Glucocorticoids are currently used to improve muscle strength and prolong ambulation in boys with DMD although the effect on bone health is still unclear. The aim of this study was to compare bone strength in healthy children and boys with DMD and investigate the interaction between diminished muscle function, loss of ambulation and high dose oral steroids, over a two year time frame. Fifty children were studied, 14 healthy boys (HB), 13 boys with DMD who remained ambulant (DMD-RA) and 23 boys with DMD who lost ambulation (DMD-LA). All boys with DMD had taken oral glucocorticoids. Peripheral quantitative computed tomography was used to measure bone geometry, density, strength and muscle mass of the non-dominant tibia and radius. Measurements were made at baseline, 12 and 24 months at the distal metaphysis and mid diaphysis sites. Differences between the three groups were evaluated using ANOVA and a repeated measures model. There were no significant differences in age between the groups: mean age was 9.4, 8.7 and 8.8 years for HB, DMD-RA and DMD-LA, respectively. There was no significant difference in steroid exposure between the DMD groups. However, boys who lost ambulation had significantly lower muscle function at baseline (North Star Ambulatory Assessment DMD-RA 23.6 vs. DMD-LA 18.8; p < 0.05). At baseline, healthy boys had significantly greater trabecular bone density at the distal radius /ulna (23%/27%) and distal tibia/fibula (30%/46%) than boys with DMD (p < 0.05). They also had significantly larger diaphyseal tibiae/fibulae (74%/36%) and radii/ulnae (49%/31%) with thicker corticies and consequently greater bone strength. In contrast, boys with DMD had greater cortical density (4%). Over time, there were small significant differences in the rate of change of both muscle and bone parameters between healthy boys and boys with DMD. For both ambulant and non-ambulant boys with DMD the greatest changes in cortical bone were evident at the tibia. After two years boys with DMD had on average, 63% less bone strength than healthy boys. However, the most strikingly significant difference was in trabecular bone density for boys who became non-ambulant. By 2 years non-ambulant DMD boys had 53% less trabecular bone density at distal tibia than their healthy age matched peers compared with boys who remained ambulant who had 27% less trabecular bone density. In conclusion, bone and muscle strength is reduced for all boys with DMD even while they remain ambulant. However, tibia trabecular bone density loss is significantly accelerated in DMD boys who lose independent ambulation compared to DMD boys who remain ambulant despite equivalent levels of corticosteroid exposure.

This is a service review of the orthotic care provision for children with neuromuscular disorders. Patients from across the region are seen in the neuromuscular clinic and assessed by a neuromuscular physiotherapist who then liaises with the local physiotherapy teams and orthotists. There was significant variation identified in the orthotic care provided to patients seen in the neuromuscular centre. This appears to be dependent on local experience, training and differences in commissioning and service arrangements. The lack of appropriate services in some areas creates a gap that is addressed on an individual case basis with an unsatisfactory journey for the patient and family. Orthoses are important in controlling contractures and maintaining or optimising joint position; appropriate provision is an essential part of managing the progression of muscle disease and promoting function. An audit of current orthotic care across the region is used in addition to patient experience to evaluate the current service. Patients with a range of neuromuscular disorders attending the neuromuscular clinic will be identified via patient database and approached to complete patient and carer questionnaires. A neuromuscular physiotherapist will review the appropriateness of the child's orthosis, compliance with their recommendations which are based on the standards of care for certain conditions and the patient satisfaction with the orthotic provision. The findings will be used to assess the current situation in orthotic care for children with neuromuscular disorders in our region and evaluate the need for a specialist orthotic provision to be established and provided directly via the neuromuscular centre. Gaps in training and services will be addressed through working collaboratively with local teams whilst considering options for centralised specialist orthotic care.

Oral glucocorticoids (GC) preserve muscle strength and prolong walking in boys with Duchenne muscular dystrophy (DMD). Although vertebral fractures have been reported in boys taking GC, fracture rates for different GC regimes have not been investigated. The aim of this pragmatic longitudinal study was to compare growth, body mass, bone mineral density (BMD), vertebral fractures (VF) and ambulatory status in boys with DMD on daily (DAILY) or intermittent (INTERMITTENT), oral GC regimens. A convenience sample of 50 DMD boys from two centres was included in the study; 25 boys each were on the DAILY or INTERMITTENT regimen. Size adjusted lumbar spine BMD (LS BMAD), total body less head BMD (TBLH), by DXA and distal forearm bone densities by pQCT, GC exposure, VF assessment and ambulatory status were analysed at three time points; baseline, 1 and 2 years. At baseline, there were no differences in age, GC duration or any bone parameters. However, DAILY boys were shorter (height SDS DAILY = -1.4(0.9); INTERMITTENT = -0.8(1.0), p = 0.04) with higher BMI (BMI SDS DAILY = 1.5(0.9); INTERMITTENT = 0.8(1.0), p = 0.01). Over 2 years, DAILY boys got progressively shorter (delta height SDS DAILY = -0.9(1.1); INTERMITTENT = +0.1(0.6), p < 0.001). At their 2 year assessment, 5 DAILY and 10 INTERMITTENT boys were non-ambulant. DAILY boys had more VFs than INTERMITTENT boys (10 versus 2; chi(2) p = 0.008). BMAD SDS remained unchanged between groups. TBLH and radius BMD declined significantly but the rate of loss was not different. In conclusion, there was a trend for more boys on daily GCs to remain ambulant but at the cost of more VFs, greater adiposity and markedly diminished growth. In contrast, boys on intermittent GCs had fewer vertebral fractures but there was a trend for more boys to loose independent ambulation.

Objective: Utrophin modulation is a putative therapeutic approach for Duchenne muscular dystrophy (DMD) regardless of the underlying dystrophin mutation. Ezutromid is a small-molecule utrophin modulator. Phase 1 trials with ezutromid's first formulation F2 revealed substantially lower exposure in DMD boys than healthy volunteers. A further trial using slightly modified F2 (F3) with a balanced diet enabled most DMD patients to achieve drug levels estimated to induce ≥30% increases in utrophin protein from in vitro data. This Phase 1 trial investigated whether a new ezutromid formulation (F6), given with a balanced diet, offers further PK improvements. Methods: The dose-escalating open-label trial enrolled eight DMD boys, 5–9 years old, and comprised three 7-day treatment periods and ≥7 day washouts Results: On day 7, geometric mean AUC (0–24) for 0.25 g bid and 0.5 g bid demonstrated near dose proportionality (528.6 ng h/mL, n=7; 1015 ng h/mL, n=5, respectively). AUC (0–24) for 1.0 g bid was 3855 ng h/mL (n=4). One patient's data were unevaluable due to protocol deviations. One patient withdrew after Period 1 due to clinical need to start a restricted medication. At 1.0 g bid, all evaluable patients achieved drug levels above those producing a 50% increase in utrophin in vitro. Final day maximum mean plasma concentration was around six times that observed previously with 2.5 g bid F3. F6 thus expands the range of blood concentrations attainable in DMD patients. F6 was generally safe and well tolerated. One patient withdrew at the 0.25 g dose, having developed conjugated hyperbilirubinaemia, which resolved within 10 days of stopping ezutromid. Another withdrew due to abdominal pain. Conclusion: Ezutromid's Phase 1 programme employed multiple approaches to address early PK issues. Potential for low-fat diets to affect absorption was addressed by diet modification; additionally, reformulation markedly increased exposure. A Phase 2 trial is now evaluating and comparing the F3 and F6 formulations of ezutromid, each with a balanced diet.

Progress in the management of patients with Duchenne muscular dystrophy (DMD), in particular respiratory and cardiac intervention, has significantly increased the life expectancy in this life-limiting disorder. The majority of patients however will have a degree of cardiac dysfunction by the age of 18 years. The effects of cardiomyopathy on other organs might be encountered increasingly with improved life expectancy and advancing respiratory and orthopaedic management. Two male patients with DMD had significant deterioration of their renal function which required careful medical management and investigation. The first patient is eighteen years old, is non-ambulant with significant cardiomyopathy. He developed acute kidney injury and severe anaemia requiring multiple blood transfusions. After extensive investigation, the conclusion was a diagnosis of anaemia of chronic disease, with the acute kidney injury caused by poor renal perfusion (secondary to cardiomyopathy and exacerbated by anaemia). The second patient is sixteen years old and developed significant transient deterioration in his renal function following a chest infection and a urinary tract infection. The full clinical details will be discussed. Acute kidney injury has been reported previously in patients with DMD. In a case series of four patients, reduced kidney perfusion related to chronic heart failure was exacerbated by reduced fluid intake or use of diuretics. In another case series of six patients with DMD who died from acute kidney injury, anaemia was also implicated. Attention should be paid to renal function in patients with DMD especially in association with cardiomyopathy and anaemia. The possibility of prerenal acute kidney injury should be considered in this group of patients when acutely unwell or during periods of reduced fluid intake.

Genetic modifiers have been identified as influencing disease course in Duchenne muscular dystrophy, particularly LTBP4 haplotype. In a single UK clinic population – serving a diverse multi-ethnic population with high levels of deprivation – we noted an apparent more severe clinical course in boys of south Asian ethnic origin and also an apparent tendency to refuse or defer steroid therapy. We explored these observations to see if they were borne out to indicate potentially modifiable factors. From 2005 to 2014, 71 children from 68 families were newly diagnosed with DMD. Their ethnic origin was white British 35, South Asian 23, white European 3, mixed heritage 7, other Asian 2, black African 1. Mean age at diagnosis (for those without known family history) was 45.5months; for white British 44.3 months (range 14–80) and for South Asians 50.2 months (range 5–98). 24 boys lost ambulation, 45 are still walking at age 4y5m – 15y9m (2 moved away). 10% of white British who had reached 9th birthday by the end of the study period had LOA whereas 53% of south Asian who had reached 9th birthday had LOA. Age starting steroids was similar in all groups; about 25% had a delay in starting steroids of >6 months; 17% of south Asians declined steroids compared to 10% white British. 47% of south Asians stopped steroids compared to 19% of white British. For the whole group, those most deprived – in the bottom 20% socioeconomically – did worse (none in the top 20% had LOA by 9y whereas 54% of the bottom 20% had LOA by 9y) but there was no difference in steroid usage and the more socially deprived 20% were diagnosed earlier and started steroids earlier. 64% of white British were in the lower 50% socioeconomically, compared to 71% of South Asians. 20% of white British were in the bottom 20% socioeconomically, compared to 47% of the South Asians.

In DMD, skeletal muscle is lost due to an inability to produce dystrophin. During foetal muscle development utrophin takes the functional role of dystrophin. Continuous muscle expression of utrophin could functionally replace dystrophin and potentially overcome the dystrophin deficit in DMD. In dystrophic animal studies, daily SMT C1100 treatment significantly reduced muscle degeneration leading to improved muscle function. Data from a recently completed Phase 1b study in DMD subjects suggest that diet is able to influence absorption of SMT C1100. This study aims to investigate this further. Twelve boys with DMD were enrolled into this Phase 1b placebo-controlled study of single and multiple oral doses of SMT C1100. Boys were randomly allocated to the three treatment sequence groups. Each patient received both doses of SMT C1100 (1250 mg twice daily (BID) and 2500 mg BID) in a dose escalating fashion, with placebo in the other study period. A minimum two week washout was included between each Treatment Period to allow for study drug washout and safety review. One of the secondary objectives of this study was to evaluate reductions in creatine phosphokinase (CPK). With 12 patients this study had 80% power of demonstrating a statistically significant reduction in CPK compared to placebo with a two-sided, 5% confidence level, if SMT C1100 reduced CPK 30% more than placebo. Data from this trial will be presented and will assist in designing future Phase 2 studies that will include functional and biomarker endpoints.

Olesoxime (TRO19622) was identified as a potential treatment of SMA based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with spinal muscular atrophy (SMA). 165 type 2 or non-ambulant type 3 SMA patients, aged 3–25 years old were enrolled from 22 sites in 7 European countries beginning in November 2010. Patients were randomized to olesoxime, 10 mg/kg, administered as a liquid oral formulation or matching placebo in a 2:1 ratio and treatment duration was for 104 weeks. The last patient completed the study in October 2013. The primary outcome measure was the change in motor function using the MFM scale. The secondary outcome measures included the HFMS for SMA, electromyography, pulmonary function, and patient-reported outcomes as well as safety. Patients in the placebo arm of the study experienced a loss of motor function at a similar rate to that previously reported (Vuillerot et al. 2013). This loss of function, assessed as the primary endpoint, was prevented for two years in olesoxime-treated patients, with fewer disease-related adverse events. Other secondary endpoints were consistent with these effects. Results from this pivotal double blind placebo-controlled clinical trial provide clinical proof of concept of olesoxime’s neuroprotective effect that is sustained over two years. This combined with fewer adverse events caused by the disease itself will be submitted for the registration of olesoxime as the first neuroprotection treatment for SMA. Olesoxime (TRO19622) was identified as a potential treatment of SMA based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with spinal muscular atrophy (SMA). 165 type 2 or non-ambulant type 3 SMA patients, aged 3–25 years old were enrolled from 22 sites in 7 European countries beginning in November 2010. Patients were randomized to olesoxime, 10 mg/kg, administered as a liquid oral formulation or matching placebo in a 2:1 ratio and treatment duration was for 104 weeks. The last patient completed the study in October 2013. The primary outcome measure was the change in motor function using the MFM scale. The secondary outcome measures included the HFMS for SMA, electromyography, pulmonary function, and patient-reported outcomes as well as safety. Patients in the placebo arm of the study experienced a loss of motor function at a similar rate to that previously reported (Vuillerot et al. 2013). This loss of function, assessed as the primary endpoint, was prevented for two years in olesoxime-treated patients, with fewer disease-related adverse events. Other secondary endpoints were consistent with these effects. Results from this pivotal double blind placebo-controlled clinical trial provide clinical proof of concept of olesoxime’s neuroprotective effect that is sustained over two years. This combined with fewer adverse events caused by the disease itself will be submitted for the registration of olesoxime as the first neuroprotection treatment for SMA.

Mutations in the MICU1 gene have been shown to cause a condition with overlapping clinical and pathological features between muscular dystrophy, congenital myopathy and mitochondrial disease. The molecular defect results in mitochondrial dysfunction secondary to disruption of calcium uptake. We present the clinical/pathological features in a cohort of 18 patients. Patients presented between birth and 8years with a mild, relatively static, proximal myopathy associated with high Creatinine Kinase (2000–10,000iu/L), learning difficulties and frequent microcephaly. At follow up (5–28yrs), all remained ambulant but variable extrapyramidal symptoms had developed in the majority by the end of the 1st decade. Other features suggestive of mitochondrial dysfunction included peripheral neuropathy, icthyosis, stroke like episodes, episodic weakness, ataxia and cataracts. Cardiomyopathy was not seen. Serum and CSF lactate were normal where tested. Two had low free carnitine. Other metabolic investigations were normal. One had abnormal signal change in globus pallidus on MRI at 10yrs. All had abnormal muscle biopsies, with myopathic features; diffuse variation in fibre size, increased internal and central nuclei and clusters of regenerating fibres without pronounced fibrosis or fatty infiltration. Necrotic fibers were rare and fibre typing was preserved. Focal areas devoid of mitochondria (minicores) were observed in both type I and type II fibres. Respiratory chain enzyme activity, where tested, was normal. All had mutations in the MICU1 gene, 2 different homozygous splice site mutations (12 and 4 cases respectively) and a deletion in a kindred of 2 cases. Although the numbers are small, there appears to be some correlation between genotype and phenotype. Testing for MICU1 mutations should be considered in children with a static proximal myopathy associated with a high CK and CNS involvement when immunohistochemical studies do not identify a protein defect.

The continual expression of utrophin protein by pharmacological maintenance of utrophin transcription in dystrophin deficient muscle fibres is a potential disease modifying treatment for Duchenne muscular dystrophy (DMD). SMT C1100 is a small molecule utrophin modulator demonstrating significant benefit on the muscular dystrophy in the dystrophin deficient mdx mouse. Assessment of the in vitro and in vivo pharmacology plus the clean toxicology and safety data from the pre-clinical work led to the nomination of SMT C1100 as the first candidate for evaluation in DMD clinical trials. We previously reported that SMT C1100 successfully completed a Phase 1 healthy volunteer trial in which an oral paediatric formulation was deemed safe and well tolerated with plasma levels above those determined to be effective to modulate utrophin levels ex-vivo in DMD myoblasts and dystrophin deficient mdx mice. The first DMD paediatric patient trials of SMT C1100 started with an open-label, single and multiple oral dose finding Phase 1b study in DMD boys earlier this year. The purpose of the study was to determine whether increasing doses of SMT C1100 were safe, well tolerated and to understand the pharmacokinetic properties in patients with DMD. The boys were studied in 3 groups (Groups A to C), with each group consisting of 4 patients aged between 5 to 11 years. The doses for Groups A to C were administered in an escalating manner after safety review for each dose group. We will present the summary data from this trial.

The secondary dystroglycanopathies are a recessively inherited diverse group of muscular dystrophies ranging in severity from congenital onset with severe cobblestone lissencephaly (Walker-Warburg Syndrome) to milder forms of limb girdle muscular dystrophy (LGMD). Their hallmark is the reduction of alpha-dystroglycan (ADG) glycosylation and an important part of this glycosylation is a unique O-mannosylation which regulates the interaction between ADG and extracellular matrix proteins including laminin alpha 2, perlecan and agrin. The genetic aetiologies of approximately 50% of the dystroglycanopathies have been attributed to nine genes that are involved in ADG glycosylation. Despite collaborative efforts of several international groups using traditional positional cloning, the causative genes for the unsolved dystroglycanopathy cases had escaped discovery. Recently bi-allelic loss of function mutations in the isoprenoid synthase domain containing (ISPD) have been described in Walker-Warburg syndrome. In a collaborative study with the UK10K Rare Disease Project from the Sanger Institute, using whole exome sequencing techniques, we have now discovered that mutations in ISPD are found in a significant proportion of ADG patients. The mutations identified are milder mutations, and the phenotype of affected patients ranges from muscle-eye-brain like disorders, to congenital muscular dystrophy without brain involvement and to limb girdle muscular dystrophy with or without evidence of brain involvement. While in eubacteria and in choloroblasts of higher plants ISPD orthologues are involved in the synthesis of isoprenoid precursors, this pathway is absent in eukaryotes and vertebrates and; therefore, the function of ISPD remains unknown. The mechanism of ISPD mutations leading to reduction of ADG glycosylation needs to be uncovered; however, our ongoing screening shows that ISPD mutations are a common cause of dystroglycanopathies.