Trajectories of motor development in Neurofibromatosis 1 in the preschool period

神经纤维瘤病1是一种常见的常染色体显性单基因神经发育障碍，出生发病率为1：2700。它是由染色体17q11.2上的NF 1基因突变引起的，该基因在细胞内信号传导、学习和突触可塑性中起重要作用。运动、认知和学习问题在NF 1中是常见的，并且在NF 1中存在约25%的自闭症谱系障碍（ASD）和约50%的注意缺陷多动障碍（ADHD）两者的高患病率。运动困难包括粗大和精细运动障碍、平衡和协调困难通常在NF 1中报告。这些障碍影响生活质量，学术功能，同伴和社会关系。新兴的研究表明，运动障碍可能是ASD表型的一个组成部分。虽然运动障碍通常在NF 1中报道，但运动发育的轨迹并不清楚。了解发展轨迹对于早期诊断和干预至关重要。了解运动发展的轨迹，以确定早期迹象可能有助于使用开发早期康复方法，这反过来又可以改善NF 1中出现的运动，认知和行为困难。这个博士项目与Nervetumours UK合作，作为我们的慈善行业合作伙伴（https：//nervetumours.org.uk/）。本研究的目的是（i）使用马伦早期学习量表和父母报告的数据确定5个月至3岁NF 1婴儿的运动发育轨迹，并将其与低风险对照进行比较（iii）检查客观测量的加速度计衍生活动的轨迹，以模拟运动稳定性（iii）与业界伙伴（Nerve Tumours UK）合作，修改由伦敦伯克贝克学院Jones教授团队开发的“Teachbrite”应用程序（https：//psyc.bbk.ac.uk/teachbrite/evolutionstudy/info.php），以研究NF 1儿童社区样本的运动发育。学生将使用眼动追踪，加速度计，神经认知和行为措施，以调查和扩展有关NF 1运动表型的知识。然后将NF 1队列的数据与低风险社区样本进行比较，使我们能够识别可能与3年时运动发育不良相关的早期风险生物标志物。然后，这些标记物将用于预测运动困难的风险，用于临床分层，并在治疗试验中定义干预目标。该博士项目将嵌入两个较大的研究（i）一个较大的MRC计划格兰特（琼斯）调查婴儿期神经认知发展（ii）EDEN（神经纤维瘤病的早期发展）。将提供发展、实验和行为评估方面的培训。该学生将在世界著名的伯克贝克婴儿实验室，伦敦琼斯和贝古姆阿里的监督下，在那里他们将在婴儿和幼儿的眼动跟踪和加速度计的收集培训12周。学生将受益于儿童神经发育的临床联系和专业知识，以及与曼彻斯特临床遗传学专业知识的紧密联系。

Neurofibromatosis 1 is a common autosomal dominant single gene neurodevelopmental disorder, with birth incidence of 1:2700. It is caused by a mutation of the NF1 gene on chromosome 17q11.2, which has an important role in intracellular signalling, learning and synaptic plasticity. Motor, cognitive and learning problems are common in NF1 and there is a high prevalence of both autism spectrum disorder (ASD) of approximately 25% and Attention Deficit Hyperactivity Disorder (ADHD) of about 50% in NF1. Motor difficulties including gross and fine motor impairments, balance and coordination difficulties are commonly reported in NF1. These impairments impact quality of life, academic functioning, peer, and social relationships. Emerging research suggests that motor impairments may be a component of the ASD phenotype. Although motor impairments are commonly reported in NF1, the trajectory of motor development is not well understood. Understanding the trajectory of development will be important for early diagnosis and intervention. Understanding the trajectory of motor development to identify early signs may help use develop early rehabilitation approaches, which could in turn ameliorate the emergence of motor, cognitive and behavioural difficulties seen in NF1.This doctoral project is in collaboration with Nerve Tumours UK as our charity industry partner (https://nervetumours.org.uk/). The aims of this study will be (i) to determine the trajectories of motor development in NF1 infants from 5months to 3 years using the Mullen Scale of Early learning, and parent reported data and compare it to low-risk controls (iii) examine the trajectory of objectively measured accelerometer-derived activity to model motor stability (sway, jerkiness, stability)(iii) to work with industry-partner(Nerve Tumours UK) to modify the app 'Teachbrite' (https://psyc.bbk.ac.uk/teachbrite/evolutionstudy/info.php) developed by Prof Jones' team at Birkbeck College London to study motor development in a community sample of children with NF1. The student will use eye-tracking, accelerometery, neurocognitive, and behavioural measures to investigate and extend knowledge on the motor phenotype in NF1. Data from the NF1 cohort will then be compared to low risk community samples allowing us to identify early risk biomarkers that may be associated with poor motor development at 3 years. Such markers will then be used to predict risk for motor difficulties, for clinical stratification and to define intervention targets in treatment trials. The doctoral project will be embedded within two larger studies (i) a larger MRC programme Grant (Jones) investigating infancy neurocognitive development (ii) the EDEN (Early Development in Neurofibromatosis. Training will be provided in developmental, experimental and behavioural assessments. The student will spend 12 weeks at the world renowned Birkbeck babylab, London under the supervision of Jones and Begum Ali, where they will be trained in the collection of eye tracking and accelerometery in infants and toddlers. The student will benefit from clinical links and expertise in child neurodevelopment and strong links to clinical genetics expertise in Manchester.