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1.
Transl Psychiatry ; 9(1): 67, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718458

RESUMO

Although various psychiatric disorders present with social-cognitive impairment, a measure assessing social-cognitive processes implicitly and reliably, with high selectivity and with enough signal-to-noise ratio (SNR) for individual evaluation of any population at any age, is lacking. Here we isolate a neural marker quantifying impaired visual coding of facial expression in individuals with 22q11.2 deletion syndrome (22q11DS) using frequency-tagging with electroencephalography (EEG). Twenty-two 22q11DS participants and 22 healthy controls were presented with changes of facial expression displayed at low, moderate, and high intensities every five cycles in a stream of one neutral face repeating 6 times per second (i.e., at a 6 Hz base rate). The brain response to expression changes tagged at the 1.2 Hz (i.e., 6 Hz/5) predefined frequency was isolated over occipito-temporal regions in both groups of participants for moderate- and high-intensity facial expressions. Neural sensitivity to facial expression was reduced by about 36% in 22q11DS, revealing impaired visual coding of emotional facial signals. The significance of the expression-change response was estimated for each single participant thanks to the high SNR of the approach. Further analyses revealed the high reliability of the response and its immunity from other neurocognitive skills. Interestingly, response magnitude was associated with the severity of positive symptoms, pointing to a potential endophenotype for psychosis risk. Overall, the present study reveals an objective, selective, reliable, and behavior-free signature of impaired visual coding of facial expression implicitly quantified from brain activity with high SNR. This novel tool opens avenues for clinical practice, providing a potential early biomarker for later psychosis onset and offering an alternative for individual assessment of social-cognitive functioning in even difficult-to-test participants.


Assuntos
Córtex Cerebral/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Emoções/fisiologia , Expressão Facial , Reconhecimento Facial/fisiologia , Percepção Social , Adolescente , Adulto , Disfunção Cognitiva/etiologia , Síndrome de DiGeorge/complicações , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto Jovem
2.
Arch Dis Child ; 104(1): 19-24, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29627765

RESUMO

OBJECTIVE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is characterised by wide phenotypic variability, including congenital heart disease (CHD), immunodeficiency and scoliosis. However, little is known regarding the prevalence and characteristics of scoliosis in patients with 22q11.2DS. The objective of this study is to assess the prevalence of scoliosis, its characteristics and the association with CHD in patients with 22q11.2DS. DESIGN: This prevalence study is based on physical examination and questionnaires of the world's largest 22q11.2DS longitudinal collected database (n=1393, Children's Hospital of Philadelphia) and was augmented with the scoliosis prevalence based on radiography in a smaller cohort (cross-sectional, University Medical Center Utrecht). PATIENTS: Patients with a laboratory-confirmed 22q11.2 deletion who visited the specialised outpatient clinics were considered for inclusion. MAIN OUTCOME MEASURES: (1) The prevalence of scoliosis, (2) its association with CHD, and (3) the similarity between 22q11.2DS curve patterns and adolescent idiopathic scoliosis (AIS) curve patterns. RESULTS: Within the Philadelphia cohort, the prevalence of scoliosis in patients older than 16 years (n=317) was 48% (n=152). A similar prevalence (49%) was shown for the younger Utrecht cohort (n=97). The occurrence of scoliosis was not associated with the presence of CHD. Sixty-three per cent of patients with scoliosis had a scoliotic curve pattern that resembled AIS. CONCLUSIONS: Clinicians should be aware that scoliosis is highly prevalent (48%-49%) in association with 22q11.2DS, irrespective of other clinical features (eg, the presence of CHD). Furthermore, 22q11.2DS may provide insights into the causes of AIS.


Assuntos
Síndrome de DiGeorge , Radiografia , Escoliose , Coluna Vertebral/diagnóstico por imagem , Adolescente , Correlação de Dados , Estudos Transversais , Bases de Dados Factuais/estatística & dados numéricos , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/epidemiologia , Síndrome de DiGeorge/fisiopatologia , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/etiologia , Humanos , Masculino , Países Baixos/epidemiologia , Radiografia/métodos , Radiografia/estatística & dados numéricos , Escoliose/diagnóstico , Escoliose/epidemiologia , Escoliose/etiologia , Estados Unidos/epidemiologia
3.
J Neurosci ; 39(7): 1301-1319, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30478034

RESUMO

The 22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional connectivity MRI studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of human youth with 22q11DS (n = 42; 59.5% female) and demographically matched healthy controls (n = 39; 53.8% female). Neuroimaging data were acquired via single-band protocols and analyzed in line with methods provided by the Human Connectome Project. We computed functional relationships between individual-specific anatomically defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain Type I error protection was achieved through nonparametric permutation-based methods. The 22q11DS patients displayed dissociable disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamocortical coupling was increased in somatomotor regions and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to somatomotor and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggests that high genetic risk for psychiatric illness is linked with disruptions in large-scale corticosubcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect copy number variants for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENT Investigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. The 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a dissociable fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Hipocampo/fisiopatologia , Tálamo/fisiopatologia , Adolescente , Adulto , Envelhecimento/psicologia , Criança , Conectoma , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Hipocampo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Neuroimagem , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/fisiopatologia , Tálamo/diagnóstico por imagem , Adulto Jovem
4.
Neuroimage ; 190: 154-171, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30195053

RESUMO

The 22q11.2 deletion is one of the most common copy number variants in humans. Carriers of the deletion have a markedly increased risk for neurodevelopmental brain disorders, including schizophrenia, autism spectrum disorders, and attention deficit hyperactivity disorder. The high risk of psychiatric disorders associated with 22q11.2 deletion syndrome offers a unique possibility to identify the functional abnormalities that precede the emergence of psychosis. Carriers of a 22q11.2 deletion show a broad range of sensory processing and cognitive abnormalities similar as in schizophrenia, such as auditory and visual sensory processing, response inhibition, working memory, social cognition, reward processing and arithmetic processing. All these processes have a significant negative impact on daily life if impaired and have been studied extensively in schizophrenia using task-based functional neuroimaging. Here, we review task-related functional brain mapping studies that have used electroencephalography or functional magnetic resonance imaging to identify functional alterations in carriers with 22q11.2 deletion syndrome within the above mentioned cognitive and sensory domains. We discuss how the identification of functional changes at the brain system level can advance the general understanding of which neurobiological alterations set the frame for the emergence of neurodevelopmental disorders in the human brain. The task-based functional neuroimaging literature shows conflicting results in many domains. Nevertheless, consistent similarities between 22q11.2 deletion syndrome and schizophrenia have been found for sensory processing, social cognition and working memory. We discuss these functional brain alterations in terms of potential biomarkers of increased risk for psychosis in the general population.


Assuntos
Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Potenciais Evocados/fisiologia , Neuroimagem Funcional , Transtornos da Percepção/fisiopatologia , Esquizofrenia/fisiopatologia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico por imagem , Suscetibilidade a Doenças/diagnóstico por imagem , Suscetibilidade a Doenças/fisiopatologia , Humanos , Transtornos da Percepção/diagnóstico por imagem , Transtornos da Percepção/etiologia , Esquizofrenia/diagnóstico por imagem
5.
Genes Brain Behav ; 18(4): e12523, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30267483

RESUMO

Hemizygous microdeletion at the chromosomal locus 22q11.2 is a copy number variation with strong genetic linkage to schizophrenia and related disorders. This association, along with its phenotypic overlap with the 22q11.2 microdeletion syndrome, has motivated the establishment of Df[h22q11]/+ mice, in which the human 22q11.2 orthologous region is deleted. Previous investigations using this model showed the presence of reduced prepulse inhibition (PPI) of the acoustic startle reflex, a form of sensorimotor gating known to be impaired in a number of psychiatric disorders. Concomitantly to reduced PPI, however, Df[h22q11]/+ mice are also characterized by a robust increase in baseline startle reactivity, which may complicate or confound the interpretation of PPI. Therefore, the present study re-examined the relationship between acoustic startle reactivity and PPI in this mouse model. We found that while PPI is reduced in Df[h22q11]/+ mice when using its relative indexation (ie, % PPI), this deficit is no longer apparent when using the absolute quantification, that is, the direct comparison between pulse-alone and prepulse-plus-pulse conditions with successively increasing prepulse intensities. We further identified marked negative correlations between % PPI and startle reactivity in Df[h22q11]/+ mice. Moreover, when stratifying Df[h22q11]/+ mice into subgroups displaying low- and high-startle reactivity, only the latter subgroup displayed a significant reduction in % PPI. Collectively, our data suggest that alterations in baseline startle reactivity can confound the outcomes and interpretation of PPI in this mouse model of the human 22q11.2 microdeletion syndrome.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Inibição Neural , Reflexo de Sobressalto , Animais , Duplicação Cromossômica , Cromossomos Humanos Par 22 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tempo de Reação
6.
Colomb Med (Cali) ; 49(3): 219-222, 2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30410196

RESUMO

Introduction: Deletion 22q11.2 occurs in 1:4,000-1:6,000 live births while 10p13p14 deletion is found in 1:200,000 newborns. Both deletions have similar clinical features such as congenital heart disease and immunological anomalies. Objective: We looked for a 22q11.2 deletion in Mexican patients with craniofacial dysmorphisms suggestive of DiGeorge or velocardiofacial syndromes and at least one major phenotypic feature (cardiac anomaly, immune deficiency, palatal defects or development delay). Methods: A prospective study of 39 patients recruited in 2012-2015 at the Instituto Mexicano del Seguro Social at Guadalajara, Mexico. The patients with velocardiofacial syndrome-like features or a confirmed tetralogy of Fallot (TOF) or complex cardiopathy were studied by G-banding and fluorescence in situ hybridization (FISH) with a dual TUPLE1(HIRA)/ARSA or TUPLE1(22q11)/22q13(SHANK3) probe, six patients without the 22q11.2 deletion (arbitrarily selected) were tested with the dual DiGeorge II (10p14)/D10Z1 probe. Results: Twenty-two patients (7 males and 15 females) had the 22q11.2 deletion and 17/39 did not have it; no patient had a 10p loss. Among the 22 deleted patients, 19 had congenital heart disease (mostly TOF). Twelve patients without deletion had heart defects such as TOF (4/12), isolate ventricular septal defect (2/12) or other disorders (6/12). Conclusion: In our small sample about ~56% of the patients, regardless of the clinical diagnosis, had the expected 22q11.2 deletion. We remark the importance of early cytogenetic diagnosis in order to achieve a proper integral management of the patients and their families.


Assuntos
Síndrome de DiGeorge/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hibridização in Situ Fluorescente , Tetralogia de Fallot/diagnóstico , Adolescente , Criança , Pré-Escolar , Análise Citogenética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatologia , Feminino , Cardiopatias Congênitas/genética , Comunicação Interventricular/diagnóstico , Comunicação Interventricular/genética , Humanos , Lactente , Masculino , México , Estudos Prospectivos , Tetralogia de Fallot/genética , Adulto Jovem
7.
Transl Psychiatry ; 8(1): 247, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429456

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d'). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0-1.0 mg/kg, i.p.) dose-dependently improved d' in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d' impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.


Assuntos
Atenção/fisiologia , Comportamento Animal/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Disfunção Cognitiva/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Sincronização de Fases em Eletroencefalografia/fisiologia , Função Executiva/fisiologia , Hipocampo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Desempenho Psicomotor/fisiologia , Anfetamina/farmacologia , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/administração & dosagem , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Função Executiva/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Modafinila/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos
8.
Am J Med Genet B Neuropsychiatr Genet ; 177(8): 765-773, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30444066

RESUMO

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness.


Assuntos
Percepção Auditiva/genética , Cognição/fisiologia , Síndrome de DiGeorge/fisiopatologia , Síndrome da Deleção 22q11/genética , Síndrome da Deleção 22q11/fisiopatologia , Adolescente , Adulto , Transtornos da Percepção Auditiva/genética , Criança , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Transtornos do Humor/genética , Música/psicologia , Testes Neuropsicológicos , Sintomas Prodrômicos , Psicopatologia/métodos , Transtornos Psicóticos/genética , Esquizofrenia/genética , Comportamento Social , Adulto Jovem
9.
Am J Med Genet A ; 176(10): 2140-2145, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30365873

RESUMO

Children with 22q11.2 deletion syndrome often come to medical attention due to signs and symptoms of neurologic dysfunction. It is imperative to understand the expected neurologic development of patients with this diagnosis in order to be alert for the potential neurologic complications, including cortical malformations, tethered cord, epilepsy, and movement disorders. We present an update of brain imaging findings from the CHOP 22q and You Center, a review of the current literature, and our current management practices for neurological issues.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Doenças do Sistema Nervoso/genética , Síndrome de DiGeorge/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/fisiopatologia
10.
Am J Med Genet A ; 176(10): 2128-2134, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30207636

RESUMO

Otorhinolaryngologic manifestations are common in 22q11.2 deletion syndrome (22q11.2DS), but poorly described. This study aimed to better define the ear-nose-throat (ENT) phenotype of 22q11.2DS patients, in the attempt to best detect subjects requiring subspecialist intervention. We enrolled 25 patients affected with 22q11.2DS. Anatomic and functional ENT findings were investigated using clinical, laboratory, and instrumental data. Immunophenotype and frequency of infections were evaluated. Univariate and multivariate analyses were performed. ENT anomalies were found in 88% of patients, and in 20% congenital palate defects required surgery. Adenoid or palatine tonsil hypertrophy was noted in 80% and 48%. Forty-eight percent of subjects had rhinolalia/phonia, severe in half of these. We also found nasal regurgitation or laryngeal penetration/aspiration in 20% and 16%, respectively. Instrumental exams revealed a mild conductive hearing loss in 32% (bilateral in most cases), tympanometric anomalies in 28%, and swallowing abnormalities in 16%. Statistical univariate analysis showed a direct association between rhinolalia/phonia and episodes of laryngeal aspiration (p = .016) and between tympanometric anomalies and increased adenoid volume (p = .044). No association between episodes of food aspiration and palatal anomalies was found. Moreover, no statistically significant association was observed between the number of airway infections and the ENT findings. This study contributes to better define the ENT phenotype in patients with 22q11.2DS, helpful to prevent potential complications. Furthermore, the identification of a subcategory of patients may allow the early adoption of specific speech therapy programs to improve the clinical outcome of 22q11.2DS patients.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Orelha/anormalidades , Nariz/anormalidades , Faringe/anormalidades , Fenótipo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto Jovem
11.
Cortex ; 108: 67-79, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30130634

RESUMO

Chromosome 22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome characterized by a variety of cognitive impairments, including difficulty with attention. 22q11DS is the strongest known genetic risk factor for developing schizophrenia, a disorder characterized by impairments in visual attention and temporal binding processes. Here we examine a specific temporal visual attention phenomenon (the attentional blink; AB) within two rapid serial visual presentation tasks, and compare those with 22q11DS to groups of typically developing individuals matched on chronological (CA) and mental age (MA). Performance of individuals with 22q11DS was sensitive to differing task demands. On a Category Task, individuals with 22q11DS performed similarly to control groups on all measures of the AB, with the exception of lower detection accuracy of the first of two targets. In contrast, on a feature-based Color Task which required temporal binding of stimulus features, individuals with 22q11DS differed from CA and MA matched control groups on all AB performance measures, exhibiting lower target accuracy, more temporal binding errors, and a deeper, more protracted AB. Temporal binding in the visual domain is thought to be dependent on a serial attention mechanism that facilitates simultaneous firing of neurons in multiple areas of the visual cortex, activating short-term working memory for storage of bound features. Given the discrepancy between these two tasks, results suggest that temporal binding processes may be significantly affected in individuals with 22q11DS, a finding that importantly, has been previously demonstrated among individuals with schizophrenia.


Assuntos
Intermitência na Atenção Visual/fisiologia , Síndrome de DiGeorge/fisiopatologia , Percepção Visual/fisiologia , Adolescente , Atenção/fisiologia , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Adulto Jovem
12.
J Craniofac Surg ; 29(6): 1480-1485, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30052607

RESUMO

The most frequent palate diagnoses in patients with chromosome 22q11.2 deletion syndrome are a classic submucous cleft, occult, and velopharyngeal insufficiency without cleft, which generates alterations in speech that require surgery. Surgical protocols are controversial owing to syndrome characteristics that make their handling more complex. Pharyngeal flap pharyngoplasty is effective for this type of patient. The objective of this study is to examine the surgical management of velopharyngeal insufficiency in patients with chromosome 22 deletion, using a pharyngeal flap as the primary surgery. The clinical records of patients with chromosome 22 deletion and velopharyngeal insufficiency between 2015 and 2017 were analyzed retrospectively. Eight patients underwent pharyngeal flap pharyngoplasty as a primary surgery, including 1 with velopharyngeal insufficiency without a cleft, 1 with a classic submucous cleft, and 6 with occult submucous cleft. The pre- and postoperative protocol performed by speech therapists and surgeons included clinical evaluation of the oral cavity; perceptual, video recording, and nasometry speech evaluation; and videonasopharyngoscopy. All perceptual parameters and nasometry results significantly changed. Of the cases, 88% achieved a flap with the expected width and height and complete closure of the velopharyngeal sphincter. One patient required flap revision. Four of the 8 patients achieved normal resonance, and 2 of 8 showed mild hypernasality. Using the pharyngeal flap pharyngoplasty as a primary technique to correct velopharyngeal insufficiency in patients with chromosome 22 deletion provides satisfactory outcomes and decreases the number of surgeries. Preoperative planning must be conducted carefully and needs to be individualized to be successful.


Assuntos
Fissura Palatina , Síndrome de DiGeorge , Faringe/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Insuficiência Velofaríngea , Adulto , Criança , Cromossomos Humanos Par 22/genética , Fissura Palatina/diagnóstico , Fissura Palatina/cirurgia , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/fisiopatologia , Síndrome de DiGeorge/cirurgia , Feminino , Humanos , Masculino , Planejamento de Assistência ao Paciente , Estudos Retrospectivos , Fala , Testes de Articulação da Fala/métodos , Retalhos Cirúrgicos , Resultado do Tratamento , Insuficiência Velofaríngea/diagnóstico , Insuficiência Velofaríngea/genética , Insuficiência Velofaríngea/cirurgia , Esfíncter Velofaríngeo/fisiopatologia , Gravação em Vídeo
13.
Am J Med Genet A ; 176(8): 1735-1741, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30055034

RESUMO

22q deletion syndrome (22q11.2DS) is most often correlated prenatally with congenital heart disease and or cleft palate. The extracardiac fetal phenotype associated with 22q11.2DS is not well described. We sought to review both the fetal cardiac and extracardiac findings associated with a cohort of cases ascertained prenatally, confirmed or suspected to have 22q11.2DS, born and cared for in one center. A retrospective chart review was performed on a total of 42 cases with confirmed 22q11.2DS to obtain prenatal findings, perinatal outcomes and diagnostic confirmation. The diagnosis was confirmed prenatally in 67% (28/42) and postnatally in 33% (14/42). The majority (81%) were associated with the standard LCR22A-LCR22D deletion. 95% (40/42) of fetuses were prenatally diagnosed with congenital heart disease. Extracardiac findings were noted in 90% (38/42) of cases. Additional findings involved the central nervous system (38%), gastrointestinal (14%), genitourinary (16.6%), pulmonary (7%), skeletal (19%), facial dysmorphism (21%), small/hypoplastic thymus (26%), and polyhydramnios (30%). One patient was diagnosed prenatally with a bilateral cleft lip and cleft palate. No fetus was diagnosed with intrauterine growth restriction. The average gestational age at delivery was 38 weeks and average birth weight was 3,105 grams. Sixty-two percentage were delivered vaginally and there were no fetal demises. A diagnosis of 22q11.2 deletion syndrome should be considered in all cases of prenatally diagnosed congenital heart disease, particularly when it is not isolated. Microarray is warranted in all cases of structural abnormalities diagnosed prenatally. Prenatal diagnosis of 22q11.2 syndrome can be used to counsel expectant parents regarding pregnancy outcome and guide neonatal management.


Assuntos
Síndrome de DiGeorge/diagnóstico , Doenças Fetais/diagnóstico , Cardiopatias Congênitas/diagnóstico , Diagnóstico Pré-Natal , Adulto , Fissura Palatina/diagnóstico , Fissura Palatina/diagnóstico por imagem , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatologia , Feminino , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/genética , Doenças Fetais/fisiopatologia , Feto/diagnóstico por imagem , Feto/fisiopatologia , Aconselhamento Genético/métodos , Idade Gestacional , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Recém-Nascido , Fenótipo , Gravidez , Resultado da Gravidez , Ultrassonografia Pré-Natal
14.
J Craniofac Surg ; 29(7): 1709-1712, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29863556

RESUMO

Velocardiofacial syndrome (VCFs) is a rare congenital disease with an incidence of 1:4000 to 1:6000. Previous studies have found that the abnormality is associated with 22qDS. As reported at the international VCFs conference held in 2006, >180 phenotypes have been identified with this syndrome. Accordingly, there is a wide range of clinical manifestations including congenital defects of the heart and palate, immune deficiencies, psychiatric illness, and speech, learning, and cognitive disabilities Among all the symptoms above, however, pharyngopalatine dysplasia has been observed in nearly every patient. Patients with VCFs often have velopharyngeal insufficiency, which may cause serious disorders in functional speech, with poor intelligibility, a glottal stop with hypernasality and a pharyngeal fricative, and dropping and weakening of consonants. Most also show defects in language learning. Therefore, specialized speech therapy is essential for patients with VCFs, mainly focused on correction of abnormal pronunciation. Long-term clinical experience has shown that speech therapy is based on 2 components: velopharyngeal function and behavior therapy. Our study focused mainly on establishing a corrective behavior guidance model of pronunciation for patients with VCFs.


Assuntos
Síndrome de DiGeorge/reabilitação , Palato Mole/cirurgia , Faringe/cirurgia , Cuidados Pós-Operatórios/métodos , Fonoterapia/métodos , Fala/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/fisiopatologia , Síndrome de DiGeorge/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Fatores de Tempo , Adulto Jovem
15.
Hum Mol Genet ; 27(14): 2454-2465, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29726930

RESUMO

The 17 genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants. The p.R20Q variant is shared by three affected family members in an autosomal dominant manner; the fourth unrelated individual has a de novo p.R305H mutation. Bioinformatics analyses indicate that these variants are rare and predict them to be damaging. In vitro transcriptional assays in cultured cells show that both variants result in reduced transcriptional repressor activity of TBX2. We also show that the variants result in reduced protein levels of TBX2. Heterologous over-expression studies in Drosophila demonstrate that both p.R20Q and p.R305H function as partial loss-of-function alleles. Hence, these and other data suggest that TBX2 is a novel candidate gene for a new multisystem malformation disorder.


Assuntos
Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Predisposição Genética para Doença , Proteínas com Domínio T/genética , Adulto , Animais , Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Criança , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Modelos Animais de Doenças , Drosophila melanogaster , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Camundongos , Linhagem , Gravidez , Adulto Jovem , Peixe-Zebra
16.
Am J Med Genet A ; 176(10): 2146-2159, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29777584

RESUMO

Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at elevated risk of developing treatable psychiatric and neurological disorders, including anxiety disorders, schizophrenia, seizures, and movement disorders, often beginning in adolescence or early to mid-adulthood. Here, we provide an overview of neuropsychiatric features associated with 22q11.2DS in adulthood. Results of a new case series of 13 individuals with 22q11.2DS and catatonic features together with 5 previously reported cases support a potential association of this serious psychomotor phenotype with the 22q11.2 deletion. As in the general population, catatonic features in 22q11.2DS occurred in individuals with schizophrenia, other psychotic and non-psychotic psychiatric disorders, and neurological disorders like Parkinson's disease. We place the results in the context of an updated review of catatonia in other genetic conditions. The complex neuropsychiatric expression and risk profile of 22q11.2DS highlights the need to consider co-morbid factors and provide care tailored to the individual patient. The results reinforce the need for periodic monitoring for the emergence of psychiatric and neurological manifestations including catatonic features. Pending further research, enhanced recognition and informed anticipatory care promise to facilitate the early diagnosis that allows for timely implementation and optimization of effective treatments.


Assuntos
Catatonia/genética , Síndrome de DiGeorge/genética , Transtornos Mentais/genética , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Síndrome de DiGeorge/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
J Neurodev Disord ; 10(1): 13, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29631546

RESUMO

BACKGROUND: Social impairments are described as a common feature of the 22q11.2 deletion syndrome (22q11DS). However, the neural correlates underlying these impairments are largely unknown in this population. In this study, we investigated neural substrates of socio-emotional perception. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to explore neural activity in individuals with 22q11DS and healthy controls during the visualization of stimuli varying in social (social or non-social) or emotional (positive or negative valence) content. RESULTS: Neural hyporesponsiveness in regions of the default mode network (inferior parietal lobule, precuneus, posterior and anterior cingulate cortex and frontal regions) in response to social versus non-social images was found in the 22q11DS population compared to controls. A similar pattern of activation for positive and negative emotional processing was observed in the two groups. No correlation between neural activation and social functioning was observed in patients with the 22q11DS. Finally, no social × valence interaction impairment was found in patients. CONCLUSIONS: Our results indicate atypical neural correlates of social perception in 22q11DS that appear to be independent of valence processing. Abnormalities in the social perception network may lead to social impairments observed in 22q11DS individuals.


Assuntos
Encéfalo/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Síndrome de DiGeorge/psicologia , Emoções/fisiologia , Percepção Social , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Criança , Síndrome de DiGeorge/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Tempo de Reação , Percepção Visual/fisiologia , Adulto Jovem
18.
Cogn Neuropsychol ; 35(7): 352-360, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29642756

RESUMO

Recent models of visuospatial (VSSP) short-term memory postulate the existence of two dissociable mechanisms depending on whether VSSP information is presented simultaneously or sequentially. However, they do not specify to what extent VSSP short-term memory is under the influence of general VSSP processing. This issue was examined in people with 22q11.2 deletion syndrome, a genetic condition involving a VSSP deficit. The configuration of VSSP information was manipulated (structured vs. unstructured) to explore the impact of arrangement on VSSP short-term memory. Two presentation modes were used to see whether the VSSP arrangement has the same impact on simultaneous and sequential short-term memory. Compared to children matched on chronological age, children with 22q11.2 deletion syndrome showed impaired performance only for structured arrangement, regardless of the presentation mode, suggesting an influence of VSSP processing on VSSP short-term memory abilities. A revised cognitive architecture for a model of VSSP short-term memory is proposed.


Assuntos
Síndrome de DiGeorge/fisiopatologia , Memória de Curto Prazo , Processamento Espacial , Percepção Visual , Adolescente , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Humanos , Masculino
19.
Hum Mol Genet ; 27(11): 1847-1857, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29509905

RESUMO

Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS.


Assuntos
Desenvolvimento Embrionário/genética , Cardiopatias Congênitas/genética , Coração/crescimento & desenvolvimento , Proteínas com Domínio T/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Animais , Aorta/fisiopatologia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Coração/fisiopatologia , Cardiopatias Congênitas/patologia , Recombinação Homóloga/genética , Humanos , Meiose/genética , Camundongos , Mutação , Persistência do Tronco Arterial/genética , Persistência do Tronco Arterial/fisiopatologia
20.
Schizophr Bull ; 44(suppl_2): S525-S535, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29548017

RESUMO

Converging evidence suggests that psychosis emerges from the complex interaction of genetic and environmental factors. Stressful life events (SLEs) play a prominent role in combination with coping strategies and with a dysfunctional hypothalamus-pituitary-adrenal axis (HPAA). It has been proposed that the framework of schizotypy might help disentangle the interaction between genetic and environmental factors in the pathogenesis of psychosis. Similarly, 22q11.2 deletion syndrome (22q11DS) is considered as a genetic model of psychosis vulnerability. However, SLE and coping strategies remain largely unexplored in 22q11DS. Moreover, the HPAA has not been systematically investigated in this population. Here, we explored the correlation between SLE, emotional coping strategies, schizotypal personality traits, subthreshold psychotic symptoms in a sample of 43 healthy controls (HCs) compared with 59 individuals with 22q11DS. In the latter, we also explored the correlation with pituitary volume as estimated from structural magnetic resonance imaging. We found that SLE and negative coping strategies were correlated with schizotypal personality traits in both HCs and 22q11DS, and with psychotic symptoms in the 22q11DS group only, whereas reduced pituitary volume correlated with general psychopathology. Moreover, dysfunctional coping mediated the effect of SLE on schizotypal personality traits and psychotic symptoms in 22q11DS. Our findings recapitulate evidence in nonsyndromic patients and confirm the central role of stress and coping in the pathogenesis of psychosis. More broadly, they highlight the importance of environmental factors in the pathway to psychosis in 22q11DS, suggesting a strong rationale for the implementation of stress and particularly coping-oriented interventions in this population.


Assuntos
Adaptação Psicológica/fisiologia , Síndrome de DiGeorge/fisiopatologia , Hipófise/anatomia & histologia , Transtornos Psicóticos/fisiopatologia , Transtorno da Personalidade Esquizotípica/fisiopatologia , Estresse Psicológico/fisiopatologia , Adolescente , Adulto , Criança , Estudos Transversais , Síndrome de DiGeorge/complicações , Feminino , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Hipófise/diagnóstico por imagem , Transtornos Psicóticos/etiologia , Transtorno da Personalidade Esquizotípica/etiologia , Estresse Psicológico/complicações , Adulto Jovem
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