Mobility Group


The Clinical Research Team:

Dr Tracey Willis, Dr Richa Kulshrestha, Mr Nigel Kiely, Dr Yvette Easthope-Mowatt, Mr Nick Emery, Mrs Claire Bassie, Mrs Kate Jones.

Visiting teams include; Dr Ashish Chikermane, Dr Adrian Morley-Davies, Dr Sumran Kundu, Dr Mark Roberts, Dr Mark Rogers, Dr Julie Vogt.

The Laboratory Research Team:

Prof. Caroline Sewry, Prof. Glenn Morris, Dr Ian Holt, Dr Le Thanh Lam, Dr. Heidi Fuller, Darija Šoltić, Dr. Nguyen Thi Man.

Funded by the Orthopaedic Institute Ltd

A major event this year was the award of a new research grant from the British Heart Foundation for a new collaboration with the National Heart and Lung Institute (Imperial College, London) and the University of Edinburgh on Emery-Dreifuss muscular dystrophy. This 3-year project will be supervised by Dr Ian Holt. A new PhD student, Darija Šoltić, joined CIND with another 3-year project on spinal muscular atrophy, supervised by Dr Heidi Fuller.

The Clinical Team.

The clinical team has continued to grow and improve its service, now offering an adult neurologist appointment for those patients who are not purely neuromuscular. A new histopathologist also started in April 2017 and we now offer joint cardiac and muscle clinics for both children and adults with neuromuscular conditions, as well as a joint adult respiratory and muscle clinic (also a ventilation clinic).

The team has also been running ‘telephone clinics’ for the last 12 months to address increasing clinic numbers and to lessen the burden of a face to face consultation, especially when patients are stable. This is being audited by our specialist nurse for future modification of this service.

Involvement in clinical teaching continued with a very successful ‘Orthopaedic complications in neuromuscular conditions’ teaching day for the Northwest Network at RJAH in September 2016, and a planned Becker Muscular Dystrophy patient education day for September 2017.

The team is represented on a number of panels in the UK, Dr Willis chairs the muscle interest group meeting and the West Midlands Neuromuscular forum, with involvement in BPNA, BMS and the paediatric and adult Northstar forum for DMD, as well as heading up the palliative care and psychology group as pioneers in the ‘symptom control clinic’. The ‘symptom control clinic’ is a joint venture between the muscle team and the Severn hospice team and as of yet this is the first of these clinics in the UK, this therefore has received publicity and we will be presenting our work on this at the World Muscle Society meeting in Oct 2017.

FSHD (Facioscapulohumeral dystrophy) Arm cycling pilot study

Half the patients required for the ‘Arm cycling feasibility study’ have been recruited. This has been funded by the Orthopaedic Institute, looking at both the strength and endurance of patients with FSHD.  Results from this will then be used to apply for funding for a more extensive study involving imaging as well as biomarkers.

Clinical trials.

We have been the first site in the UK to recruit to the SIDEROS trial, which is a placebo controlled study looking into the use of Idebenone, an anti-oxidant for the improvement and preservation of lung function in both ambulant and non-ambulant patients with DMD.

We are a site for the Italfarmaco study in ambulant DMD boys and due to start recruiting in June 2017. This is a phase 2 trial looking at the anti-fibrotic nature of this drug in ambulant boys with DMD. Investigators found that Givinostat increases the size of myofibers, decreases inflammation and prevents formation of fibrosis in the mdx mouse model of muscular dystrophy.

We are continuing to recruit to the rare diseases study which is an NIHR funded study in DMD, looking at modifier genes that may contribute to the phenotype in DMD and in particular those genes that are ‘helper genes’ as these may present potential therapeutic use for up-regulation.

100K Genome project.

The team is recruiting families and patients for the 100K Genome Project, which aims to sequence the genomes of 100,000 patients with rare diseases, and has applied for an award by Genomics England (outcome known in July 2017). After a site visit by Genomics England, they felt that our model of service should be adopted across the whole West Midlands.

The MDA Monoclonal Antibody Resource.

New funding from the Muscular Dystrophy Association, a US Charity, until 2018 will enable Dr Le Thanh Lam to continue the characterisation of monoclonal antibodies and their distribution all over the world to researchers and clinicians involved in finding treatments, or improving diagnosis, for a wide variety of neuromuscular disorders. The antibodies are made freely available internationally and the cell lines that produce them will be given a permanent home in the Developmental Studies Hybridoma Bank (University of Iowa). The neuromuscular disorders to which the antibodies relate are Duchenne and Becker muscular dystrophies, myotonic dystrophy, congenital, limb-girdle and Emery-Dreifuss muscular dystrophies, spinal muscular atrophy and nemaline myopathy. Between October 2007 and May 2017, the Resource distributed 4,167 units of 396 different antibodies to 336 laboratories (46.0% in North America; 22% in EU; 26% in UK and 6% in the Rest of the World). This is an average of over 400 mAbs per year over the past 10 years. In addition, the Iowa Hybridoma Bank has distributed over 1,000 units on our behalf (mainly within the USA). These mAbs have played a major role worldwide in clinical trials of new treatments for the muscular dystrophies.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, resulting from low levels of the survival motor neuron (SMN) protein. Though promising approaches for the modest treatment of SMA have recently entered clinical trials, further work is necessary to bring hope of a cure closer to the horizon.

Dr Heidi Fuller, who leads SMA research within the team, completed a two-year SMA Trust-funded Fellowship last summer; the results of which were published in several journal articles, and presented at the Cure SMA research meeting in California and at the Mercia Stem Cell Alliance annual research meeting in Manchester. Following her permanent appointment to Lecturer in Medical Sciences in September 2016, Heidi has since turned her attention to developing the SMA research group capacity at RJAH. To this end, award of funding from the Keele University ACORN scheme has enabled a new PhD student, Darija Šoltić, to join the group for three years from Croatia. Darija’s project focuses on finding ways to rescue defects in SMA patient cells by pharmacological manipulation of molecular targets identified recently by the group using proteomics and bioinformatics technology (see Figure below). The project is further supported by the recent award of a “therapeutics mini-grant” that will enable the group to forge closer links with leading researchers at Edinburgh - and Glasgow University.

Nemaline Myopathy

Nebulin is a very large (600kDa) protein of the muscle contractile system and genetic mutations are a major cause of the inherited mobility disorder, nemaline myopathy. There are two forms of nebulin, one containing “exon 143 protein” and another in which this is replaced by “exon 144 protein” but no-one knows if these have different functions. Dr Le Thanh Lam is working with Prof Caroline Sewry to find out how the two forms are linked to the two major muscle types found in adult human muscle. They initially found that “fast” muscle fibres produce both nebulin forms, but “slow” muscle fibres contain only one of them. This study was done on biopsies from quadriceps muscle, but further work with different human muscles has shown that the relationship between nebulin-143 expression and fibre-type depends on the particular muscle being studied. Further work on this Institute-funded study may determine whether the contractile properties of different muscles are influenced by nebulin isoform expression.

Nesprins and Emery-Dreifuss muscular dystrophy.

Ian Holt and Heidi Fuller used site-directed mutagenesis and proteomics to show that the main interaction partner of the highly-conserved “STAR” domain of nesprins is kinesin, a protein which links nesprins to the microtubule system in cells. This explains why nesprins are essential for the correct movement and location of nuclei within muscle fibres. In a proteomics study to see which proteins in cultured muscle cells attached to normal nesprin only, and not to nesprin with the STAR domain deleted, kinesin stood out as the major protein involved. This study, supported by the Institute of Orthopaedics, won second poster prize on Research Day, 2017.

Popeye Proteins and Cardiac Conduction.

Dr Ian Holt has made new monoclonal antibodies (mAbs) against Popeye proteins for a collaborative project with Thomas Brand of the National Heart and Lung Institute (London) funded by the British Heart Foundation.

Conduction defects are a characteristic feature of Emery-Dreifuss muscular dystrophy (EDMD), which usually requires a pacemaker or, in extreme cases, a heart transplant. They also occur sub-clinically, however, in about half the UK population and understanding regulatory mechanisms in cardiac conduction (how the regular beating of the heart is maintained) is a major aim of cardiac research.

Mice lacking Popeye proteins have cardiac conduction defects that mimic “sick sinus syndrome” in humans, a disorder that require a pacemaker to be fitted. Popeye proteins are made from 3 genes, POPDC1, 2 & 3, and are transmembrane proteins that interact with the main cardiac-specific sodium channel in cardiac membranes and bind cyclic AMP very strongly. Recently, a mutation in POPDC1 was shown to underlie a limb-girdle muscular dystrophy with heart-block, a disorder closely-related to EDMD. We have made mAbs against all 3 POPDC proteins and work is continuing to produce a library of mAbs with different properties and applications to aid in understanding Popeye function. As expected, the new mAbs locate Popeye proteins to the plasma membrane of muscle fibres in cross-sections of human muscle biopsies (se Figure below).



This year has been a busy one for ORLAU.  Our clinical services continue to be very popular with patients and referring clinicians so we have had to work hard to make sure our patients are not kept waiting too long.  Despite being very busy with patients ORLAU staff have made progress on a number of research projects, including some new initiatives which we hope will bear fruit in the coming year.

The majority of ORLAU’s assessments and treatments are focused on the lower limbs and mobility problems.  We do, however, have a growing interest in providing services for patients with upper limb problems, in particular for hemiplegic children and adults.  Sarah Jarvis and Rob Freeman have been working with Simon Pickard from the Trust’s upper limb surgical team to develop new services.  They are particularly interested in using our movement analysis technology, which is usually used to measure the leg, to analysis upper limb motion.  In particular they are exploring the use of electromyography (EMG) to plan treatments including functional electrical stimulation (FES) and muscle transfers.  This work has provided an opportunity for collaboration with colleagues at Keele University, including Ed Chadwick, Dimitra Blana and Anand Pandyan.  In the Autumn of 2016 a new PhD student started work with the team.  Mohammad Alshehab will be looking at the effectiveness of Lycra garments for children with a hemiplegia.

Will Bromwich has also been involved in a project to improve upper limb function.  For many years ORLAU has helped patients manage their tight muscles with a device known as a Contracture Correction Device or CCD.  Jane Bisiker, a clinical specialist occupational therapist working in Wolverhampton, is keen to use a CCD with patients who have suffered a stroke to prevent contractures, particularly in their elbows, wrists and fingers.  Will has been able to contribute ORLAU’s expertise to a project involving Keele University and manufacturer Beagle Orthopaedic.  Over the last year the team have been working on their protocols and developing pilot devices.

Historically the ORLAU CCD has mostly been used to stretch the joints in the lower limb, particularly the knee and ankle.  Keith Miller and the rehabilitation engineering team are keen to continue to develop the ORLAU designs.  The CCD incorporates a gas spring to apply a stretching force and this spring needs to be compressed before the device is applied.  The compression and release of the spring can be difficult for patients to do on their own and so the team having been working on new design options to make this process more straightforward.  The rehabilitation engineering team are also planning to work on improvements to other key ORLAU devices, including the standing frame.

In our design development work we have been assisted by a number of clinical scientist trainees.  ORLAU is a training centre, taking a new graduate engineer every other year for a three year training programme.  Whilst they are with us these engineers are able to get involved in a number of pilot development and measurement projects.  They have been calibrating equipment, writing analysis code, implementing computer models and producing conceptual designs.  There is also a requirement to conduct a research project as part of their MSc studies.  Our current third year trainee, Piotr Rymaszewski has been building and testing computer models of the calf muscle, using a software package, OpenSim.  This project fits in with a long history of musculoskeletal modelling work in ORLAU and recent work by Caroline Stewart looking at the length of the calf muscle during gait.  Piotr made use of optimisation techniques to predict the muscle morphology of children who walk on their toes, either due to an idiopathic gait pattern or because they have cerebral palsy.  His approach looks promising and he has been able to submit an abstract to the annual ESMAC conference.

Piotr’s work will be continued by another new Keele PhD student, Shallum Sardar, who began his studies in Autumn 2016.  He will continue to refine the musculoskeletal modelling optimisation techniques, incorporating ultrasound measurements of muscle morphology.  In the latter stages of his research he will look at ankle foot orthosis (AFO) design, in conjunction with the orthopaedic company Opcare.  Opcare are co-funding Shallum’s PhD along with the Institute of Orthopaedics and Keele’s ACORN scheme.

2017 saw the final publication of a series of papers prepared by Andrew Metcalfe, in conjunction with the ORLAU team on knee arthritis.  Andy’s PhD focussed on gait patterns before and after total knee replacement, looking at muscle activity and joint loading in both the affected and unaffected knee joints. 

Pictured is Andrew Metcalfe Associate Professor in Truma & Orthopaedics at University of Warwick

Knee mechanics continues to be an area of interest for ORLAU, with Neil Postans and Justine Bee producing work on the biomechanics of movement after anterior cruciate ligament (ACL) repair, work  which was presented at the 2016 ESMAC meeting in Seville.  Justine’s data collection produced a very substantial data set which requires further detailed analysis over the next year.  We are also looking forward to working with Jan Herman Kuiper and John Garcia on the recently awarded MRC funded project looking at the mechanisms whereby knee cartilage defects heal.  ORLAU’s contribution will include gait analysis for patients with defects in order to determine the local biomechanical conditions experienced by the defect during walking.  We are also participating in the national Osteoarthritis Technology NetworkPlus programme, running from Cardiff University.

In 2016 ORLAU was given permission by the Trust to recruit some new clinical, technical and administrative staff to cope with our high level of clinical demand.  From April 2017 we have been able to increase our clinical capacity and so, hopefully, staff will have time to develop these exciting new ideas further in the next year.