Determining the mechanisms of nigro-striatal dysfunction in SGCE mutation positive Myoclonus Dystonia using an iPSC-derived neuronal cell model
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: School of Medicine
Abstract
Aims
1. To develop individual nerve cell models of Myoclonus Dystonia using skin cells (fibroblasts) from patients
2. Detailed study of the nerve cell models to determine what effect SGCE gene mutations have on the cells, in particular the neurotransmitter (chemical allowing communication between nerves) dopamine and its receptors.
Background to the research and its importance
Dystonia is one of the most common movement disorders, affecting 1 in 900 per population head. Well recognised forms include writer's cramp, although more severe forms are frequently observed. Dystonia is associated with significant lifetime disability, which has an impact on education and employment. There are currently no effective treatments for dystonia, necessitating an improved understanding of the underlying disease causing mechanisms in order to allow development of novel and potentially disease-modifying therapies to be developed.
This project is focused on Myoclonus Dystonia, an inherited, childhood-onset movement disorder with significant associated psychiatric symptoms. It is one of the most common forms of inherited dystonia and one of the few subtypes caused by mutations to a specific gene (SGCE). These characteristics make Myoclonus Dystonia an opportune disorder in which to study the underlying mechanisms of dystonia. The SGCE gene encodes the epsilon-sarcoglycan protein whose role in the brain, and how defects in its function give rise to dystonia, remain uncertain. Evidence from human brain imaging studies and animal models indicate that the communication (synapse) between dopaminergic neurons arising in the midbrain and medium spiny neurons in the striatum form a focal point of the neuronal disruption in dystonia.
My previous research work involved recruiting one of the largest worldwide cohorts of patients with Myoclonus Dystonia. All of these patients underwent detailed examination of their movement disorder and any psychiatric symptoms. I have selected fibroblast samples from two patients (with different gene mutations) in order to generate these nerve cell models.
Design and methods
The fibroblasts will be used to generate induced pluripotent stem cell (iPSc), cells that are capable of developing into all tissue types. Using a series of well-established techniques, these cells will be converted into nerve cells, more specifically dopaminergic nerve cells (from the midbrain) and medium spiny nerve cells (in the striatum), two nerve cell types thought to be important in dystonia. Both nerve cell types will be examined to determine the effect of SGCE mutations on the epsilon-sarcoglycan protein. Detailed study will also be carried out of the enzymes involved in producing dopamine, the proteins involved in the transporting it across the cell membrane, and the receptors that signal its effect between the two cell types. The second stage of experiments will involve culturing both cell types together, examining their electrical communication and the structure of the neuronal processes.
Results will be compared to nerve models produced from tissue donated by healthy, unrelated individuals. We also plan to use a new genetic technique (Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)) to 'edit' the cells from the patients with Myoclonus Dystonia, returning the SGCE gene sequence to normal, in order to demonstrate that the changes seen in the original nerve cell model are due to the SGCE mutations.
Detailing these processes will improve our understanding of why dystonia, and potentially some psychiatric symptoms arise, as well as providing a platform for the development of new drugs and therapeutic options.
1. To develop individual nerve cell models of Myoclonus Dystonia using skin cells (fibroblasts) from patients
2. Detailed study of the nerve cell models to determine what effect SGCE gene mutations have on the cells, in particular the neurotransmitter (chemical allowing communication between nerves) dopamine and its receptors.
Background to the research and its importance
Dystonia is one of the most common movement disorders, affecting 1 in 900 per population head. Well recognised forms include writer's cramp, although more severe forms are frequently observed. Dystonia is associated with significant lifetime disability, which has an impact on education and employment. There are currently no effective treatments for dystonia, necessitating an improved understanding of the underlying disease causing mechanisms in order to allow development of novel and potentially disease-modifying therapies to be developed.
This project is focused on Myoclonus Dystonia, an inherited, childhood-onset movement disorder with significant associated psychiatric symptoms. It is one of the most common forms of inherited dystonia and one of the few subtypes caused by mutations to a specific gene (SGCE). These characteristics make Myoclonus Dystonia an opportune disorder in which to study the underlying mechanisms of dystonia. The SGCE gene encodes the epsilon-sarcoglycan protein whose role in the brain, and how defects in its function give rise to dystonia, remain uncertain. Evidence from human brain imaging studies and animal models indicate that the communication (synapse) between dopaminergic neurons arising in the midbrain and medium spiny neurons in the striatum form a focal point of the neuronal disruption in dystonia.
My previous research work involved recruiting one of the largest worldwide cohorts of patients with Myoclonus Dystonia. All of these patients underwent detailed examination of their movement disorder and any psychiatric symptoms. I have selected fibroblast samples from two patients (with different gene mutations) in order to generate these nerve cell models.
Design and methods
The fibroblasts will be used to generate induced pluripotent stem cell (iPSc), cells that are capable of developing into all tissue types. Using a series of well-established techniques, these cells will be converted into nerve cells, more specifically dopaminergic nerve cells (from the midbrain) and medium spiny nerve cells (in the striatum), two nerve cell types thought to be important in dystonia. Both nerve cell types will be examined to determine the effect of SGCE mutations on the epsilon-sarcoglycan protein. Detailed study will also be carried out of the enzymes involved in producing dopamine, the proteins involved in the transporting it across the cell membrane, and the receptors that signal its effect between the two cell types. The second stage of experiments will involve culturing both cell types together, examining their electrical communication and the structure of the neuronal processes.
Results will be compared to nerve models produced from tissue donated by healthy, unrelated individuals. We also plan to use a new genetic technique (Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)) to 'edit' the cells from the patients with Myoclonus Dystonia, returning the SGCE gene sequence to normal, in order to demonstrate that the changes seen in the original nerve cell model are due to the SGCE mutations.
Detailing these processes will improve our understanding of why dystonia, and potentially some psychiatric symptoms arise, as well as providing a platform for the development of new drugs and therapeutic options.
Technical Summary
Aims
Generate a neuronal cell model for SGCE mutation-positive Myoclonus Dystonia (MD) using patient derived fibroblasts
Characterise this model to determine changes to monoaminergic neurotransmission at the nigro-striatal junction
Background
Dystonia is a common and disabling movement disorder. Poor understanding of its pathophysiology has led to few effective treatment options. MD is one of few genetically determined dystonias caused by fully penetrant, autosomal dominant mutations (epsilon-sarcoglycan gene, SGCE), providing a unique opportunity for investigation. Previous studies suggest that disruption of the nigro-striatal junction, specifically dopamine-2-receptor (D2R) function, is central to pathogenesis. My previous work involved detailed phenotyping of a large MD cohort (n=30). Two mutation types will be used to develop induced pluripotent stem cell (iPSC) lines: nonsense (c.289C>T,p.Arg97X) and missense (c.622G>A,p.Gly441Asp) mutations.
Methodology
IPSC lines will be generated using Sendai virus vector techniques and differentiated using dual SMAD inhibition and Activin A into midbrain dopaminergic and striatal medium spiny neurons (MSNs) respectively. Characterisation of the neuronal models will include measurement of dopamine synthetic enzymes, transport proteins and the density and distribution of dopamine receptors. A co-culture platform of the two neuronal cell types will undergo phenotyping using electrophysiological techniques, calcium imaging and detailing of dendritic spine morphology. Control neuronal models will include those from healthy, unrelated individuals and isogenic 'rescue' cell lines of the MD patient samples by use of CRISPR technology.
Scientific and Medical opportunities
This project provides an excellent model system with which to investigate the cellular mechanisms that underlie dystonia pathogenesis. Findings from this work will inform future studies, particularly the identification of novel therapeutic targets.
Generate a neuronal cell model for SGCE mutation-positive Myoclonus Dystonia (MD) using patient derived fibroblasts
Characterise this model to determine changes to monoaminergic neurotransmission at the nigro-striatal junction
Background
Dystonia is a common and disabling movement disorder. Poor understanding of its pathophysiology has led to few effective treatment options. MD is one of few genetically determined dystonias caused by fully penetrant, autosomal dominant mutations (epsilon-sarcoglycan gene, SGCE), providing a unique opportunity for investigation. Previous studies suggest that disruption of the nigro-striatal junction, specifically dopamine-2-receptor (D2R) function, is central to pathogenesis. My previous work involved detailed phenotyping of a large MD cohort (n=30). Two mutation types will be used to develop induced pluripotent stem cell (iPSC) lines: nonsense (c.289C>T,p.Arg97X) and missense (c.622G>A,p.Gly441Asp) mutations.
Methodology
IPSC lines will be generated using Sendai virus vector techniques and differentiated using dual SMAD inhibition and Activin A into midbrain dopaminergic and striatal medium spiny neurons (MSNs) respectively. Characterisation of the neuronal models will include measurement of dopamine synthetic enzymes, transport proteins and the density and distribution of dopamine receptors. A co-culture platform of the two neuronal cell types will undergo phenotyping using electrophysiological techniques, calcium imaging and detailing of dendritic spine morphology. Control neuronal models will include those from healthy, unrelated individuals and isogenic 'rescue' cell lines of the MD patient samples by use of CRISPR technology.
Scientific and Medical opportunities
This project provides an excellent model system with which to investigate the cellular mechanisms that underlie dystonia pathogenesis. Findings from this work will inform future studies, particularly the identification of novel therapeutic targets.
Planned Impact
Onset of primary dystonias is typically in the first two decades of life, at a time of great developmental and educational importance. A lack of understanding of the pathophysiology and poor recognition of these disorders in society often leads to late presentation to health services, under recognition and frequent misdiagnosis. The increasing evidence for psychiatric symptoms as a primary component of the disorder phenotype adds to the need for accurate diagnosis and effective management.
This project will have an impact on several significant groups. These benefits will be seen in the short-, medium- and long-term.
1. Individuals and families affected by Myoclonus Dystonia
This project aims to develop a neuronal model for Myoclonus Dystonia that will aid in understanding the cellular mechanisms that underpin the disorder. This will allow patients to have a greater understanding of the cause of their disorder, and why those with one mutation type may differ from another. Ultimately the aim of this work is to develop novel therapeutic strategies that will benefit patient care and potentially lead to the beginnings of personalized medicine.
2. Individuals affected by dystonia
The findings and understanding from this project will have implications for the wider spectrum of dystonic disorders. Points of commonality of pathways and mechanisms may provide areas to target in drug development. Results from this work are also likely to facilitate greater understanding from systems based approaches, such as animal models and human imaging studies.
3. Healthcare Professionals
An improved understanding of cellular mechanisms and underlying pathophysiology will allow clinicians (and other healthcare professionals) to better explain the disorder to their patients. It may also provide some explanation as to why some currently used therapies are more effective in some patients than others, and allow more targeted guiding of treatment.
4. Researchers
Successful development of this neuronal model would be a significant contribution to this field of research. It would provide valuable insights and help guide the work of the International Myoclonus Dystonia Study Group (of which I am a member), facilitate greater understanding of the findings from more systems based approaches, as well as impact the research into other neurodevelopmental disorders.
5. Development of therapeutics
Although beyond the scope of this study, the long-term aim of this project is the identification of novel therapeutic targets and development of large scale clinical trials. This would represent a significant outcome for a group of disorders whose current treatments are extremely limited.
6. Professionals involved with the project
This project will form a platform for the development of an exciting and cutting edge research group at Cardiff University, focused on the development of translational models and effective therapeutics for patients with dystonia. We would form one of very few groups internationally with this as their primary focus, and contribute significantly to the many ongoing collaborative initiatives.
7. Wider society
Dystonia is the third most common form of movement disorder with an estimated prevalence of 1/900 (dystonia.org.uk) and significant social, educational and health economic implications. Improved therapeutic strategies could have a widespread impact on these and workforce employment. Positive results in this project would also raise the public profile of Dystonia and potentially lead to further fundraising and charity-led funding of research. Policy makers have recognized the importance of this with the establishment of the European COST Dystonia initiative (BMBS COST Action BM1101) and the NIH funded Dystonia Coalition in North America (rarediseasesnetwork.org).
This project will have an impact on several significant groups. These benefits will be seen in the short-, medium- and long-term.
1. Individuals and families affected by Myoclonus Dystonia
This project aims to develop a neuronal model for Myoclonus Dystonia that will aid in understanding the cellular mechanisms that underpin the disorder. This will allow patients to have a greater understanding of the cause of their disorder, and why those with one mutation type may differ from another. Ultimately the aim of this work is to develop novel therapeutic strategies that will benefit patient care and potentially lead to the beginnings of personalized medicine.
2. Individuals affected by dystonia
The findings and understanding from this project will have implications for the wider spectrum of dystonic disorders. Points of commonality of pathways and mechanisms may provide areas to target in drug development. Results from this work are also likely to facilitate greater understanding from systems based approaches, such as animal models and human imaging studies.
3. Healthcare Professionals
An improved understanding of cellular mechanisms and underlying pathophysiology will allow clinicians (and other healthcare professionals) to better explain the disorder to their patients. It may also provide some explanation as to why some currently used therapies are more effective in some patients than others, and allow more targeted guiding of treatment.
4. Researchers
Successful development of this neuronal model would be a significant contribution to this field of research. It would provide valuable insights and help guide the work of the International Myoclonus Dystonia Study Group (of which I am a member), facilitate greater understanding of the findings from more systems based approaches, as well as impact the research into other neurodevelopmental disorders.
5. Development of therapeutics
Although beyond the scope of this study, the long-term aim of this project is the identification of novel therapeutic targets and development of large scale clinical trials. This would represent a significant outcome for a group of disorders whose current treatments are extremely limited.
6. Professionals involved with the project
This project will form a platform for the development of an exciting and cutting edge research group at Cardiff University, focused on the development of translational models and effective therapeutics for patients with dystonia. We would form one of very few groups internationally with this as their primary focus, and contribute significantly to the many ongoing collaborative initiatives.
7. Wider society
Dystonia is the third most common form of movement disorder with an estimated prevalence of 1/900 (dystonia.org.uk) and significant social, educational and health economic implications. Improved therapeutic strategies could have a widespread impact on these and workforce employment. Positive results in this project would also raise the public profile of Dystonia and potentially lead to further fundraising and charity-led funding of research. Policy makers have recognized the importance of this with the establishment of the European COST Dystonia initiative (BMBS COST Action BM1101) and the NIH funded Dystonia Coalition in North America (rarediseasesnetwork.org).
Organisations
- CARDIFF UNIVERSITY (Fellow, Lead Research Organisation)
- NORTH BRISTOL NHS TRUST (Collaboration)
- UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST (Collaboration)
- University College London (Collaboration)
- Portsmouth Hospitals NHS Trust (Collaboration)
- University of Calgary (Collaboration)
- Dystonia Medical Research Foundation Canada (DMRFC) (Collaboration)
- BETSI CADWALADR UNIVERSITY HEALTH BOARD (Collaboration)
- Solent NHS Trust (Collaboration)
- Salisbury NHS Foundation Trust (Collaboration)
- Hospital Sant Joan de Deu (Collaboration)
- Trinity College Dublin (Collaboration)
- THE WALTON CENTRE NHS FOUNDATION TRUST (Collaboration)
- Cardiff University (Collaboration)
- Emory University (Collaboration)
- Guy's and St Thomas' NHS Foundation Trust (Collaboration)
- International Parkinson and Movement Disorder Society (MDS) (Collaboration)
- ANEURIN BEVAN UNIVERSITY HEALTH BOARD (Collaboration)
- CARDIFF AND VALE UNIVERSITY HEALTH BOARD (Collaboration)
- LEICESTERSHIRE PARTNERSHIP NHS TRUST (Collaboration)
- HAMPSHIRE HOSPITALS NHS FOUNDATION TRUST (Collaboration)
- UNIVERSITY OF SYDNEY (Collaboration)
- University Medical Center Gronigen (Collaboration)
People |
ORCID iD |
Kathryn Peall (Principal Investigator / Fellow) |
Publications
Carroll LS
(2018)
Dentatorubral-pallidoluysian Atrophy: An Update.
in Tremor and other hyperkinetic movements (New York, N.Y.)
Cunningham AC
(2019)
Using kinematic analyses to explore sensorimotor control impairments in children with 22q11.2 deletion syndrome.
in Journal of neurodevelopmental disorders
Cunningham AC
(2020)
Movement Disorder Phenotypes in Children With 22q11.2 Deletion Syndrome.
in Movement disorders : official journal of the Movement Disorder Society
Eggink H
(2020)
The Effectiveness of Deep Brain Stimulation in Dystonia: A Patient-Centered Approach.
in Tremor and other hyperkinetic movements (New York, N.Y.)
Eggink H
(2019)
Motor and non-motor determinants of health-related quality of life in young dystonia patients.
in Parkinsonism & related disorders
Fearon C
(2020)
Medical management of myoclonus-dystonia and implications for underlying pathophysiology.
in Parkinsonism & related disorders
Fung W
(2018)
Does 22q11.2 deletion syndrome contribute to the genetic aetiology of Parkinson's disease?
in Journal of Neurology
Fung W
(2019)
What is the role of the cerebellum in the pathophysiology of dystonia?
in Journal of Neurology
J Peall K
(2017)
The long-term neuropsychological features of basal ganglia encephalitis
in Developmental Medicine & Child Neurology
Jones LA
(2019)
A Case of Treatment Resistance and Complications in a Patient with Stiff Person Syndrome and Cerebellar Ataxia.
in Tremor and other hyperkinetic movements (New York, N.Y.)
Description | Dystonia group within Welsh Neurological Alliance |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | This has led to improvements in the provision of care for individuals with movement disorders in South Wales and the wider region. |
Description | James Lind Alliance Priority Setting Partnership for adult-onset dystonia |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Description | Medical Advisor to The Dystonia Society UK |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Involvement with The Dystonia Society has highlighted the shortfall in therapeutic services provided to patients with Dystonia in Wales. This has lead to discussions with clinical leads and Heath Board directors in several of the regions to review access to services, delivery and future development. This is an ongoing advisory role. |
Description | Member of the International Myoclonus Dystonia Study Group |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Description | A comprehensive assessment of motor and non-motor symptoms in primary blepharospasm to aid stratification of disorder phenotypes |
Amount | £15,000 (GBP) |
Organisation | Fight for Sight |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2019 |
End | 01/2020 |
Description | A microstructural imaging approach to determine morphological neuronal differences in adult-onset focal cervical dystonia |
Amount | £180,000 (GBP) |
Organisation | Association of British Neurologists (ABN) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2021 |
End | 08/2024 |
Description | Dystonia Medical Research Foundation |
Amount | $70,000 (USD) |
Organisation | Dystonia Medical Research Foundation Canada (DMRFC) |
Sector | Charity/Non Profit |
Country | Canada |
Start | 03/2017 |
End | 04/2019 |
Description | Exploring the feasibility of an internet-based cognitive behavioural therapy programme as a non-pharmaceutical therapeutic intervention for people diagnosed with primary dystonia. |
Amount | £115,000 (GBP) |
Organisation | Gossweiler Foundation |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 03/2019 |
End | 03/2021 |
Description | Heath and Care Research Wales Health PhD Studentship |
Amount | £60,000 (GBP) |
Organisation | Health and Care Research Wales |
Sector | Public |
Country | United Kingdom |
Start | 01/2021 |
End | 01/2024 |
Description | Hodge Translational Neuroscience PhD Programme |
Amount | £130,000 (GBP) |
Organisation | Cardiff University |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2023 |
End | 10/2026 |
Description | KESS2 East PhD Fellowship |
Amount | £70,000 (GBP) |
Organisation | European Union |
Sector | Public |
Country | European Union (EU) |
Start | 06/2019 |
End | 07/2022 |
Description | MRC Clinician-Scientist |
Amount | £800,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 04/2021 |
Description | MRC Transition Support award CSF Kathryn Peall |
Amount | £484,585 (GBP) |
Funding ID | MR/V036084/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2022 |
End | 07/2025 |
Description | Myoclonus Dystonia Project Grant |
Amount | $15,000 (USD) |
Funding ID | 512415 |
Organisation | Dystonia Medical Research Foundation Canada (DMRFC) |
Sector | Charity/Non Profit |
Country | Canada |
Start | 03/2017 |
End | 12/2018 |
Description | Neuroscience and Mental Health Research Institute Seedcorn Funding |
Amount | £5,000 (GBP) |
Organisation | Cardiff University |
Department | Neuroscience and Mental Health Research Institute |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2017 |
End | 07/2018 |
Description | Ser Cymru Enhancing Competitiveness Infrastructure Award application |
Amount | £5,000 (GBP) |
Organisation | Government of Wales |
Sector | Public |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2021 |
Description | Translation of novel microstructural imaging techniques for use in prognosis and management of adult-onset focal dystonia |
Amount | £30,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2021 |
End | 08/2024 |
Description | WCAT scheme - trainee appointed to runthrough academic training, including fully funded PhD |
Amount | £1,000,000 (GBP) |
Organisation | Health Education and Improvement Wales |
Sector | Learned Society |
Country | United Kingdom |
Start | 07/2020 |
End | 07/2028 |
Title | Diagnostic code algorithm for identification of dystonia cohort through clinical record linked data |
Description | Through work with the SAIL databank at Swansea University, we have developed an algorithm for identification of patients diagnosed with adult-onset dystonia which has also undergone clinical validation and shown to have a sensitivity of 79%. We have applied this algorithm to derive a dystonia cohort from both the SAIL databank and UK Biobank. |
Type Of Material | Computer model/algorithm |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This algorithm has been published in the European Journal of Neurology, with the details of the algorithm made publicly available with this publication. This has been used to establish annual prevalence and incidence rates for dystonia over a 20-year period, as well as as going on to investigate diagnostic and prescription rates for psychiatric disorders over this time period. |
Title | Dystonia DNA sample set |
Description | Recruitment of one of the largest cohorts of individuals with dystonia, with associated motor and non-motor clinical data, and biological samples. |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | No |
Impact | None as yet - we are hoping to publish the first tranche of work from this cohort this year. |
Title | Establishment on an international Myoclonus Dystonia Registry and online non-motor symptoms study |
Description | This is an entirely electronic registry and study, whereby individuals are able to registry and consent to involvement via an online portal. For those over 18 years of age we have developed an online series of questionnaires covering memory, mood, sleep, pain and quality of life to be able to be completed at their convenience. This portal also facilitates repeated annual information collection to allow of longitudinal data collection. |
Type Of Material | Database/Collection of data |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | This registry is available to the International Myoclonus Dystonia Study Group to help guide the future direction of work. |
Title | Move Wales data base |
Description | This work has resulted in the development of the Welsh Movement Disorder Research Network, an intranet based database allowing entry points at each patient visit. |
Type Of Material | Database/Collection of data |
Provided To Others? | No |
Impact | This database has allowed us to begin to collect longitudinal information regarding symptoms relating to motor, psychiatric, cognitive, sleep and pain features. |
Description | Co-Chair of the International Movement Disorders Society Dystonia Study Group |
Organisation | International Parkinson and Movement Disorder Society (MDS) |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | I co-chair this group with Davide Martino (Calgary) with a multi-national steering group spanning Europe, the Americans, Oceana and Africa. This group has several ongoing initiatives: a) the development of a clinical non-motor screening tool for dystonia *Dr Martino and I run this project. b) an update on the dystonia classification system c) clinical determinants of the differences between dystonic and essential tremor |
Collaborator Contribution | Other partners in this group are leading projects (b) and (c) above. We also encourage set-up of new projects iteratively with the aim of s many centres as possible becoming involved. |
Impact | This group has already published the outcomes of a dystonia non-motor workshop undertaken in 2023 (https://doi.org/10.3389/dyst.2023.11860; Non-motor symptoms in dystonia: from diagnosis to treatment). We also plan to publish the development of our novel non-motor screening tool. |
Start Year | 2024 |
Description | Collaboration with Betsi Cadwaladr University Health Board |
Organisation | Betsi Cadwaladr University Health Board |
Country | United Kingdom |
Sector | Public |
PI Contribution | Betsi Cadwaladr University Health Board have been established as a further recruitment site for our longitudinal dystonia phenotypic study. This has involved the research delivery network within Wales. |
Collaborator Contribution | Our partners are involved in participant identification, recruitment and blood sample collection. |
Impact | We are anticipating several future publications. |
Start Year | 2019 |
Description | Collaboration with DRI Transcriptomic group - Webber & Sandor |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This collaboration has resulted in the award of a PhD studentship focusing on transcriptomic analysis of samples from longitudinal cohorts involving recruitment of patients diagnosed with Parkinson's disease. My contribution involved project conception, contribution to grant writing and selection of individual to post. |
Collaborator Contribution | Professor Webber and Dr Sandor provide world-leading expertise in transcriptomic analysis and have worked for many years with the datasets being used for this project. |
Impact | PhD Studentship award from Health and Care Research Wales. |
Start Year | 2020 |
Description | Collaboration with Dr Manju Kurian's group - UCL |
Organisation | University College London |
Department | Institute of Child Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The genetic findings from this work have provided some input to the ongoing work of this group. It has also led to further work between the two groups on CSF neurotransmitter analysis. |
Collaborator Contribution | Dr Kurian's group principally focuses on the identification of novel disease-causing genes and their translation into cellular and animal models, mainly in relation to disruption to monoaminergic neurotransmission and movement disorders. Collaboration with group has greatly helped with development of my skills and interpretation of whole exam sequencing analysis. |
Impact | Outputs include one article in submission and another in preparation. |
Start Year | 2014 |
Description | Collaboration with Movement Disorders Research and Clinical Teams in Dublin, Ireland |
Organisation | Trinity College Dublin |
Department | Neurology |
Country | Ireland |
Sector | Academic/University |
PI Contribution | I was invited to speak at one of their lay information days in Dublin. From here we realised that there was significant overlap in the work that we were doing, and that there would be significant value in working together. We are currently looking to gain ethical approval for our work in Ireland. |
Collaborator Contribution | They have been involved in participant identification, and notification of study to patients who potentially ma be interested in participating. |
Impact | Nil as yet. |
Start Year | 2018 |
Description | Collaboration with NIH funded Dystonia Coalition |
Organisation | Emory University |
Country | United States |
Sector | Academic/University |
PI Contribution | This collaboration involved each group contributing an independently recruited cohort for comparative analysis. Our group therefore contributed a cohort of deeply phenotypes participants diagnosed with adult-onset idiopathic, isolated focal cervical dystonia. |
Collaborator Contribution | Our collaborators, the Dystonia Coalition located at Emory University (USA) contributed data from an already recruited cohort of participants with the same disorder. |
Impact | We currently have a manuscript of this work in submission. We anticipate that this should form the framework for multiple future collaborations. |
Start Year | 2020 |
Description | Collaboration with Paediatric Movement Disorders Team, Barcelona, Spain |
Organisation | Hospital Sant Joan de Deu |
Country | Spain |
Sector | Hospitals |
PI Contribution | We ar working with the team in Barcelona to facilitate participation of the Spanish Myoclonus Dystonia community to participate in the international registry and online study. |
Collaborator Contribution | They have provided assistance with local ethical applications and ensuring that the language of the questionnaires is appropriate for a clinical study. They have also actively advertised the study to their patients and the wider neurological community. |
Impact | No formal outcomes as yet. We anticipate several high-impact publications. |
Start Year | 2017 |
Description | Collaboration with Professor Marina Tijssen, The Netherlands. |
Organisation | University Medical Center Gronigen |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | We are collaborating in developing an international database of patients with Myoclonus Dystonia. In addition a PhD student from The Netherlands will be visiting Cardiff to undertake further clinical research. |
Collaborator Contribution | Data and visiting PhD student. |
Impact | No outcomes as yet. |
Start Year | 2017 |
Description | Collaboration with Sydney Adult and Paediatric Movement Disorders Teams as part of the Global MD Registry |
Organisation | University of Sydney |
Department | Obstetrics Sydney |
Country | Australia |
Sector | Academic/University |
PI Contribution | We have instigated this collaborative partnership as part of the Global Myoclonus Dystonia Registry, for which we are the lead centre. The local teams are involved in identifying potential participants and directing them towards are website, where they are able to consent to involvement and complete a series of questionnaires. |
Collaborator Contribution | Identificaion of study participants, and advertisement of the study throughout Australia. |
Impact | No outputs as yet, although we anticipate a number of publications one the registry has completed the first full data set. |
Start Year | 2018 |
Description | Dystonia Non-Motor Care Pathways |
Organisation | University of Calgary |
Department | Department of Clinical Neurosciences |
Country | Canada |
Sector | Academic/University |
PI Contribution | Led my the Calgary team, and also involving US members of the Dystonia Coalition, as well as collaborators in Australia. Collectively we are evaluating psychiatric measures in dystonia to determine the most helpful and efficient assessment protocol. We're undertaking 20 clinical questionnaire assessments to contribute to the wider pool (target 200 participants) - this involves completion of a number of psychiatric questionnaires both online and face-to-face. |
Collaborator Contribution | Calgary team were the leads in the grant application writing and overall study protocol. They will also lead in the collation, clean up and analysis of the data. This will ultimately lead to peer-review publication with contribution from all centres. |
Impact | Not as yet, but very likely important contribution to the field. |
Start Year | 2022 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Aneurin Bevan University Health Board |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Betsi Cadwaladr University Health Board |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Cardiff and Vale University Health Board |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Guy's and St Thomas' NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Hampshire Hospitals NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Leicestershire Partnership NHS Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | North Bristol NHS Trust |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Portsmouth Hospitals NHS Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Salisbury NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | Solent NHS Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | The Walton Centre NHS Foundation Trust |
Country | United Kingdom |
Sector | Public |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | Establishment of dystonia recruitment network in England and Wales |
Organisation | University Hospital Southampton NHS Foundation Trust |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | With Cardiff as the lead centre, we have set up recruitment sites in 3 Welsh NHS sites and 10 English NHS sites (through the HCRW and NIHR portfolio study system). The aim with each of these sites is the recruitment of individuals with diagnoses of dystonia with the aim of collecting longitudinal motor and non-motor clinical data, as well as DNA samples for future genetic analysis. |
Collaborator Contribution | Partner sites are involved in the identification and recruitment of participants. |
Impact | We have now recruited >1000 participants with a target number of 5000. |
Start Year | 2019 |
Description | The International Myoclonus Dystonia Study Group |
Organisation | Dystonia Medical Research Foundation Canada (DMRFC) |
Country | Canada |
Sector | Charity/Non Profit |
PI Contribution | This is a recently established group. I was invited to speak at the Dystonia Medical Research Foundation event on Myoclonus Dystonia (Miami, USA February 2016), talk entitled: Psychiatric co-morbidty in Myoclonus Dystonia |
Collaborator Contribution | This group is made up of the principal movement disorder centres throughout the US, Canada, France, Netherlands and the UK. A commitment to regular meetings has been made. Funding is now available as seed corn grants every two years for projects that relate directly to Myoclonus Dystonia. This group also has strong links with the lay community and the Dystonia Coalition (NIH Rare Disorders project) |
Impact | Outcomes: 1. Clinical update to be reported in Movement Disorders Clinical Practice journal 2. Meeting set for June 2016 3. Development of therapeutic guidelines |
Start Year | 2016 |
Title | Online CBT intervention for treatment of mood disorders in dystonia |
Description | This issue a validated online CBT programme for the treatment of anxiety and depression in dystonia. We have completed feasibility work (published) demonstrating success with an entirely virtual model for delivery and assessment. We are currently applying for further funding to undertake pilot work to introduce a psychologist led guided component as well as to integrate sleep assessments, creating a far more comprehensive clinical care pathway for dystonia, involving both motor and non-motor symptoms. |
Type | Therapeutic Intervention - Psychological/Behavioural |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2022 |
Development Status | Actively seeking support |
Impact | The development process has highlighted the importance of fully integrated psychology services into clinical care pathways for dystonia. |
URL | https://pubmed.ncbi.nlm.nih.gov/34927048/ |
Description | Chair, James Lind Alliance Priority Setting Partnership for adult-onset dystonia |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | This is a formalised co-production process involving healthcare professionals, individuals with lived experience of dystonia, and the third sector. Through a combination of workshops and large external questionnaires, the final top 10 research priorities for the field will be generated. |
Year(s) Of Engagement Activity | 2024 |
Description | Dystonia Europe: Platform presentation to lay audience (non-motor symptoms in dystonia) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Presentation to largest lay dystonia meeting in Europe (organised every 4-years) combining Dystonia Europe and Dystonia UK. |
Year(s) Of Engagement Activity | 2019 |
Description | Dystonia Lay Group Virtual Event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Due to the covid pandemic the majority of planned events for 2020 had been cancelled. However, our local team - in collaboration with Dystonia UK - set up a series of virtual events, including a patient day highlighting region-specific services, areas in need of improvement and plans afoot to address these. |
Year(s) Of Engagement Activity | 2020 |
Description | Dystonia Medical Research Foundation: Myoclonus Dystonia Webinar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Interactive webinar highlighting resources available for those interested in participating in, or are involved in, research relating to Myoclonus Dystonia. |
Year(s) Of Engagement Activity | 2020 |
Description | Dystonia UK Virtual Sleep Event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | This was a virtual session discussing the evidence for sleep disturbance in dystonia, and what measures can be undertaken to help improve this. This focused on our previous work, now published, evaluating the information derived from wrist wearable devices in objectively understanding sleep disturbance in dystonia. |
Year(s) Of Engagement Activity | 2022 |
Description | Focus piece for Academy of Medical Sciences Newsletter |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | This was a focus piece written about by career to date, and how an earlier award of an AMS Clinical Starter Grant had been pivotal in onward grant and fellowship award success. |
Year(s) Of Engagement Activity | 2021 |
Description | International Dystonia Non-Motor Study Group - Co-Chair - Supported by the Dystonia Medical Research Foundation |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Co-Chairing, with publication of key outcomes, of a non-motor symptoms in dystonia workshop. International participation with the aim of evaluating where we are with evidence and look at key strategies for effective and meaningful work to move these areas forward. |
Year(s) Of Engagement Activity | 2023 |
Description | International virtual workshop - Dystonia Think tank |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I provided a detailed overview of our work examining the non-motor phenotypes of dystonia from the UK Biobank, and how these can be related to genetic underpinnings. This was an expert think tank group, aimed at generating discussion and ideas for future research projects. |
Year(s) Of Engagement Activity | 2022 |
Description | Lay Advisory Group for ongoing research projects |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | We are establishing a lay advisory group to work alongside the movement disorder research group, to provide advice, reading of participant information and develop research ideas. |
Year(s) Of Engagement Activity | 2016,2017 |
Description | Meeting with Welsh Health Minister and local lay organisation |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Policymakers/politicians |
Results and Impact | Meeting with Welsh Government Minister for Health (Vaughn Gethin) and civil servants to discuss development of local movement disorders services, notably those for individuals with dystonia. Result of this was a letter from government to all regional health boards asking for greater investment. Over the past 12-months we have appointed another movement disorders specialist and specialist nurse practitioner. |
Year(s) Of Engagement Activity | 2019 |
Description | Non-motor symptoms in Dystonia (DBS Conference, London) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation of the evidence for non-motor symptoms in dystonia, the more common symptom groups that are identified and how best to ensure that these are not missed in routine clinical practice. Talk given to >100 professionals working in the DBS field (predominantly specialist nurses), industry partners and members of lay organisations. |
Year(s) Of Engagement Activity | 2018 |
Description | Parkinson's UK Excellence Group meting - lay and professional members |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk given about genetic testing in Parkinson's disease. This needed to cover a broad group of attendees including patients, their relatives, medical practitioners in general and professional fields. |
Year(s) Of Engagement Activity | 2017 |
Description | Radio broadcast interview following Nature Medicine publication - with Times Radio |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Following publication of our manuscript relating to the ability of accelerometers to be able to predict development of Parkinson's disease up to 7-years in advance of disease development (published in Nature Medicine) this interview was to discuss the main findings of the study. |
Year(s) Of Engagement Activity | 2023 |
Description | Talk given at Parkinson's Disease Specialist Nurses Annual Meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Talk given regarding the genetic underpinning of Parkinson's Disease, and how and when to undertake genetic testing. This was to a national audience of Parkinson's Disease Specialist Nurses. |
Year(s) Of Engagement Activity | 2018 |
Description | Talk on non-motor symptoms in primary dystonia to lay meeting organised by Dystonia Ireland. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I gave a talk giving an overview of our previous research into the non-motor symptoms in dystonia, our findings and how this had influenced our current longitudinal study. This was also an opportunity to establish further collaborations, and recruitment of participants to our study. |
Year(s) Of Engagement Activity | 2018 |
Description | Talk to the British Neurotoxin Network Annual Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | I gave a talk at the annual BNN meeting discussing our ongoing research, and in particular our longitudinal study exploring the non-motor phenotype in primary dystonia. |
Year(s) Of Engagement Activity | 2018 |