A pilot clinical trial for McArdle disease
On 10 October 2011 the Muscular Dystrophy Campaign (MDC) announced a significant grant for a McArdle Disease trial. We hope that AGSD-UK will also assist with this trial, which will be the first ever 'safety and effectiveness' trial of a drug in McArdle Disease. This is early stage work and any possible treatment is still many years away, but is a very exciting development.
You can read more about the grant here.
The AGSD-UK has been involved in supporting or cooperating with the following research projects.
Cognitive Function in McArdle Disease
The project was jointly funded by the Institute of Orthopaedics, Oswestry, and AGSD-UK. Researchers: Dr R Quinlivan and Dr NMJ Edelstyn.
The aims of the project were to explore high level cognitive functioning in patients with McArdle (GSDV). The project builds on two earlier studies:
• A pilot (see below) which identified an impairment in prefrontal-mediated decision making and reasoning in GSDV compared to age and IQ matched neuromuscular (nonGSD) control patients (Edelstyn & Quinlivan, 2007).
• A brain imaging study which showed glycogen accumulation in the centrum semiovale of a patient with GSDV (Salvan et al., 1997). This is a white matter tract which links the cerebellum with prefrontal areas. Imaging studies of people with autistic spectrum disorder, who show abnormalities in decision-making, reasoning and social activities have consistently reported structural abnormalities in this tract.
The aim of the reported study was, therefore, to explore cognitive function in a new group of 10 GSD patients. Specifically, we focused on decision-making, reasoning and social activities, driven by the prediction that abnormal accumulation of glycogen in the centrum semiovale of patients with GSDV would impair these cognitions compared to a nonGSD neuromuscular patient control group and healthy volunteers.
During the academic year 2009-2010 Ms Connie Parker, MSc student, successfully recruited three demographic- and IQ-matched groups participant groups consisting of 9 GSDV, 8 neuromuscular control patients and 8 healthy controls. Participants completed a neuropsychological test battery which assessed executive functioning, strategic memory and social functioning.
The key findings are these:
1. Compared to the healthy controls, the GSDV showed significant impairments on tests of strategic memory (source misattribution), and in the domains of social skills, attention switching and imagination.
2. There were NO significant differences between the GSDV and patient controls, however the GSDV mean scores were consistently poorer than the control patients.
Three interpretations of the findings are possible:
• patients with neuromuscular disorders exist on a continuum of cognitive impairment, with GSDV patients showing a more severe impairment than nonGSD patients;
• qualitative differences in cognitive function DO exist between GSDV and nonGSD neuromuscular patients, but these failed to materialise in our study due to small participant numbers;
• GSDV and nonGSD share certain cognitive changes (dependent on a common factor such as anxiety, depression, pain) as well as qualitative differences (contingent on glycogen accumulation disrupting cognitions dependent on the centrum semiovale).
The main outcome is a 3 year PhD application to the Muscular Dystrophy Campaign for Connie Parker to combine more extensive assessments of cognitive function with brain imaging in GSDV, nonGSD neuromuscular control patients and healthy volunteers. (No funding has so far been secured.)
Dr Quinlivan and Dr Edelstyn presented the main study findings at overseas conferences: World Muscle Society meeting in Japan, October 2010 (Quinlivan) and the Federation of European Societies of Neuropsychology in Holland, September 2010 (Edelstyn).
Model Systems for Developing Therapies for McArdle Disease
This is pathfinder research aimed at finding novel approaches to therapies. It is a three year project based at the Centre for Inherited Neuromuscular Disease (CIND) at the Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry. The main aim is to create tissue culture cell models with the R50X (previously R49X) mutation. (This is the mutation present in approx 85% of UK McArdle patients.) The project will then use this model for testing various treatments designed to efficiently correct the mutation. AGSD (UK) supported the research with a grant of £20,000. For a progress report see under Workshop Reports, 2006, Type V.
News release - 2nd February 2006
Psychological processes in McArdle disease
In 2007 Dr Ros Quinlivan and Dr Nicky Edelstyn completed a small study looking at psychological processes in 10 patients with McArdle disease and 10 control patients with other musculoskeletal conditions, such as central core myopathy and limb-girdle muscular dystrophy. The aim of this research project was to investigate whether McArdle disease patients process information differently to control patients.
Since this was the first study of its kind, a broad range of processes were examined, which included ability to divide attention between competing tasks as well as single modality visual and auditory attention, reaction time, phonetic fluency, learning, memory for pictures and words, immediate and delayed memory. The test of phonetic fluency required participants to produce a list of words beginning with F, A, S, on 3 separate trials. Participants were given 60 seconds to retrieve as many words as they could, and they were also instructed to avoid repetitions and neologisms (nonwords). Given these demands, phonetic fluency tasks engage several high-level or ‘executive’ processes such as working memory, self-awareness or self-monitoring, decision making and inhibition of inappropriate responses.
No differences emerged between the patient groups on tests of reaction time, attention, learning and memory pictures. However, the McArdle patients performed less well on the phonetic fluency and delayed memory tasks. This pilot data implies that McArdle disease may be marked by an alteration in executive processes and a subtle change in delayed memory. However, these are preliminary findings which need to be replicated and explored in more depth in a larger research study which assesses a wider range of executive and memory processes.
Many thanks to those attendees of the Oswestry clinic who participated in this study.
Dr Nicky Edelstyn, Senior Lecturer in Cognitive Neuroscience, School of Psychology, University of Keele.
Dr Ros Quinlivan, Consultant in Musculo-skeletal disorders, The Agnes Jones and Robert Hunt Orthopaedic Hospital, Oswestry.
Association for Glycogen Storage Disease (UK) LimitedRegistered Charity No 1132271