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1.
Hum Mol Genet ; 31(4): 625-637, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-34559195

RESUMO

Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22/genética , Estudos de Associação Genética , Humanos
2.
Am J Med Genet A ; 191(8): 2015-2044, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37392087

RESUMO

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.


Assuntos
Transtornos Cromossômicos , Humanos , Fenótipo , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Deleção Cromossômica , Proteínas do Tecido Nervoso/genética , Cromossomos Humanos Par 22/genética
3.
J Clin Child Adolesc Psychol ; : 1-15, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37706638

RESUMO

OBJECTIVE: To examine predictors of implementation and perceived usefulness of four empirically supported strategies for treating externalizing behavior in youths with ASD. METHOD: Participants were 557 providers in the United States with experience treating externalizing behavior in youths with ASD. Generalized estimating equations were used to determine whether self-reported use and usefulness of four empirically supported intervention strategies (functional communication training, functional behavior analysis, visual tools/supports, token economy) were predicted by key provider characteristics: professional discipline, experience, and practice specialization (across three indices) in ASD. Post-hoc contrasts were performed to identify provider groups reporting the greatest use and usefulness of the four strategies. RESULTS: Strategies were most often used by providers with behavioral backgrounds, though perceived usefulness of strategies varied by providers' professional discipline. Compared to providers with more than 10 years of experience, less experienced providers endorsed the highest average use and usefulness of almost all strategies. Regarding ASD practice specialization, a lower volume of ASD cases, treating fewer youths with ASD over a 5-year period, and having a higher proportion of practice time working with youths with ASD reported were associated with greater use and usefulness of the strategies. CONCLUSIONS: Empirically supported strategies are widely used by and perceived as useful by providers who treat youths with ASD and co-occurring externalizing behaviors. Use and usefulness varies based on provider discipline, experience, and ASD practice specialization.

4.
Cogn Dev ; 582021.
Artigo em Inglês | MEDLINE | ID: mdl-33833479

RESUMO

Testing cognitive skill development is important for diagnostic, prognostic, and monitoring purposes, especially for young children and individuals with neurodevelopmental disorders. Developmental tests have been created for infants and toddlers, while traditional IQ tests are often employed beginning in the later preschool period. However, IQ tests rely on developmental skills that are rapidly changing during early childhood. Here, we introduce the idea of prerequisite skills in developmental domains, which are discrete skills required for, but not explicitly tested by, traditional IQ tests. Focusing on general cognition, particularly among children with a chronological or mental age under 4 years, may fail to capture important nuances in skill development. New skill-based assessments are needed in general, and in particular for categorization, which is foundational to higher-order cognitive skills. Novel measures quantifying categorization skills would provide a more sensitive measure of development for young children and older individuals with low developmental levels.

5.
J Clin Child Adolesc Psychol ; 48(sup1): S247-S268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29384389

RESUMO

Understanding usual care is important to reduce health disparities and improve the dissemination of evidence-based practices for youth (ages 7-22 years) with autism spectrum disorder (ASD). A barrier to describing "usual ASD care" is the lack of a common vocabulary and inventory of the practices used by a diverse provider field. To address this barrier, we gathered input from expert providers to develop an inventory of usual care practices and assess expert familiarity and perceptions of these practices as interventions for anxiety, externalizing, and social difficulties in ASD. Purposeful sampling recruited 66 expert ASD providers representing multiple disciplines from 5 sites. Via a 2-round Delphi poll, experts reviewed, suggested revisions to and rated 49 literature-derived practices on several dimensions (familiarity, usefulness, common use, research support). A revised list of 55 practices and anonymous summary of group characteristics and ratings was then returned for further review. Results yielded 55 intervention practices, 48 of which were identified as "familiar" approaches by consensus (≥ 75% endorsement). Greater variation was observed in practices identified by consensus as most often used, useful, and research supported, depending upon the target problem. Findings provide an inventory of practices, reflective of the multidisciplinary language and approaches of expert ASD providers. This inventory may be used to better assess what constitutes usual care for youth with ASD in the United States. Moreover, findings offer insights from clinical experts regarding the range and acceptability of practices that may inform and ground treatment research, dissemination, and implementation efforts.


Assuntos
Transtorno do Espectro Autista/terapia , Adolescente , Adulto , Criança , Consenso , Técnica Delphi , Feminino , Humanos , Masculino , Instituições Acadêmicas , Adulto Jovem
6.
Eur J Neurosci ; 47(6): 592-601, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28452081

RESUMO

Autism spectrum disorder (ASD) is marked by both socio-communicative difficulties and abnormalities in sensory processing. Much of the work on sensory deficits in ASD has focused on tactile sensations and the perceptual aspects of somatosensation, such as encoding of stimulus intensity and location. Although aberrant pain processing has often been noted in clinical observations of patients with ASD, it remains largely uninvestigated. Importantly, the neural mechanism underlying higher order cognitive aspects of pain processing such as pain anticipation also remains unknown. Here we examined both pain perception and anticipation in high-functioning adults with ASD and matched healthy controls (HC) using an anticipatory pain paradigm in combination with functional magnetic resonance imaging (fMRI) and concurrent skin conductance response (SCR) recording. Participants were asked to choose a level of electrical stimulation that would feel moderately painful to them. Compared to HC group, ASD group chose a lower level of stimulation prior to fMRI. However, ASD participants showed greater activation in both rostral and dorsal anterior cingulate cortex during the anticipation of stimulation, but not during stimulation delivery. There was no significant group difference in insular activation during either pain anticipation or perception. However, activity in the left anterior insula correlated with SCR during pain anticipation. Taken together, these results suggest that ASD is marked with aberrantly higher level of sensitivity to upcoming aversive stimuli, which may reflect abnormal attentional orientation to nociceptive signals and a failure in interoceptive inference.


Assuntos
Antecipação Psicológica/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Giro do Cíngulo/fisiopatologia , Percepção da Dor/fisiologia , Adulto , Transtorno do Espectro Autista/diagnóstico por imagem , Resposta Galvânica da Pele/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto Jovem
7.
Am J Hum Genet ; 94(5): 677-94, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24768552

RESUMO

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA , Redes e Vias Metabólicas/genética , Criança , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Família Multigênica , Linhagem , Deleção de Sequência
8.
Hum Brain Mapp ; 36(9): 3323-38, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25995134

RESUMO

Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling in seventeen unmedicated high-functioning adults with ASD and seventeen matched controls while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insular cortex. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Encéfalo/fisiopatologia , Empatia/fisiologia , Resposta Galvânica da Pele/fisiologia , Adulto , Teorema de Bayes , Mapeamento Encefálico/métodos , Discriminação Psicológica , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética/métodos , Masculino , Modelos Neurológicos , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Dor/psicologia , Processamento de Sinais Assistido por Computador
9.
Brain ; 137(Pt 1): 153-71, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24424916

RESUMO

Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Encéfalo/fisiopatologia , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Adulto , Algoritmos , Síndrome de Asperger/fisiopatologia , Síndrome de Asperger/psicologia , Transtornos Globais do Desenvolvimento Infantil/psicologia , Interpretação Estatística de Dados , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Resposta Galvânica da Pele/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Análise de Regressão , Escalas de Wechsler , Adulto Jovem
10.
Nature ; 459(7246): 569-73, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19404257

RESUMO

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.


Assuntos
Transtorno Autístico/genética , Dosagem de Genes/genética , Variação Genética/genética , Genoma Humano/genética , Neurônios/metabolismo , Ubiquitina/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Estudos de Coortes , Europa (Continente)/etnologia , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes
11.
J Neurodev Disord ; 16(1): 25, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730350

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 22 , Convulsões , Humanos , Masculino , Feminino , Convulsões/genética , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 22/genética , Criança , Pré-Escolar , Adolescente , Estudos Longitudinais , Adulto Jovem , Adulto , Estudos Prospectivos , Lactente , Proteínas do Tecido Nervoso/genética
12.
Acta Neuropsychiatr ; 25(5): 275-82, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25287727

RESUMO

OBJECTIVE: Here, we examined the cingulum bundle, a long-range white matter tract mediating dorsal limbic connectivity, using diffusion tensor imaging (DTI) tractography, in children and adolescents with autism spectrum disorder (ASD) versus controls. We hypothesised that cingulum bundle microstructure would be altered in ASD, based on evidence implicating abnormal white matter connectivity in this disorder. METHODS: DTI data were acquired for 19 ASD participants (IQ ⩾ 70; 7-18 years; mean = 12.4 ± 3.1) and 16 age-matched controls (7-18 years; mean = 12.3 ± 3.6) on a 3 T magnetic resonance imaging system. Deterministic tractography was used to isolate the cingulum bundle. Left and right cingulum bundles were examined for differences in several DTI metrics in ASD children/adolescents versus controls, including: fractional anisotropy (FA), mean, axial, and radial diffusivity. RESULTS: Significant age × group interaction effects were found for all DTI metrics (mean diffusivity: F 1,28 = 9.5, p = 0.005, radial diffusivity: F 1,28 = 7.8, p = 0.009, axial diffusivity: F 1,28 = 5.2, p = 0.03, FA: F 1,28 = 4.4, p = 0.04). Interaction effects were driven by increases in cingulum bundle diffusivity (mean, radial, and axial diffusivity), and decreased FA, in younger ASD participants within our sample versus controls. CONCLUSION: Our results point to immature microstructural organisation of the cingulum bundle in ASD, particularly during the early years of life, with implications for limbic network synchronisation and complex socio-emotional performance.

13.
Front Behav Neurosci ; 17: 1102516, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37255619

RESUMO

Background: Parents of autistic children experience increased levels of caregiver strain and adverse mental health outcomes, even in comparison to parents of children with other neurodevelopmental disabilities. Previous studies have largely attributed these increased levels of mental health concerns to their child behavioral concerns and autism symptomatology, but less attention has been given to other potential child factors, such as child adaptive functioning. Additionally, little is known about potential protective factors, such as parents' emotion regulation (ER) abilities, that may ameliorate the experience of caregiver strain, anxiety, and depression. Objective: The current study examined the impact of child characteristics (restricted and repetitive behaviors, adaptive functioning and behavioral concerns) on parent mental health outcomes (caregiver strain, anxiety, depression and wellbeing). Additionally, we explore parents' ER abilities as a moderator of the impact of child characteristic on parents' mental health outcomes. Results: Results of linear mixed effect models indicated a significant relationship between parents' ER abilities and all four parent outcomes. Additionally, children's adaptive functioning abilities and repetitive behaviors (RRBs) were significant predictors of caregiving strain. Parents' ER abilities were a significant moderator of the effect of children's repetitive behaviors and adaptive functioning challenges on caregiver strain, such that better ER abilities mitigated the impact of child clinical factors on caregiver strain. Finally, a significant difference was detected for mothers' and fathers' mental health, with mothers reporting higher caregiver strain, and more symptoms of anxiety and depression than did fathers. Conclusion: This study leveraged a large sample of autistic children and their biological parents to examine the relationship between children's clinical characteristics and parents' psychological wellbeing. Results indicate that, although parents of autistic children do experience high rates of internalizing mental health concerns that relate to child adaptive functioning and RRBs, parent ER abilities act as a protective factor against parents' adverse mental health outcomes. Further, mothers in our sample reported significantly higher rates of depression, anxiety, and caregiver strain, as compared with fathers.

14.
Front Psychiatry ; 14: 1212084, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37791130

RESUMO

Introduction: To illustrate the landscape of community-based care for autistic youth in the United States, we identified transdisciplinary psychosocial intervention practice sets that community providers report utilizing to care for this population, and examined characteristics associated with provider-reported utilization. Methods: The Usual Care for Autism Study (UCAS) Survey assessed provider demographics and provider-reported use of transdisciplinary practices for common ASD co-occurring problems: social difficulties, externalizing behaviors, and anxiety. Community practitioners (N = 701) from allied health, behavioral, education, medical, mental health and other disciplines who treat or work with autistic youth (7-22 years) participated. Results: Exploratory factor analysis yielded four factors: Consequence-Based Strategies (CBS), Cognitive-Behavioral and Therapy Strategies (CBTS), Antecedent-Based Strategies (ABS), and Teaching Strategies (TS). Providers across disciplines reported utilizing ABS more often than other sets. Providers from behavioral disciplines, with less than 4-year or Master degrees, or with more experience reported the most use of ABS, CBS and CBTS. Medical and behavioral providers reported the most use of TS. Setting and child characteristics were associated with practice set use, indicating variability by disability and client socioeconomic status. Discussion: Findings reflect the complexity and inconsistency of the service landscape for autistic youth across the U.S. Only by understanding the service landscape and predictors of practice utilization, can researchers, policymakers, provider groups, and the autistic community facilitate effective implementation strategy development and use to ultimately improve community-based care.

15.
HGG Adv ; 4(1): 100145, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36276299

RESUMO

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Phenotypic differences have been reported between PMS participants carrying small "class I" mutations and large "class II" mutations; however, the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning class I (n = 37) and class II mutations (n = 39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Furthermore, we uncover 208 underexpressed genes in PMS participants with class II mutations, which were unchanged in class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions, and cytotoxic natural killer (NK) immune cell signatures. In silico predictions estimated a reduction in CD56+ CD16- NK cell proportions in class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered in PMS participants with class II mutations and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.


Assuntos
Proteínas do Tecido Nervoso , Transcriptoma , Transcriptoma/genética , Proteínas do Tecido Nervoso/genética , Metabolômica , Esfingolipídeos
16.
Am J Med Genet A ; 158A(5): 1170-7, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22488896

RESUMO

Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 17 , Pré-Escolar , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/genética , Masculino , Pais
17.
Front Psychiatry ; 13: 923025, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958649

RESUMO

Objective: To examine patterns and predictors of familiarity with transdisciplinary psychosocial (e.g., non-pharmacologic) practices for practitioners treating youths with autism spectrum disorder (ASD) in the United States. Method: Practitioners (n = 701) from behavioral, education, medical, and mental health backgrounds who worked with youth (ages 7-22) with ASD completed the Usual Care for Autism Survey, which assessed provider demographics and self-reported familiarity with transdisciplinary treatment practices for the most common referral problems of ASD. We examined relations between provider-, setting-, and client-level characteristics with familiarity of key groups of the treatment practices (practice sets). Practice sets were identified using exploratory factor analysis (EFA), and demographic predictors of practice subsets were examined using generalized estimating equations (GEE). Results: The EFA yielded a three-factor solution: (1) environmental modifications/antecedent strategies; (2) behavior analytic strategies; and (3) cognitive strategies, with overall familiarity ranked in this order. Medical providers indicated the least familiarity across disciplines. More experience with ASD and treating those with intellectual disabilities predicted greater familiarity with only environmental modifications/antecedent strategies and behavior analytic, but not cognitive strategies. Experience treating low SES clients predicted familiarity with environmental modification and behavior analytic strategies while experience treating high SES clients predicted familiarity with behavior analytic and cognitive strategies. Conclusion: This is the first study to identify transdisciplinary, interpretable sets of practices for treating youth with ASD based on community providers' reported familiarity. Results highlight factors associated with familiarity with practice sets, which is essential for mapping practice availability, and optimizing training and dissemination efforts for youth with ASD.

18.
Front Neurosci ; 16: 829415, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35516796

RESUMO

Background: Atypical processing of unfamiliar, but less so familiar, stimuli has been described in Autism Spectrum Disorder (ASD), in particular in relation to face processing. We examined the construct of familiarity in ASD using familiar and unfamiliar songs, to investigate the link between familiarity and autism symptoms, such as repetitive behavior. Methods: Forty-eight children, 24 with ASD (21 males, mean age = 9.96 years ± 1.54) and 24 typically developing (TD) controls (21 males, mean age = 10.17 ± 1.90) completed a music familiarity task using individually identified familiar compared to unfamiliar songs, while magnetoencephalography (MEG) was recorded. Each song was presented for 30 s. We used both amplitude envelope correlation (AEC) and the weighted phase lag index (wPLI) to assess functional connectivity between specific regions of interest (ROI) and non-ROI parcels, as well as at the whole brain level, to understand what is preserved and what is impaired in familiar music listening in this population. Results: Increased wPLI synchronization for familiar vs. unfamiliar music was found for typically developing children in the gamma frequency. There were no significant differences within the ASD group for this comparison. During the processing of unfamiliar music, we demonstrated left lateralized increased theta and beta band connectivity in children with ASD compared to controls. An interaction effect found greater alpha band connectivity in the TD group compared to ASD to unfamiliar music only, anchored in the left insula. Conclusion: Our results revealed atypical processing of unfamiliar songs in children with ASD, consistent with previous studies in other modalities reporting that processing novelty is a challenge for ASD. Relatively typical processing of familiar stimuli may represent a strength and may be of interest to strength-based intervention planning.

19.
Mol Autism ; 12(1): 32, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33964979

RESUMO

BACKGROUND: Intervention during the first years of life for children with autism spectrum disorder (ASD) may have the strongest impact on long-term brain development and functioning. Yet, barriers such as a shortage of trained professionals contribute to significant delays in service. The goal of this proof-of-concept study was to explore strategies that support timely and equitable deployment of ASD-specific interventions. METHODS: This 15-week, randomized proof-of-concept study explored the acceptability of a digital parent mediated intervention online reciprocal imitation training (RIT; a naturalistic developmental behavioral intervention) and compared it to a treatment as usual (TAU) control on parent and child outcomes. Eligible children were between 18 and 60 months, met the cutoff for ASD on the Autism Diagnostic Observation Schedule-2nd Edition and demonstrate significant social imitation deficits. Primary outcomes include the acceptability of RIT (Scale of Treatment Perceptions) and the feasibility of the Online RIT digital intervention (online RIT attributes). Secondary outcomes included parent fidelity (RIT parent fidelity form) and parental self-efficacy (Early Intervention Parenting Self-Efficacy Scale). Exploratory outcome measures included child social communication (Social Communication Checklist), child imitation skills (Unstructured Imitation Assessment), and family quality of life (Beach Center Family Quality of Life Scale). RESULTS: Twenty participants were randomized in a 1:1 fashion. The acceptability and feasibility of RIT and the Online RIT digital intervention were rated highly. Among the secondary outcomes, there were significant group differences in parent fidelity (p < .001) and self-efficacy (p = .029). On exploratory outcomes, there were group differences in child social communication (p = .048). There were no significant group differences in imitation ability (p = .05) or family quality of life (p = .22). LIMITATIONS: There are several limitations with this study, including the small sample size as well as lack of data on enactment and website engagement. This study was not able to address questions related to which variables predict program engagement and treatment response, which will be critical for determining which families may benefit from such a stepped-care delivery model. CONCLUSIONS: Overall, the Online RIT program delivered in a stepped-care format shows strong acceptability and holds promise as an innovative delivery model. Trial registration ClinicalTrials.gov, NCT04467073. Registered 10 July 2020- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04467073.


Assuntos
Transtorno Autístico , Telemedicina , Transtorno do Espectro Autista/terapia , Criança , Pré-Escolar , Humanos , Pais , Qualidade de Vida
20.
J Child Adolesc Psychopharmacol ; 31(7): 475-484, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34543081

RESUMO

Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Memória/efeitos dos fármacos , Comportamento/efeitos dos fármacos , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Projetos Piloto , Resultado do Tratamento
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