a hemizygous microdeletion on the long arm of chromosome 22 and is associated with a high risk for psychosis and cognitive impairment. One of the genes located in the deleted region of 22q11DS is Proline Dehydrogenase (PRODH) which is important for conversion of proline to glutamate. Glutamate is the primary excitatory neurotransmitter and is involved in the pathophysiology of psychosis as well as in cognition. Excessive concentrations are toxic. Possibly, neuroprotective drugs modulating glutamatergic neurotransmission could be effective in treating psychotic symptoms and cognitive enhancement in patients with 22q11DS. Riluzole is a potent anti-glutamatergic drug that reduces glutamatergic neurotransmission. Here we report acute (single dose) and long-term effects of riluzole on glutamate and GABA levels in the anterior cingulate cortex (ACC) and striatum (measured with magnetic resonance spectroscopy, 1H-MRS) as well as on psychotic symptoms and cognitive functioning in a medication-free 23-year old woman with 22q11DS. Patient presented with frequent auditory and visual hallucinations and mild paranoid ideas. The 1H-MRS measurements showed that after a single dose riluzole (50 mg), glutamate in the ACC and striatum was reduced whereas striatal GABA increased compared to baseline. Strikingly, hallucinations and paranoia disappeared. Therefore, riluzole treatment was initiated and patient was followed up after 18 months of treatment. At follow-up, patient reported no hallucinations or paranoia and several cognitive functions were improved. Furthermore, glutamate concentrations in the ACC and striatum decreased whereas GABA concentrations increased in the striatum but decreased in the ACC. These results suggests that riluzole may be an effective treatment option for psychotic symptoms and cognitive enhancement in 22q11DS. Results warrant replication in a bigger sample.


Assuntos
Síndrome de DiGeorge/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Riluzol/administração & dosagem , Adulto , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Prolina/metabolismo , Prolina Oxidase/genética , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Adulto Jovem
18.
Pathobiology ; 86(4): 190-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238314

RESUMO

OBJECTIVE: This study aims to investigate the association of 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase reductase (MTRR A66G) gene polymorphisms with neural tube defects (NTDs) in a Tunisian population. METHODS: Genotyping was performed by polymerase chain reaction with restriction fragment length polymorphisms (PCR-RFLPs) using the restriction enzymes. Allele and genotype frequencies were compared between mothers and fathers of fetuses with NTDs with matched controls based on an association analysis using SPSS software. RESULTS: MTHFR (C677T, A1298C) and MTRR A66G polymorphisms were found to be protector factors for NTD fetuses in the mother group. In addition, a combination of the three wild-type alleles C677/A1298/A66 has increased four-fold the incidence of NTDs (p = 0.004, OR = 3.96, 95% CI: 1.53-10.23). In the father group, MTHFR C677T was a risk factor for NTDs. However, no association was found between MTHFR A1298C, MTRR A66G, and the occurrence of this anomaly. The analysis of MTHFR C677T and MTRR A66G polymorphisms has demonstrated a significant difference in vitamin B12 levels between recessive and dominant genotypes in case mothers (p < 0.05). CONCLUSION: Additional studies are required to better understand the roles of parental gene polymorphisms related to folate-homocysteine metabolism in the pathogenesis of NTD.


Assuntos
Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único , Alelos , Pai , Feminino , Ácido Fólico/metabolismo , Genótipo , Homocisteína/metabolismo , Homocistinúria/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Mães , Espasticidade Muscular/genética , Defeitos do Tubo Neural/fisiopatologia , Polimorfismo de Fragmento de Restrição , Gravidez , Transtornos Psicóticos/genética , Tunísia
19.
Soc Psychiatry Psychiatr Epidemiol ; 54(9): 1045-1054, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31209522

RESUMO

PURPOSE: Whilst childhood trauma (CT) is a known risk factor across the spectrum of psychosis expression, little is known about possible interplay with genetic liability. METHODS: The TwinssCan Study collected data in general population twins, focussing on expression of psychosis at the level of subthreshold psychotic experiences. A multilevel mixed-effects linear regression analysis was performed including 745 subjects to assess the interaction between genetic liability and CT. The Symptom Checklist-90 (SCL-90-R) score of the co-twin was used as an indirect measure of genetic liability to psychopathology, while the Childhood Trauma Questionnaire Short-Form (CTQ-SF) was used to assess CT in the domains of physical, emotional and sexual abuse, as well as physical and emotional neglect. The Community Assessment of Psychic Experience (CAPE) questionnaire was used to phenotypically characterize psychosis expression. RESULTS: In the model using the CAPE total score, the interaction between CT and genetic liability was close to statistical significance (χ2 = 5.6, df = 2, p = 0.06). Analyses of CAPE subscales revealed a significant interaction between CT and genetic liability (χ2 = 8.8, df = 2, p = 0.012) for the CAPE-negative symptoms subscale, but not for the other two subscales (i.e. positive and depressive). CONCLUSION: The results suggest that the impact of CT on subthreshold expression of psychosis, particularly in the negative subdomain, may be larger in the co-presence of significant genetic liability for psychopathology.


Assuntos
Maus-Tratos Infantis/psicologia , Predisposição Genética para Doença/psicologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/psicologia , Adulto , Criança , Emoções , Feminino , Humanos , Masculino , Fatores de Risco , Inquéritos e Questionários , Avaliação de Sintomas
20.
Pharmacogenomics ; 20(8): 567-570, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31190622

RESUMO

Pharmacogenetic analysis to explain or predict the response of a specific patient to drug therapy is increasingly used in clinical practice. This holds especially true for CYP genotyping in psychiatry. We present a patient with genetic polymorphisms in more than one CYP450 enzyme, resulting in reduced effectiveness of CYP enzymes, explaining the high drug serum trough levels of antipsychotics and antidepressants and difficulty in optimizing therapy and dosing. Mrs X was found to be a CYP1A2, CYP2D6, CYP3A4 intermediate and in addition a CYP2C19 poor metabolizer. For Mrs X, pharmacogenetic analysis has contributed to reconsider choice and use of medication. Prior knowledge of the genetic polymorphisms in this patient might have avoided treatment delay and discomfort.


Assuntos
Antidepressivos/administração & dosagem , Antipsicóticos/administração & dosagem , Sistema Enzimático do Citocromo P-450/genética , Transtornos Psicóticos/tratamento farmacológico , Antidepressivos/efeitos adversos , Antidepressivos/sangue , Antipsicóticos/efeitos adversos , Antipsicóticos/sangue , Biomarcadores Farmacológicos/sangue , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Clozapina/sangue , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo Genético/genética , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/patologia
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