A single gene test can now explain why a child has cerebral palsy, ending years of uncertainty for families. Cerebral palsy has long been blamed on birth injuries or oxygen deprivation, but genetic causes account for over half of cases. In a pilot study of 95 children, researchers identified a genetic cause in 49. This matters because without a diagnosis, families face a tortuous path of tests and no clear answers, while children miss out on treatments tailored to their specific condition. If this research succeeds, genetic testing for cerebral palsy will become standard NHS practice. Clinicians will have consensus guidelines for diagnosis and management. Patient-derived nerve cells grown in the lab will allow researchers to test drugs and gene therapies for each genetic subtype. Some children could receive existing precision medicines that dramatically improve their symptoms, as the team has already achieved for certain neurogenetic disorders. The work will also inform genetic counselling for future pregnancies and medicolegal decisions.
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Background Cerebral palsy (CP) is an early-onset life-long motor disorder occurring in the developing fetal or infant brain. It is one of the most commonly encountered neurological disorders of childhood, with an estimated UK incidence of 2.5/1000. A number of different motor patterns are described in CP, including spastic, hemiplegic, dystonic, dyskinetic, ataxic and hypotonic forms. CP is commonly associated with significant morbidity and mortality. The rising economic burden of CP is of significant global medical and socioeconomic concern. CP has been traditionally attributed to acquired brain injury and recognised risk factors include birth asphyxia, prematurity and low birth weight. Over time, it has become apparent that acquired injury accounts for only a proportion of patients with CP. In the current genomic era, an underlying genetic aetiology is identified in a significant number of children labelled as having CP. Indeed, in my pilot study of 95 cases, I established a genetic aetiology in 49 children, just over 50% of the cohort. For certain neurogenetic disorders, I have been able to instigate a personalized medicine approach leading to striking improvements in some patients. Gene identification can therefore have significant implications for accurate diagnosis, therapy, future prognostication, genetic counselling and medicolegal matters. Aims In this proposed NIHR Research Professorship, I aim to improve quality of life for patients with CP phenotypes. I will Establish genetic diagnoses for patients with CP phenotypes of suspected genetic origin Initiate gene-specific precision medicine strategies Develop guidelines to help clinicians both diagnose genetic forms of CP and manage these conditions Develop patient-derived neuronal models of disease to evaluate gene therapy and novel drug discovery Summary of Plan of Investigation At Great Ormond Street Hospital, I run a quaternary movement disorder service for children with complex motor disorders of undetermined aetiology. To date, I have recruited over 300 patients labelled as having CP but in whom I suspect an underlying genetic disorder. Following on from my successful pilot study, I plan to: Undertake genetic investigations in children with CP phenotypes in order to identify causative genes and new human diseases that mimic CP Confirm mutation pathogenicity where necessary through an established functional pipeline in my research laboratory Rapidly translate research findings into clinical practice by prompt addition of validated genes to NHS multigene panels and diagnostic exomes Develop consensus guidelines for investigating CP and managing genetic forms of CP Develop human induced pluripotent stem cells from patient fibroblasts for differentiation into neurons. These neuronal cell models of genetic CP will be ideal for drug discovery and evaluation of gene therapy strategies Summary of Potential Benefits to Patients and NHS My proposed fellowship will have clear rapid benefit to NHS patients. Gene discovery will aid accurate diagnosis, which can provide enormous relief for families, who have often had a difficult and tortuous diagnostic path. It can give families a sense of 'closure', allow prognostication and inform genetic counselling for future pregnancies. My research functional pipeline will further aid diagnostic certainty by determining the pathogenicity of novel, previously unreported variants. My work will also improve NHS diagnostic genetic testing as research genes will be rapidly translated into clinical practice by prompt addition to multigene panels and diagnostic exomes. My plan to develop consensus guidelines for genetic forms of CP will no doubt optimise patient diagnosis and treatment. Finally, gene discovery will facilitate a precision medicine approach for NHS patients, either through currently available therapies or through novel drug development. Using patient-derived neuronal cell models of genetic CP will be the perfect research platform to develop treatments for these neurological disorders.
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