M. Eagle

The phenotype of limb-girdle muscular dystrophy type 2I

Background: Mutations in the fukutin-related protein gene FKRP cause limb-girdle muscular dystrophy (LGMD2I) as well as a form of congenital muscular dystrophy (MDC1C). Objective: To define the phenotype in LGMD2I. Methods: The authors assessed 16 patients from 14 families with FKRP gene mutations and LGMD and collected the results of mutation analysis, protein studies, and respiratory and cardiac investigations. Results: Thirteen patients, most with adult presentation, were homozygous for the common C826A mutation in FKRP. The three other cases were compound heterozygotes for C826A and two of them presented in childhood, with more progressive disease. The pattern of muscle involvement, frequently including calf hypertrophy, was similar to dystrophinopathy. Complications in patients with LGMD2I were common and sometimes out of proportion to the skeletal muscle involvement. Six patients had cardiac involvement, and 10 had respiratory impairment: five required nocturnal respiratory support. All patients had serum creatine kinase at least 5 to 70 times normal. The most consistent protein abnormality found on muscle biopsy was a reduction of laminin α2 immunolabeling, either on muscle sections or immunoblotting alone. Conclusions: LGMD2I due to FKRP mutations appears to be a relatively common cause of LGMD, with respiratory and cardiac failure as prominent complications.

Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients

The aim of this prospective longitudinal multi centric study was to evaluate the correlation between the Hammersmith Functional Motor Scale and the 20 item version of the Motor Function Measure in non ambulant SMA children and adults at baseline and over a 12 month period. Seventy-four non-ambulant patients performed both measures at baseline and 49 also had an assessment 12 month later. At baseline the scores ranged between 0 and 40 on the Hammersmith Motor function Scale and between 3 and 45 on the Motor Function Measure 20. The correlation between the two scales was 0.733. The 12 month changes ranged between -11 and 4 for the Hammersmith and between -11 and 7 for the Motor Function Measure 20. The correlation between changes was 0.48. Our results suggest that both scales provide useful information although they appeared to work differently at the two extremes of the spectrum of abilities. The Hammersmith Motor Function Scale appeared to be more suitable in strong non ambulant patients, while the Motor Function Measures appeared to be more sensitive to capture activities and possible changes in the very weak patients, including more items capturing axial and upper limb activities. The choice of these measures in clinical trials should therefore depend on inclusion criteria and magnitude of expected changes.

Six minute walk test in type III spinal muscular atrophy: a 12month longitudinal study.

The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was -1.46 (SD 50.1; range: -183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients.

Why are some patients with Duchenne muscular dystrophy dying young: An analysis of causes of death in North East England.

INTRODUCTION Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in children. Recent years have seen an increase in age of survival into adulthood following the introduction of proactive standards of care. We reviewed mortality in DMD in our population in order to identify potential underlying risk factors for premature death and improve clinical care. METHOD A retrospective case note review of all deaths in the DMD population over the last 10 years in North East England. We identified 2 groups of patients: patients who died from underlying cardiac and/or respiratory failure (group 1) and patients who died unexpectedly in the absence of underlying cardio-respiratory failure (group 2). RESULTS Detailed information was available on 21 patients. Mean age of death in group 1 (17 patients) was 23.9 (14.4-39.5) years, in group 2 (4 patients) 14 (12.7-14.9) years. Causes of death in group 2 were acute pneumonia, cardiac arrest, acute respiratory distress and multi-organ failure. Across both groups we identified concerns regarding respiratory failure, inadequate nutrition, non-attendance at appointments, suboptimal coordination of care and decreased psychological wellbeing. In group 2, fat embolism, cardiac arrhythmia and adrenal insufficiency were also potential contributing factors. CONCLUSIONS The main cause of death in DMD in our population remains cardio-respiratory failure. Four patients (19%) died in their teenage years in the absence of severe cardiorespiratory failure. A more thorough understanding of the impact of DMD and its treatment on all organs systems is required to minimise the risk of an untimely death.

Developing standardized corticosteroid treatment for Duchenne muscular dystrophy

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

P.2.5 Performance of Upper Limb Scale for use in Duchenne muscular dystrophy – An iterative process to establish its suitability for clinical trials

In 2012 a group of international physiotherapists specializing in neuromuscular assessments devised a ClinRO to assess upper limb performance (PUL) for use in Duchenne muscular dystrophy (DMD). An exploratory Rasch analysis helped establish version one of the PUL although it was recognized at the time further analysis was required in a larger subset to confirm these preliminary findings and potentially remove redundant items. The aim of this study is to repeat the analysis in a larger cohort, again on an international level. Over 300 assessments from both ambulant and non-ambulant individuals with DMD were analysed using RUMM2030 from Italy, UK, Belgium and USA. The age range was from 4 to 25 and data were examined for psychometric properties including clinical meaning, targeting, response categories, fit, reliability, dependency, stability and interval level measurement. Following analysis each item was reviewed both for scoring options and redundancy and a revised scale produced (Version two). Psychometric analysis confirmed the preliminary findings and also highlighted areas where some items were potentially redundant. A shortened/ revised scale was created by the expert group. This iterative process of ClinRO development is essential to establish a robust measure. Further work needs to be conducted on reliability and responsiveness to confirm the PUL’s suitability for inclusion in clinical trials.

The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy

Objective With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids. Methods Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores. Results On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively. Conclusions Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials.

P71 International clinical outcomes study in dysferlinopathy (COS): results of screening questionnaires in UK patients

Mutations in dysferlin cause a variety of phenotypes collectively known as dysferlinopathies, including Limb Girdle Muscular Dystrophy type 2B and Myoshi Myopathy. Although there is currently no treatment for dysferlinopathies there is a need to develop clinically validated outcome measures in dysferlinopathy in preparation for future clinical trials. The International Clinical Outcomes Study for Dysferlinopathy (COS) is a multicentre international study, funded by The Jain Foundation and sponsored by Newcastle upon Tyne NHS Foundation Trust, which aims to develop and validate clinical outcome measures in addition to collecting natural history data. The recruitment target of 150 patients has now been successfully achieved, with a total of 193 patients recruited in 14 centres worldwide, including 38 UK patients. Data will be collected over 3years, including physiotherapy and medical assessments, MRI and questionnaires. In this poster we present data from screening questionnaires, including mutations identified and patient-reported details of disease presentation in all 38 UK patients. In total 49 different mutations were identified. Mean age at symptom onset was 22.3years and mean time to subsequent diagnosis was 6.1years. Polymyositis was initially incorrectly diagnosed in 6/38 patients. Lower limbs were the most common first affected area (23/38), and muscle weakness the most frequent first symptom (20/38). This data confirms that dysferlinopathies primarily present in young adulthood, often initially with lower limb symptoms, and are associated with significant allelic heterogeneity. Completion of this study and subsequent analyses will enhance our understanding of the natural history this variable condition.

S.P.18 Clinical Evaluator training for the GSK DEMAND programme

Abstract High quality standardised training of Clinical Evaluators (CEs) in multi-centre clinical trials in Duchenne Muscular Dystrophy (DMD) is essential for reliable data. GSK is conducting clinical trials to evaluate the efficacy of an antisense oligonucleotide GSK2402968 in boys with DMD. The data by which interventions are measured are collected by CEs, primarily physiotherapists, but in some centres other professionals have been trained. Standardised, reliable and repeatable clinical evaluation is critical to the success of this clinical trial. Appropriate outcomes for ambulant boys including six minute walk distance, respiratory function tests, quantitative muscle testing, North Star Ambulatory Assessment and timed function tests were chosen. A ‘Master Physiotherapy’ team, consisting of eight experienced Neuromuscular Physiotherapists from the UK, Italy, Australia and the USA was established to provide a manual of operation, train in the standardised assessments and provide ongoing support to each CE and site. The team has developed a comprehensive package of training. Initial training included practical hands on sessions repeated over two days to facilitate learning, with the aim to standardise assessments, minimise inter and intra rater variability and reduce the potential for data drift. To ensure quality data collection throughout the duration of the trials and to support evaluators, sites submit video assessments at key points in the studies to Master Physiotherapists whom evaluate performance and provide feedback. Each CE receives follow up training via site visit or WebEx prior to the primary endpoint (efficacy) assessment. Since May 2010, the Master Physiotherapy team has trained 159 CEs in 65 sites across 24 countries, demonstrating that linguistic and cultural differences can be accommodated to give all sites the same opportunity to perform quality standardised assessments and work as a global team.

S.P.9 Development of an upper limb functional scale in dystrophinopathies

Abstract Development of appropriate outcome measures that are able to measure both deterioration and therapeutic effectiveness across the spectrum of severity in dystrophinopathies is complex. A multi-disciplinary international Clinical Outcomes Group consisting of clinicians, scientists, and patient advocacy groups specifically identified a need for a scale to measure motor performance of the upper limb. Out of this larger group, a Physiotherapy Focus Group was formed. Two in person meetings were held where existing upper extremity scales were reviewed for common elements and functional relevance in DMD. Individuals with DMD contributed in these meetings by participating in the proposed assessments and offering their expert opinion on task difficulty and relevance. In parallel, patient focus groups identified patient related outcome measures. The aim of the two parallel groups was to ensure that the scale clearly related to meaningful functional activities. A new scale, PUL (Performance of the Upper Limb), was then designed according to a specific contextual framework, of upper limb function in both ambulant and non-ambulant individuals with dystrophinopathy. The methodology included establishment of the scale framework considering functional muscle strength, growth and contractures on motor performance. Item generation was based on expert review of the assessments and test implementation. Item suitability was based on clinical progression patterns, patient testing and observation, scoring detail, and video review of movement patterns with item performance. Operational definitions and manuals were generated to standardize PUL assessments and piloted across seven international sites. The results from a preliminary Rasch analysis of 70 patients were then interpreted for clinical sensibility and the scale appropriately modified.