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NF1基因突变引起的，该基因在细胞内信号传递、学习和突触可塑性方面发挥着重要作用。运动、认知和学习问题在NF1中很常见，在NF1中，自闭症谱系障碍(ASD)和注意力缺陷多动障碍(ADHD)的患病率都很高，约为25%。运动障碍，包括粗大和精细的运动障碍，平衡和协调困难，在NF1中经常被报道。这些障碍会影响生活质量、学术功能、同伴关系和社会关系。新的研究表明，运动障碍可能是ASD表型的一个组成部分。尽管运动障碍在NF1中经常被报道，但运动发育的轨迹还没有被很好地理解。了解其发展轨迹对早期诊断和干预具有重要意义。了解运动发育的轨迹以识别早期迹象可能有助于开发早期康复方法，这反过来可以改善NF1中出现的运动、认知和行为困难。这个博士项目是与英国神经肿瘤公司合作的，作为我们的慈善行业合作伙伴(https://nervetumours.org.uk/).这项研究的目的将是(I)使用马伦早期学习量表和父母报告的数据来确定5个月到3岁的NF1婴儿的运动发育轨迹，并将其与低风险对照组进行比较(Iii)检验客观测量的加速计衍生活动的轨迹，以模拟运动稳定性(摇摆、跳跃、稳定性)(Iii)与行业合作伙伴(神经肿瘤英国)合作，修改由伦敦伯克贝克学院琼斯教授的团队开发的应用程序‘Teachbrite’(https://psyc.bbk.ac.uk/teachbrite/evolutionstudy/info.php)，以研究患有NF1的儿童的社区样本中的运动发育。学生将使用眼球跟踪、加速测量、神经认知和行为测量来调查和扩展关于NF1运动表型的知识。然后，来自NF1队列的数据将与低风险社区样本进行比较，从而使我们能够识别可能与3岁后运动发育不良有关的早期风险生物标志物。然后，这些标记物将被用于预测运动困难的风险，用于临床分层，并在治疗试验中确定干预目标。博士项目将嵌入两个更大的研究中(I)一个更大的MRC项目Grant(Jones)，研究婴儿期神经认知发展(Ii)伊甸园(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。这名学生将在伦敦著名的Birkbeck BabyLab在琼斯和贝古姆·阿里的监督下度过12周，在那里他们将接受有关婴儿和幼儿的眼球跟踪和加速测量收集方面的培训。该学生将受益于儿童神经发育方面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密切联系。

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.