A Precision Medicine Initiative To Target Paediatric Cerebral Palsy, A Movement Disorder

Movement disorders (cerebral palsy, dystonia, chorea, and ataxia etc.) are non-progressive, heterogeneous conditions with multiple causes, affecting neuro-motor function in 3-4 out of every 1000 children in Qatar. The occurrence of which matches with worldwide prevalence. Some of the major challenges in diagnosing movement disorders are no accurate biomarker, no single identified causative factor, differences in patient’s response to available therapies, and lack of personalized medicine targets. Thus, there is a significant need to initiate and establish a Precision Medicine platform to diagnose, stratify, correctly identify and functionally characterize molecular targets in patients with movement disorders. The proposed research aims to establish such a functional platform in Qatar that can be utilized for tailored diagnosis and therapy, i.e., personalized medicine. Patients affected with cerebral palsy (CP) are the most common (Data and Statistics for Cerebral Palsy, CDC, 2020, December 31). CP is a heterogeneous condition with a spectrum of clinical manifestations, multiple causes, multiple pathology patterns and multiple degrees of disability. Although genetic causes have long been suspected, however, to date, there are very few studies that could delineate a clear link between genetic variants and CP, and these studies are especially lacking in Arabic populations. This research will focus on pediatric CP cases and investigate parent-offspring trios to identify rare and de novo mutations in CP patients. This project will assess samples collected from pediatric patients registered and treated at the pediatric rehabilitation clinic at the SIDRA Hospital. Sidra’s rehabilitation clinic has already implemented a working procedure to recruit, follow-up and collect samples from patients and their family members. This research employs a multifaceted approach; firstly, gait and motor function-based differentiation of CP patients will be conducted using state-of-the-art 3-Dimensional (3-D) analysis techniques for measuring gait in movement disorder (kinematics and kinetics); secondly, exome sequencing and EPIC methylation arrays will be used to elucidate genetic and epigenetic elements linked to motor dysfunction and their severity. Finally, novel candidate genes harboring disease-associated mutations will be functionally characterized in Drosophila fruit flies by knocking them down in the brains of developing embryos and subjecting fruit flies to locomotor assays for assessing motor output and motor coordination using movement tracking based platforms. Throughout this project, we aim to answer the following key questions: 1. Is it possible to use 3-D analysis-based systems to measure gait and gross motor function and characterize CP patients? 2. Does the genetic landscape differ in CP patients in comparison to non-affected family members? 3. What are the genetic and epigenetic alterations involved in disease manifestation? 4. Can we use Drosophila movements to characterize identified genetic mutations functionally? This will be the first approach to stratify cerebral palsy patients using 3-D analysis techniques. Also, it will be the first family-based whole-exome and epigenome-based study of patients with CP from the Middle East, providing both an investigative genetic landscape and functional characterization of cerebral palsy mutations and epigenetic aberrations in Qatar. These functionally characterized cerebral palsy-associated mutations may contribute to building a genotyping panel for pre-diagnostic analysis. Besides, genetic and epigenetic analysis and data from in vivo Drosophila models will provide substantial insights into disease mechanisms to develop evidence-based therapies. Although CP is a lifelong disability, there are symptomatic interventions that can reduce the effect on the body. The current interventions involve physical and occupational therapy and drugs that can relieve muscle spasms. However, specific treatment options are lacking. Hence there is a need for better informative behavioral, genetic, epigenetic measures which together can inform on molecular targets. Through this project, genetic and epigenetic analysis of CP may provide information about the disrupted genetic mechanism and may provide potential drug targets that will be useful in finding new therapeutics. Beyond this project's scope, we could readily adopt this platform to study various mutations related to movement disorders. We will establish a pipeline (patient —lab —patient) that will move Qatar towards precision medicine for movement disorders through this project. Therefore, we believe that the project will lead to multiple high-impact publications in movement disorders and provide Qatar with a precision medicine initiative. Such findings will refine future approaches to address and quantify other movement disorders such as dystonia, ataxia, chorea, tremors, etc.

Hamad Bin Khalifa University (HBKU)