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Age of diagnosis for children with chromosome 15q syndromes. 染色体15q综合征患儿的诊断年龄。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-11-07 DOI: 10.1186/s11689-023-09504-x
Anne C Wheeler, Marie G Gantz, Heidi Cope, Theresa V Strong, Jessica E Bohonowych, Amanda Moore, Vanessa Vogel-Farley

Objective: The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]).

Methods: Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences.

Results: The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications.

Conclusion: Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.

目的:本研究的目的是确定患有由15号染色体改变引起的三种神经遗传疾病之一(Angelman综合征[AS]、Prader-Willi综合征[PWS]和重复15q综合征[Dup15q])的儿童的诊断年龄。方法:有关每种疾病的诊断过程的数据由倡导组织提供。根据分子亚型和年份计算每种情况的中位数和四分位数间距。进行比较测试以探究组间差异。结果:AS和Dup15q的中位诊断年龄均为1.8岁。PWS在中位年龄1个月时被诊断为明显年轻。PWS和AS的缺失亚型比非缺失亚型更早被诊断,Dup15q中有等心重复的儿童比有间质重复的儿童更早被诊断。结论:了解15号染色体疾病诊断年龄的变异性是减少诊断困难和改善这些人群获得干预的重要一步。这项研究的结果为评估降低这些疾病患者诊断年龄的努力提供了一个基线。
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引用次数: 0
Autism through midlife: trajectories of symptoms, behavioral functioning, and health. 自闭症到中年:症状、行为功能和健康的轨迹。
IF 4.1 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-11-03 DOI: 10.1186/s11689-023-09505-w
Jinkuk Hong, Leann Smith DaWalt, Julie Lounds Taylor, Aasma Haider, Marsha Mailick

Background: This study describes change in autism symptoms, behavioral functioning, and health measured prospectively over 22 years. Most studies tracking developmental trajectories have focused on autism during childhood, although adulthood is the longest stage of the life course. A robust understanding of how autistic people change through midlife and into older age has yet to be obtained.

Methods: Using an accelerated longitudinal design with 9 waves of data, developmental trajectories were estimated from adolescence through midlife and into early old age in a community-based cohort (n = 406). The overall aim was to determine whether there were age-related increases or decreases, whether the change was linear or curvilinear, and whether these trajectories differed between those who have ID and those who have average or above-average intellectual functioning. Subsequently, the slopes of the trajectories were evaluated to determine if they differed depending on age when the study began, with the goal of identifying possible cohort effects.

Results: There were significant trajectories of age-related change for all but one of the measures, although different measures manifested different patterns. Most autism symptoms improved through adulthood, while health worsened. An inverted U-shaped curve best described change for repetitive behavior symptoms, activities of daily living, maladaptive behaviors, and social interaction. For these measures, improved functioning was evident from adolescence until midlife. Then change leveled off, with worsening functioning from later midlife into early older age. Additionally, differences between autistic individuals with and without ID were evident. Although those who have ID had poorer levels of functioning, there were some indications that those without ID had accelerating challenges in their aging years that were not evident in those with ID - increases in medications for physical health problems and worsening repetitive behaviors.

Conclusions: Meeting the needs of the increasingly large population of autistic adults in midlife and old age requires a nuanced understanding of life course trajectories across the long stretch of adulthood and across multiple domains. Given the heterogeneity of autism, it will be important not to generalize across sub-groups, for example those who are minimally verbal and those who have above-average intellectual functioning.

背景:本研究描述了22年来前瞻性测量的自闭症症状、行为功能和健康状况的变化。大多数追踪发展轨迹的研究都集中在童年时期的自闭症上,尽管成年是生命历程中最长的阶段。对于自闭症患者如何在中年和老年期发生变化,我们还没有获得强有力的理解。方法:采用9波数据的加速纵向设计,在一个基于社区的队列(n = 406)。总体目的是确定是否存在与年龄相关的增加或减少,变化是线性的还是曲线的,以及这些轨迹在ID患者和智力功能平均或高于平均水平的患者之间是否不同。随后,对轨迹的斜率进行了评估,以确定它们是否因研究开始时的年龄而不同,目的是确定可能的队列效应。结果:除了一项指标外,所有指标都有显著的年龄变化轨迹,尽管不同的指标表现出不同的模式。大多数自闭症症状在成年后得到改善,而健康状况恶化。倒U型曲线最能描述重复行为症状、日常生活活动、适应不良行为和社交互动的变化。从这些指标来看,从青春期到中年,功能的改善是显而易见的。然后变化趋于平稳,从中年后期到老年早期,功能不断恶化。此外,有ID和没有ID的自闭症患者之间的差异也很明显。尽管有ID的人的功能水平较差,但有一些迹象表明,没有ID的人在衰老过程中面临着加速的挑战,而ID的人并不明显——治疗身体健康问题的药物增加和重复行为恶化。结论:要满足越来越多的中老年自闭症成年人的需求,需要对成年期和多个领域的生命历程轨迹有细致的了解。考虑到自闭症的异质性,重要的是不要在亚组中进行概括,例如那些言语能力最低的人和那些智力功能高于平均水平的人。
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引用次数: 0
Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder. 唐氏综合征和自闭症谱系障碍患者的维生素D缺乏。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-25 DOI: 10.1186/s11689-023-09503-y
Natalie K Boyd, Julia Nguyen, Mellad M Khoshnood, Timothy Jiang, Lina Nguyen, Lorena Mendez, Noemi A Spinazzi, Melanie A Manning, Michael S Rafii, Jonathan D Santoro

Background: Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls.

Methods: A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient.

Results: In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63).

Conclusions: Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

背景:据报道,唐氏综合症(DS)患者的血浆维生素D水平较低,现有数据仅限于小型同质队列。鉴于DS患者自身免疫性疾病的发病率很高,以及维生素D与免疫功能之间的已知关系,这对DS患者尤为重要。这项研究试图调查DS患者的多中心队列中的维生素D状况,并将其与自闭症谱系障碍(ASD)和神经典型(NT)对照组进行比较。方法:采用多中心回顾性研究。这三个地点的纬度分别为42.361145、37.44466和34.05349。根据国际疾病分类(ICD)-9或ICD-10代码,对NT患者进行DS、ASD或健康儿童检查。本研究使用了电子病历(EMR)中记录的第一个维生素D 25-OH水平,因为它被认为是最能反映自然和未补充状态的。维生素D 25-OH水平低于30 ng/mL被认为是缺乏的。结果:总共确定了1624名DS患者、5208名ASD患者和30775名NT对照者。DS患者的维生素D 25-OH平均水平最低,为20.67ng/mL,与ASD患者(23.48 ng/mL)和NT对照组(29.20 ng/mL)相比(p<0.001,95%CI:8.97至-6.44)。共有399名DS患者(24.6%)被认为维生素D缺乏,而ASD患者为1472名(28.3%),NT对照组为12397名(40.3%)(p<001,95%CI:5.43至-2.36)维生素D(p<0.001,95%置信区间:-0.3849至-0.1509)。此外,同时患有DS和神经系统诊断增加了维生素D水平较低的可能性(p<001,95%可信区间:-5.02至-1.28)。患有DS和自身免疫性疾病的个体更可能具有较低的维生素D水平(p<0.001,95%可信区间:-6.22至-1.55)。同样,一级亲属的自身免疫史也增加了DS患者维生素D水平较低的可能性(p=0.01,95%CI:2.45至-0.63)。结论:与ASD和NT对照组相比,DS患者的维生素D水平降低。在DS患者中,维生素D缺乏与高BMI、个人自身免疫和家族自身免疫之间存在关联。
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引用次数: 0
The microstructural change of the brain and its clinical severity association in pediatric Tourette syndrome patients. 儿童抽动秽语综合征患者大脑的微观结构变化及其临床严重程度的相关性。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-25 DOI: 10.1186/s11689-023-09501-0
Chia-Jui Hsu, Lee Chin Wong, Hsin-Pei Wang, Yi-Chun Chung, Te-Wei Kao, Chen-Hsiang Weng, Wen-Chau Wu, Shinn-Forng Peng, Wen-Yih Isaac Tseng, Wang-Tso Lee

Background: Gilles de la Tourette syndrome (GTS) is a prevalent pediatric neurological disorder. Most studies point to abnormalities in the cortico-striato-thalamocortical (CSTC) circuits. Neuroimaging studies have shown GTS's extensive impact on the entire brain. However, due to participant variability and potential drug and comorbidity impact, the results are inconsistent. To mitigate the potential impact of participant heterogeneity, we excluded individuals with comorbidities or those currently undergoing medication treatments. Based on the hypothesis of abnormality within the CSTC circuit, we investigated microstructural changes in white matter using diffusion spectrum imaging (DSI). This study offers the first examination of microstructural changes in treatment-naïve pediatric patients with pure GTS using diffusion spectrum imaging.

Methods: This single-center prospective study involved 30 patients and 30 age- and gender-matched healthy volunteers who underwent sagittal T1-weighted MRI and DSI. We analyzed generalized fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.

Results: No significant differences were observed in mean diffusivity and axial diffusivity values between the two groups. However, the patient group exhibited significantly higher generalized fractional anisotropy values in the right frontostriatal tract of the dorsolateral prefrontal cortex, the right frontostriatal tract of the precentral gyrus, and bilateral thalamic radiation of the dorsolateral prefrontal cortex. Additionally, the generalized fractional anisotropy value of the right frontostriatal tract of the precentral gyrus is inversely correlated with the total tic severity scores at the most severe condition.

Conclusion: Treatment-naïve pediatric GTS patients demonstrated increased connectivity within the CSTC circuit as per diffusion spectrum imaging, indicating possible CSTC circuit dysregulation. This finding could also suggest a compensatory change. It thus underscores the necessity of further investigation into the fundamental pathological changes in GTS. Nevertheless, the observed altered connectivity in GTS patients might serve as a potential target for therapeutic intervention.

背景:抽动秽语综合征(GTS)是一种常见的儿科神经系统疾病。大多数研究都指出皮质-纹状体-丘脑皮质(CSTC)回路异常。神经影像学研究表明GTS对整个大脑有广泛的影响。然而,由于参与者的变异性以及潜在的药物和共病影响,结果并不一致。为了减轻参与者异质性的潜在影响,我们排除了患有合并症的个体或目前正在接受药物治疗的个体。基于CSTC电路异常的假设,我们使用扩散光谱成像(DSI)研究了白质的微观结构变化。这项研究首次使用扩散光谱成像检查了患有纯GTS的治疗幼稚儿童患者的微观结构变化。方法:这项单中心前瞻性研究涉及30名患者和30名年龄和性别匹配的健康志愿者,他们接受了矢状T1加权MRI和DSI检查。我们分析了广义分数各向异性、平均扩散率、轴向扩散率和径向扩散率。结果:两组之间的平均扩散率和轴向扩散率值没有显著差异。然而,患者组在背外侧前额叶皮层的右额纹状体束、中央前回的右额丘脑束和背外侧前皮层的双侧丘脑辐射中表现出显著更高的广义各向异性分数值。此外,中央前回右额纹状体束的广义各向异性分数值与最严重情况下的抽动严重程度总分呈负相关。结论:根据扩散光谱成像,治疗幼稚的儿童GTS患者表现出CSTC回路内的连接增加,表明CSTC回路可能失调。这一发现也可能预示着一种补偿性的变化。因此,它强调了进一步研究GTS的基本病理变化的必要性。然而,在GTS患者中观察到的连接改变可能是治疗干预的潜在目标。
{"title":"The microstructural change of the brain and its clinical severity association in pediatric Tourette syndrome patients.","authors":"Chia-Jui Hsu, Lee Chin Wong, Hsin-Pei Wang, Yi-Chun Chung, Te-Wei Kao, Chen-Hsiang Weng, Wen-Chau Wu, Shinn-Forng Peng, Wen-Yih Isaac Tseng, Wang-Tso Lee","doi":"10.1186/s11689-023-09501-0","DOIUrl":"10.1186/s11689-023-09501-0","url":null,"abstract":"<p><strong>Background: </strong>Gilles de la Tourette syndrome (GTS) is a prevalent pediatric neurological disorder. Most studies point to abnormalities in the cortico-striato-thalamocortical (CSTC) circuits. Neuroimaging studies have shown GTS's extensive impact on the entire brain. However, due to participant variability and potential drug and comorbidity impact, the results are inconsistent. To mitigate the potential impact of participant heterogeneity, we excluded individuals with comorbidities or those currently undergoing medication treatments. Based on the hypothesis of abnormality within the CSTC circuit, we investigated microstructural changes in white matter using diffusion spectrum imaging (DSI). This study offers the first examination of microstructural changes in treatment-naïve pediatric patients with pure GTS using diffusion spectrum imaging.</p><p><strong>Methods: </strong>This single-center prospective study involved 30 patients and 30 age- and gender-matched healthy volunteers who underwent sagittal T1-weighted MRI and DSI. We analyzed generalized fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.</p><p><strong>Results: </strong>No significant differences were observed in mean diffusivity and axial diffusivity values between the two groups. However, the patient group exhibited significantly higher generalized fractional anisotropy values in the right frontostriatal tract of the dorsolateral prefrontal cortex, the right frontostriatal tract of the precentral gyrus, and bilateral thalamic radiation of the dorsolateral prefrontal cortex. Additionally, the generalized fractional anisotropy value of the right frontostriatal tract of the precentral gyrus is inversely correlated with the total tic severity scores at the most severe condition.</p><p><strong>Conclusion: </strong>Treatment-naïve pediatric GTS patients demonstrated increased connectivity within the CSTC circuit as per diffusion spectrum imaging, indicating possible CSTC circuit dysregulation. This finding could also suggest a compensatory change. It thus underscores the necessity of further investigation into the fundamental pathological changes in GTS. Nevertheless, the observed altered connectivity in GTS patients might serve as a potential target for therapeutic intervention.</p>","PeriodicalId":16530,"journal":{"name":"Journal of Neurodevelopmental Disorders","volume":"15 1","pages":"34"},"PeriodicalIF":4.9,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50161891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study. Rett综合征和相关疾病的首要护理者关注点:来自美国自然史研究的数据。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-10-13 DOI: 10.1186/s11689-023-09502-z
Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Bernhard Suter, Lori Silveira, Cary Fu, Sarika U Peters, Alan K Percy

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.

Methods: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.

Results: The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.

Conclusion: The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

目的:最近对Rett综合征(RTT)等神经发育障碍的理解取得了进展,从而发现了需要正式临床疗效评估的新治疗方法。临床试验的成功取决于评估对受影响个体影响最大的临床特征的结果指标。为了确定RTT和RTT相关疾病的首要关注点,我们要求护理人员列出护理人员的首要关注问题,以指导制定和选择针对这些疾病的适当临床试验结果指标。方法:参与美国RTT和RTT相关疾病自然史研究的参与者的护理人员(n = 925)被要求确定影响受影响参与者的前3个问题。我们为每种诊断类别生成了一份护理人员最关心的问题的加权列表,并比较了疾病之间的结果。此外,对于经典RTT,根据年龄、临床严重程度和MECP2中常见的RTT引起突变来分析护理人员的担忧。结果:经典RTT的主要护理人员担忧是有效沟通、癫痫发作、行走/平衡问题、缺乏手部使用和便秘。经典RTT的主要护理者关注的频率因年龄、临床严重程度和特定突变而异,与这些领域临床特征频率的已知变化一致。癫痫发作严重程度增加的参与者的护理人员通常将癫痫发作列为首要问题,而没有活动性癫痫发作的参与者的照顾人员通常将用手或交流列为首要关注。疾病之间的比较发现,经典RTT、非典型RTT、MECP2重复综合征、CDKL5缺乏症和FOXG1综合征之间的主要照顾者关注点存在共性;然而,这些疾病在照顾者关注方面的明显差异与特定临床特征的相对流行率和影响是一致的。结论:RTT和RTT相关疾病患者最关心的护理问题反映了这些疾病的主要临床症状的影响。这项工作对于开发有意义的疗法至关重要,因为最佳疗法应该解决这些问题。此外,临床试验中使用的结果指标应评估护理人员最关心的这些临床问题。
{"title":"Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study.","authors":"Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Bernhard Suter, Lori Silveira, Cary Fu, Sarika U Peters, Alan K Percy","doi":"10.1186/s11689-023-09502-z","DOIUrl":"10.1186/s11689-023-09502-z","url":null,"abstract":"<p><strong>Objective: </strong>Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.</p><p><strong>Methods: </strong>Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.</p><p><strong>Results: </strong>The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.</p><p><strong>Conclusion: </strong>The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.</p>","PeriodicalId":16530,"journal":{"name":"Journal of Neurodevelopmental Disorders","volume":"15 1","pages":"33"},"PeriodicalIF":4.9,"publicationDate":"2023-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41203545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). 结节性硬化症综合征相关神经精神障碍(TAND)的识别和治疗的国际共识建议。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-09-14 DOI: 10.1186/s11689-023-09500-1
Petrus J de Vries, Tosca-Marie Heunis, Stephanie Vanclooster, Nola Chambers, Stacey Bissell, Anna W Byars, Jennifer Flinn, Tanjala T Gipson, Agnies M van Eeghen, Robert Waltereit, Jamie K Capal, Sebastián Cukier, Peter E Davis, Catherine Smith, J Chris Kingswood, Eva Schoeters, Shoba Srivastava, Megumi Takei, Sugnet Gardner-Lubbe, Aubrey J Kumm, Darcy A Krueger, Mustafa Sahin, Liesbeth De Waele, Anna C Jansen

Background: Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific.

Methods: The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community.

Results: At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to "screen" for TAND at least annually, to "act" using appropriate next steps for evaluation and treatment, and to "repeat" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families.

Conclusions: The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a "TAND toolkit" of "what to seek" and "what to do" when difficulties are identified in TAND clusters.

背景:结节性硬化综合征(TSC)与广泛的身体表现有关,国际临床诊断和治疗建议已经确立。然而,TSC也与广泛的TSC相关神经精神疾病(TAND)有关,这些疾病通常被低估和治疗不足,但与严重的疾病负担有关。识别和治疗TAND的当代证据基础要有限得多,到目前为止,对TAND的诊断和管理的共识建议也有限且不明确,来自世界卫生组织(世界卫生组织)除一个区域以外的所有区域。TANDem项目的目标之一是为TAND的识别和治疗提出共识建议。在本项目实施时,没有国际上采用的标准方法和方法清单来生成临床实践建议。因此,我们制定了自己的证据审查和建立共识的系统程序,以产生与全球TSC社区相关的基于证据的共识建议。结果:共识建议的核心是十项核心原则,围绕着文献中确定的七个自然TAND集群(自闭症样、行为失调、饮食/睡眠、情绪/焦虑、神经心理学、过度活跃/冲动和学术)中的每一个集群的特定建议,以及一组全面的心理社会集群建议。总体建议是至少每年对TAND进行“筛查”,使用适当的下一步评估和治疗措施“采取行动”,并“重复”这一过程,以确保早期识别和早期干预,采用最合适的生物、心理和社会证据知情的方法来支持TSC患者及其家人。结论:共识建议应为健康、教育、社会护理团队和TSC患者家庭提供一个系统的TAND识别和治疗框架。为了确保这些建议在全球传播和实施,与国际贸易和供应链界建立伙伴关系将是重要的。其中一个步骤将包括生成一个“TAND工具包”,其中包括在TAND集群中发现困难时“寻求什么”和“做什么”。
{"title":"International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).","authors":"Petrus J de Vries, Tosca-Marie Heunis, Stephanie Vanclooster, Nola Chambers, Stacey Bissell, Anna W Byars, Jennifer Flinn, Tanjala T Gipson, Agnies M van Eeghen, Robert Waltereit, Jamie K Capal, Sebastián Cukier, Peter E Davis, Catherine Smith, J Chris Kingswood, Eva Schoeters, Shoba Srivastava, Megumi Takei, Sugnet Gardner-Lubbe, Aubrey J Kumm, Darcy A Krueger, Mustafa Sahin, Liesbeth De Waele, Anna C Jansen","doi":"10.1186/s11689-023-09500-1","DOIUrl":"10.1186/s11689-023-09500-1","url":null,"abstract":"<p><strong>Background: </strong>Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific.</p><p><strong>Methods: </strong>The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community.</p><p><strong>Results: </strong>At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to \"screen\" for TAND at least annually, to \"act\" using appropriate next steps for evaluation and treatment, and to \"repeat\" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families.</p><p><strong>Conclusions: </strong>The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a \"TAND toolkit\" of \"what to seek\" and \"what to do\" when difficulties are identified in TAND clusters.</p>","PeriodicalId":16530,"journal":{"name":"Journal of Neurodevelopmental Disorders","volume":"15 1","pages":"32"},"PeriodicalIF":4.9,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10503032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10284841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: Pleiotropy between language impairment and broader behavioral disorders-an investigation of both common and rare genetic variants. 更正:语言障碍和更广泛的行为障碍之间的多重性——对常见和罕见基因变异的调查。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-09-06 DOI: 10.1186/s11689-023-09499-5
Ron Nudel, Vivek Appadurai, Alfonso Buil, Merete Nordentoft, Thomas Werge
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引用次数: 0
Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort. 多动症风险的神经遗传学机制:研究人群队列中多基因评分和脑容量的相关性。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-31 DOI: 10.1186/s11689-023-09498-6
Quanfa He, Taylor J Keding, Qi Zhang, Jiacheng Miao, Justin D Russell, Ryan J Herringa, Qiongshi Lu, Brittany G Travers, James J Li

Background: ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes.

Methods: Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe.

Results: A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC.

Conclusions: The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.

背景:多动症多基因评分(PGSs)先前在几项研究中被证明可以预测多动症的结果。然而,ADHD PGS通常与ADHD相关,但不一定反映因果机制。需要更多的研究来阐明多动症的神经生物学机制。我们在ADHD PGS中利用了功能注释信息,以(1)与未注释的ADHD PGS相比,提高预测性能;(2)测试被认为与ADHD相关的大脑区域的体积变化是否介导了PGS与ADHD结果之间的关联。方法:数据来自费城神经发育队列(N = 555)。测试了多个中介模型,以检验两种ADHD PGS的间接影响——一种使用涉及聚类和阈值的传统计算,另一种使用功能注释方法(即AnnoPred)——通过扣带回、角回、尾状回的灰质体积,对ADHD注意力不集中(IA)和多动冲动(HI)症状进行间接影响,背外侧前额叶皮层(DLPFC)和颞下叶。结果:青少年的AnnoPred ADHD PGS和IA症状之间存在直接影响。IA或HI症状均未检测到通过脑容量产生的间接影响。然而,两种ADHD PGS均与DLPFC呈负相关。然而,脑容量并不能介导传统或AnnoPred ADHD PGS对ADHD症状的影响,这表明我们可能在使用基因测量来阐明基于大脑的ADHD生物标志物方面仍然能力不足。
{"title":"Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort.","authors":"Quanfa He, Taylor J Keding, Qi Zhang, Jiacheng Miao, Justin D Russell, Ryan J Herringa, Qiongshi Lu, Brittany G Travers, James J Li","doi":"10.1186/s11689-023-09498-6","DOIUrl":"10.1186/s11689-023-09498-6","url":null,"abstract":"<p><strong>Background: </strong>ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes.</p><p><strong>Methods: </strong>Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs-one using a traditional computation involving clumping and thresholding and another using a functionally annotated approach (i.e., AnnoPred)-on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe.</p><p><strong>Results: </strong>A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC.</p><p><strong>Conclusions: </strong>The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.</p>","PeriodicalId":16530,"journal":{"name":"Journal of Neurodevelopmental Disorders","volume":"15 1","pages":"30"},"PeriodicalIF":4.9,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10469494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10514099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dorsal visual stream and LIMK1: hemideletion, haplotype, and enduring effects in children with Williams syndrome. 背侧视流和LIMK1:威廉姆斯综合征儿童的半缺失、单倍型和持久影响。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-26 DOI: 10.1186/s11689-023-09493-x
J Shane Kippenhan, Michael D Gregory, Tiffany Nash, Philip Kohn, Carolyn B Mervis, Daniel P Eisenberg, Madeline H Garvey, Katherine Roe, Colleen A Morris, Bhaskar Kolachana, Ariel M Pani, Leah Sorcher, Karen F Berman

Background: Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed "hypersociability") and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS.

Methods: We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5-22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population.

Results: IPS structural (p < 10-4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, IPS gray matter volume (pdiscovery < 0.05 SVC, preplication = 0.0015) and imputed LIMK1 expression (pdiscovery = 10-15, preplication = 10-23) varied according to LIMK1 haplotype.

Conclusions: This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.

背景:威廉姆斯综合征(WS)是一种罕见的神经发育障碍,由染色体带7q11.23中约25个基因的半合子缺失引起,为研究遗传异常与特征明确的神经行为特征之间的关系提供了一个绝佳的机会。临床上,WS的典型特征是社交冲动增加(通常称为“过度社交”)和严重的视觉空间构建缺陷。先前的研究将WS的视觉空间问题与背侧视觉处理流的改变联系起来。我们研究了LIMK1的半缺失和单倍型变异对背流结构和功能的影响,特别是顶叶内沟(IPS),这是一个已知在成年WS患者中发生改变的区域。方法:我们在5-22岁的发展中WS儿童队列中使用纵向MRI检测IPS结构和功能变化(来自33名参与者的76次访问,相比于来自94名年龄和性别匹配的典型发展参与者的280次访问)。我们还对12名罕见的7q11.23较短的半缺失患者进行了MRI研究,所有这些患者都包括LIMK1。最后,我们测试了LIMK1变异对IPS结构的影响,并在两个独立的健康人群中计算了LIMK1表达。结果:IPS结构(p -4 FDR校正)、功能(p发现复制= 0.0015)和估算LIMK1表达(p发现= 10-15,复制= 10-23)因LIMK1单倍型而异。结论:这项工作提供了对WS表型的神经生物学和遗传机制的深入了解,也更广泛地提供了一个引人注目的例子,说明遗传变异通过对神经中介的分子效应来影响人类认知,并在某些情况下导致神经认知障碍。
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引用次数: 0
Why are only some children with autism spectrum disorder misclassified by the social communication questionnaire? An empirical investigation of individual differences in sensitivity and specificity in a clinic-referred sample. 为什么只有部分自闭症谱系障碍儿童被社会交往问卷错误分类?在临床参考样本的敏感性和特异性的个体差异的实证调查。
IF 4.9 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-22 DOI: 10.1186/s11689-023-09497-7
Chimei M Lee, Melody R Altschuler, Amy N Esler, Catherine A Burrows, Rebekah L Hudock

Background: The Social Communication Questionnaire (SCQ) is a checklist for autism spectrum disorder (ASD) commonly used in research and clinical practice. While the original validation study suggested that the SCQ was an accurate ASD screener with satisfactory sensitivity and specificity, subsequent studies have yielded mixed results, with some revealing low sensitivity, low specificity, and low utility in some settings.

Method: The present study examined the psychometric properties of the SCQ as well as the individual difference characteristics of 187 individuals with and without autism spectrum disorder (ASD) who were misclassified or accurately classified by the SCQ in a clinic-referred sample.

Results: The SCQ showed suboptimal sensitivity and specificity, regardless of age and sex. Compared to true positives, individuals classified as false positives displayed greater externalizing and internalizing problems, whereas individuals classified as false negatives displayed better social communication and adaptive skills.

Conclusions: The findings suggest that non-autistic developmental and behavioral individual difference characteristics may explain high rates of misclassification using the SCQ. Clinicians and researchers could consider using the SCQ in combination with other tools for young children with internalizing and externalizing symptoms and other more complex clinical presentations.

背景:社会沟通问卷(Social Communication Questionnaire, SCQ)是一份用于自闭症谱系障碍(autism spectrum disorder, ASD)研究和临床实践的检查表。虽然最初的验证研究表明SCQ是一种准确的ASD筛查方法,具有令人满意的灵敏度和特异性,但随后的研究得出了不同的结果,一些研究显示在某些情况下灵敏度低、特异性低、实用性低。方法:对187例被SCQ错误分类或准确分类的自闭症谱系障碍(ASD)患者进行SCQ的心理测量特征和个体差异特征的检测。结果:无论年龄和性别,SCQ的敏感性和特异性都不理想。与真阳性相比,被归类为假阳性的个体表现出更大的外化和内化问题,而被归类为假阴性的个体表现出更好的社会沟通和适应技能。结论:研究结果表明,非自闭症发育和行为的个体差异特征可能解释了SCQ误分率高的原因。临床医生和研究人员可以考虑将SCQ与其他工具结合使用,用于有内在化和外在化症状以及其他更复杂的临床表现的幼儿。
{"title":"Why are only some children with autism spectrum disorder misclassified by the social communication questionnaire? An empirical investigation of individual differences in sensitivity and specificity in a clinic-referred sample.","authors":"Chimei M Lee, Melody R Altschuler, Amy N Esler, Catherine A Burrows, Rebekah L Hudock","doi":"10.1186/s11689-023-09497-7","DOIUrl":"10.1186/s11689-023-09497-7","url":null,"abstract":"<p><strong>Background: </strong>The Social Communication Questionnaire (SCQ) is a checklist for autism spectrum disorder (ASD) commonly used in research and clinical practice. While the original validation study suggested that the SCQ was an accurate ASD screener with satisfactory sensitivity and specificity, subsequent studies have yielded mixed results, with some revealing low sensitivity, low specificity, and low utility in some settings.</p><p><strong>Method: </strong>The present study examined the psychometric properties of the SCQ as well as the individual difference characteristics of 187 individuals with and without autism spectrum disorder (ASD) who were misclassified or accurately classified by the SCQ in a clinic-referred sample.</p><p><strong>Results: </strong>The SCQ showed suboptimal sensitivity and specificity, regardless of age and sex. Compared to true positives, individuals classified as false positives displayed greater externalizing and internalizing problems, whereas individuals classified as false negatives displayed better social communication and adaptive skills.</p><p><strong>Conclusions: </strong>The findings suggest that non-autistic developmental and behavioral individual difference characteristics may explain high rates of misclassification using the SCQ. Clinicians and researchers could consider using the SCQ in combination with other tools for young children with internalizing and externalizing symptoms and other more complex clinical presentations.</p>","PeriodicalId":16530,"journal":{"name":"Journal of Neurodevelopmental Disorders","volume":"15 1","pages":"28"},"PeriodicalIF":4.9,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Journal of Neurodevelopmental Disorders
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