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Duchenne muscular dystrophy (DMD) is an X-linked muscular dystrophy in relation with dystrophin deficient. Heart and respiratory function are classically involved and affect long-term prognosis. Significant atrio-ventricular block may occur in some patients. Implantation of traditional pacemaker may be challenging in patients with tracheotomy and on permanent home mechanical ventilation. We report the first case of a successful leadless intra-cardiac trans-catheter pacing system implantation in an adult DMD on wheelchair and on permanent home mechanical ventilation.

Expiratory muscle strength training (EMST) exercise programmes aim to improve respiratory function by increasing the force generating capability of expiratory muscles by resistance training. In neuromuscular conditions, in which cough flow generation is often decreased, there is increasing interest in EMST as a therapeutic intervention. We present data showing efficacy of EMST in a patient with adult onset Myotonic Dystrophy Type 1 (DM1). A domiciliary training programme (5 days per week over 32 weeks) resulted in increases in maximum expiratory mouth pressure (from 15 cmH2O to 38 cmH2O) and peak cough flow (300 L/min to 390 L/min). Improvements were also seen in maximum inspiratory mouth pressure (26 cmH2O to 52 cmH2O) and sniff nasal inspiratory pressure (40 cmH2O to 69 cmH2O). No changes were detected in speech or swallowing. This novel study demonstrates that cough flow generation in DM1 may be increased by a programme of expiratory muscle training. A clinical trial of EMST in DM1 is warranted.

The aim of this study was to evaluate quality of life (QoL) and its possible determinants in patients affected by Duchenne muscular dystrophy (DMD) in late stages of their disease, when non-invasive ventilation (NIV) is already established. Forty-eight DMD patients who were treated by NIV were enrolled. QoL was assessed by the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. By this questionnaire, different aspects of QoL were assessed on a scale from 0 (best) to 100 (worst). In addition, motor and respiratory function tests were performed. Dysautonomia symptoms, sleep quality, sleepiness, anxiety, and depression were evaluated by validated questionnaires. The global INQoL score was 42.8 ± 19, reflecting a moderately altered QoL. The physical health domain was heavily impaired while the psychosocial domain was only mildly affected. Independence had the highest scores (81.1 ± 21.2), proving to be the most affected item. On multivariate analysis, maximal inspiratory pressure and Pittsburgh Sleep Quality Index, but not daily duration of NIV therapy, predicted global INQoL score. Respiratory impairment and sleep quality were independent predictors of poor QoL in DMD patients under NIV. Sleep quality in DMD is often disregarded, while it should be carefully addressed to ensure a better QoL.

The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, self-reported outcome measure that assesses total disease burden and 17 areas of Myotonic Dystrophy type 1 (DM1) specific health. This study translated the MDHI into Italian and validated the instrument using a cohort of Italian DM1 patients. Italian DM1 patients were interviewed regarding the form and content of the instrument. Thirty-eight DM1 patients were subsequently recruited to test the reliability and concurrent validity of the instrument by serially completing the MDHI and a battery of clinical tests. Lastly, we determined the internal consistency of the Italian MDHI and each of its subscales. The internal consistency was excellent in the total Italian MDHI score and acceptable in all of its subscales; the test-retest reliability was high (intraclass correlation coefficient = 0.95); Italian MDHI total scores and subscales were associated with neuromuscular function, cognitive and social health, respiratory function, and quality of life. Overall, the Italian MDHI is valid and well suited to measure the multi-dimensional aspects of disease burden in Myotonic Dystrophy clinical trials.

The natural history of Duchenne Muscular Dystrophy (DMD) is undoubtedly a shifting target, as shown by numerous recent studies [1–3]. And by “natural history” it is intended DMD-with-all-the-intervention-available-to-date, which are summarised and elucidated in the standard of care documents published by Bushby and colleagues [4,5]. The natural history of this disorder goes hand in hand with the on-going evolution of therapies; hence this phenomenon needs to be respected and factored into the design of clinical trials. Applying metrics based on old knowledge of the condition without taking into account new interventions, risks making clinical trial design poorly adapted or obsolete, and recruitment into studies is very challenging. For example, most ambulant patients are now on glucocorticoid therapy, and the age of starting steroids is indeed shifting towards a younger age as shown in the UK clinical practice [6]; hence, designing studies with steroid therapy as an exclusion criterion in the young ambulant population risks making recruitment virtually impossible in most specialised centres. This could in turn skew recruitment and introduce recruitment biases. Furthermore, cardiac medications used prophylactically (i.e. beta blockers and ACE-inhibitors) are increasingly supported by evidence that their use is beneficial for DMD patients [7–9], although a consensus on what is the optimal age for commencing therapy is still lacking. An on-going 5-year clinical trial funded by the British Heart Foundation testing ACE-inhibitor (perindopril) combined with beta-blocker therapy (bisoprolol) is targeting DMD boys 7–12 years of age who have not developed signs of cardiomyopathy (EudraCT number: 2007-005932-10). This study will likely strengthen the body of literature in support of early intervention [10] and indeed prevention; hence, clinical trial design will have to become permissive towards heart medication given prophylactically. However, at least in animal models, medications targeting angiotensin not only impact on cardiac load, but appear also beneficial for skeletal muscle [11] making it difficult to assess if such medications introduce a bias into skeletal muscle-based trial outcome. A similar scenario will apply to anti-oxidative treatment such as ibedenone; with the recently published study [12] supporting the beneficial effect on respiratory function it is expected that soon enough many patients will be treated with ibedenone alongside steroids, although the study results were obtained on steroid-naive patients and it is unknown to what degree the two drugs are complementary.

Respiratory insufficiency in facioscapulohumeral muscular dystrophy has rarely been studied. We compared two age- and sex-matched groups of 29 patients, with and without respiratory dysfunction. Tests in the 29 patients with respiratory dysfunction suggested predominant expiratory muscle dysfunction, leading to ineffective cough in 17 patients. Supine and upright vital capacities were not different (P = 0.76), suggesting absence of diaphragmatic dysfunction. By stepwise regression, only expiratory reserve volume correlated with the Walton and Gardner-Medwin score (R 2 = 0.503; P = 0.001). Compared to controls, patients with respiratory dysfunction had higher values for the Walton and Gardner-Medwin score (6.1 ± 1.9 vs. 3.2 ± 1.2; P < 0.0001) and body mass index (26.9 ± 6.0 vs. 22.9 ± 4.0 kg/m 2 ; P = 0.003) and a smaller number of D4Z4 allele repeats (4.8 ± 1.6 vs. 5.7 ± 1.8; P = 0.05). Mechanical ventilation was required eventually in 20 patients, including 14 who were wheelchair bound. Three patients had acute respiratory failure requiring mechanical ventilation; 16 patients had poor airway clearance, including 10 with sleep apnea syndrome, responsible in 7 for chronic hypercapnia. Two patients presented isolated severe sleep apnea syndrome. Respiratory dysfunction in facioscapulohumeral muscular dystrophy is predominantly related to expiratory muscle weakness. Respiratory function and cough effectiveness should especially be monitored in patients with severe motor impairment and high body mass index. © 2015 Elsevier B.V. All rights reserved.

Relatively little is known about frequency and extent of respiratory problems in sporadic inclusion body myositis (IBM). To address this issue a study of peripheral muscle and respiratory function and related symptoms was performed in a cohort with biopsy-proven IBM. Dyspnoea, daytime sleepiness, dysphagia, spirometry, respiratory muscle strength, arterial blood gas tensions and ventilation during sleep were assessed. Sixteen patients were studied (10 males; age 68.1±9.9years; disease duration 11.9±5.0years; body mass index 28.5±4.0kg/m(2)). Four reported excessive daytime sleepiness; 8 had at least mild dysphagia; forced vital capacity was

Mutations in the glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene cause GNE myopathy, a mildly progressive autosomal recessive myopathy. We performed a prospective natural history study in 24 patients with GNE myopathy to select evaluation tools for use in upcoming clinical trials. Patient clinical conditions were evaluated at study entry and one-year follow-up. Of the 24 patients, eight (33.3%) completed a standard 6-min walk test without assistance. No cardiac events were observed. Summed manual muscle testing of 17 muscles, grip power, and percent force vital capacity (%FVC) were significantly reduced (p0.05), and scores for 6-min walk test and gross motor function measure were decreased (p0.1) after one year. The decrement in %FVC was significant among non-ambulant patients, whereas the decrement in grip power tended to be greater among ambulant patients. The 6-min walk test, gross motor function measure, manual muscle testing, grip power, and %FVC reflect annual changes and are thus considered good evaluation tools for clinical trials.

Collagen VI-related myopathies are hereditary disorders causing progressive restrictive respiratory insufficiency. Specific diaphragm involvement has been suggested by a drop in supine volumes. This pilot study aimed at characterizing the respiratory muscle phenotype in patients with COL6A1-3 genes mutations. Lung function, blood gases, muscle strength and respiratory mechanics were measured in 7 patients between 2002 and 2012. Patients were classified as Early-Severe (n = 3), Moderate-Progressive (n = 2) and Mild (n = 2) according to clinical disease presentation. Seven patients (aged 6-28) were evaluated. Forced vital capacity distinguished the Mild group (60% predicted) from the two other groups (50% predicted). This distinction was also possible using the motor function measure scale. Diaphragmatic dysfunction at rest was observed in all the Early-Severe and Moderate-Progressive patients. During a voluntary sniff maneuver diaphragmatic dysfunction was observed in all patients, as assessed by a negative gastric pressure. All patients had diaphragmatic fatigue assessed by a tension-time index over the threshold of 0.15. Diaphragmatic dysfunction during a maximal voluntary maneuver and diaphragmatic fatigue are constant features in Collagen VI myopathies. These observations can assist the diagnosis and should be taken in account for the clinical management, with the early detection of sleep-disordered breathing.

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa doubleblind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8–16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena )( n = 13) or placebo (n = 8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p = 0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p = 0.039 for PEF and p = 0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided the basis for the planning of a confirmatory study. 2011 Elsevier B.V. All rights reserved.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory or cardiac failure and results in death at about 20 years of age. An animal model of DMD, the mdx mouse, is commonly used to estimate dystrophic pathology. The pathological features of limb muscles are relatively mild, however the diaphragm is severely affected and exhibits a degenerative pattern similar to that observed in human DMD. Although, the muscle strength assay of the dystrophic diaphragm has been used to estimate mdx respiratory impairment, systemic functional assessments compared with histopathological analysis have not been demonstrated. Here, we report a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected during early respiratory insufficiency in the mdx mouse. The dystrophic changes in the diaphragm lead to respiratory dysfunctions. These methods may be useful to assess the therapeutic approaches for the mdx mouse.

Thirty-two participants representing parents, funding agencies and clinicians involved in the care of children with Duchenne Muscular Dystrophy (DMD) from Belgium, Canada, Denmark, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden, the UK and the USA met in Naarden on 2–4th April 2004. The meeting was held under the auspices of the ENMC Clinical Trials Network, and with the additional support of the United Parent Project. The aims of the workshop were to define the need for clinical trials in DMD and develop a protocol for such trials, relating primarily to the use of steroids (prednisolone, prednisone and deflazacort) in DMD. The first part of the meeting summarised the current state of practice on the use of steroids in DMD. Elizabeth Vroom (Netherlands) and Pat Furlong (USA) presented the views of parents surveyed by questionnaire by the United Parent Project. A major worry for parents was the lack of use of steroids at all in some countries, the multiplicity of steroid regimes used and the problems of getting firm information about which type of steroid or which regime for using steroids was best. This was reflected in the variation in practice amongst the participants at the Workshop, who between them used at least seven different regimes for giving steroids, and some did not use steroids at all. Adnan Manzur (UK), co-author of the Cochrane report on the use of glucocorticosteroids in DMD described the major findings of this systematic review [1]. Only five randomised controlled trials of the use of steroids in DMD were published in sufficient detail to be able to be included in the review. These trials did, however, present evidence that use of daily prednisolone (0.75 mg/kg per day) or deflazacort (0.9 mg/kg per day) increased strength in DMD. Robert Griggs, Richard Moxley (USA) and Doug Biggar (Canada) were able to confirm that long-term follow up of cohorts of patients treated under one or other of these regimes and who mostly continued using steroids beyond the loss of independent ambulation shows that this increase in strength is mirrored by improvement in function (with age at loss of ambulation in the mid teens, preservation of respiratory function, lack of need for scoliosis surgery and possibly preservation of cardiac function) [2–4]. With longterm use of steroids, the per kilogram dose of corticosteroid tended to reduce with time. In some cases, this was in response to side effects such as weight gain or behaviour changes, but in the majority represented a tendency not to keep up strictly with change in weight over time. Many different regimes for giving steroids in DMD have been suggested as a way to reduce the risk of the well-known side effects associated with the long-term use of daily steroids. The dose of 0.75 mg/kg per day was shown to be Neuromuscular Disorders 14 (2004) 526–534 www.elsevier.com/locate/nmd

Sleep disordered breathing with or without nocturnal hypercapnic hypoventilation is a common complication of respiratory muscle weakness in childhood neuromuscular disorders. Nocturnal hypercapnic hypoventilation as a sign of respiratory muscle fatigue, portends a particularly poor prognosis. We aimed at identifying daytime predictors of sleep disordered breathing at its onset and sleep disordered breathing with nocturnal hypercapnic hypoventilation. Forty-nine children and adolescents (11.3+/-4.4 years) with progressive neuromuscular disorders were studied with inspiratory vital capacity, peak inspiratory pressure, arterial blood gases, polysomnography, and a ten-item symptoms questionnaire. Daytime respiratory function was prospectively compared with polysomnographic variables. Sleep disordered breathing was found in 35/49 patients (71%). Twenty-four (49%) had sleep disordered breathing with nocturnal hypercapnic hypoventilation. Inspiratory vital capacity and peak inspiratory pressure, but not symptom score, correlated with sleep disordered breathing and severity of nocturnal hypercapnic hypoventilation. Sleep disordered breathing-onset was predicted by inspiratory vital capacity60% (sens. 97%, spec. 87%). Sleep disordered breathing with nocturnal hypercapnic hypoventilation was predicted by inspiratory vital capacity40% (sens. 96%, spec. 88%) and PaCO(2)40 mmHg (sens. 92%, spec. 72%,). Sleep disordered breathing can reliably be predicted from simple daytime respiratory function tests, which, if applied systematically, will improve recognition of nocturnal respiratory failure.

Duchenne muscular dystrophy (DMD) is the most common and severe type of muscular dystrophy. Respiratory involvement, which accounts for early morbidity and mortality in this patient population, is characterized by progressive respiratory muscle weakness and ineffective cough, nocturnal hypoventilation, sleep disordered breathing, recurrent chest infections and atelectasis, leading to respiratory failure. 1,2

Considering the clinical heterogeneity of patients with a late onset form of Pompe disease, we clearly need reliable quantitative surrogate markers allowing to accurately determine the effects of enzyme replacement therapy (ERT). In the present study, we investigated, using quantitative MRI and usual clinical tests, the effects ERT in three patients with a late onset form of the Pompe disease. Data were compared before and throughout a 4-year ERT period. MR images were processed using a robust automatic segmentation tool in order to quantify muscle, subcutaneous adipose tissue and intramuscular adipose tissue. Motor (6-min walking test (6MWT), manual motor testing, Motor Function Measure scale) and respiratory function (vital capacity, (FVC)) were investigated once a year. Clinical tests remained stable in patient 2 and worsened in patient 1. In patient 3, the 6MWT improved whereas the FVC remained stable. In two patients (patient 1 and 2), the rate of intramuscular infiltration was substantially slowed throughout the treatment period whereas it increased in patient 3 who required nocturnal ventilation. We demonstrated a variable effect of the ERT while clinical and MRI results were not directly related. The quantitative MRI kinetic index we selected might be of interest for further investigations in a larger group which are warranted in order to clearly delineate the effects of ERT in adult patients with Pompe disease.

Laminin alpha 2 – deficient congenital muscular dystrophy (MDC1A) patients present with significant skeletal muscle weakness and develop progressive respiratory insufficiency due to scoliosis, intercostal skeletal muscle weakness and multi-joint contractures with decreased compliance of their thoracic cavity. The longitudinal progression of pulmonary function in patients with MDC1A has not been previously characterized. Force vital capacity (FVC) is a standard quantitative measurement of respiratory function with FVC percent predicted (FVCpp) measurements being sensitive to both positive and negative change in serial respiratory function assessments. The aim of this study was (1) to determine the longitudinal progression of FVCpp in patients with MDC1A, analyzing both ambulatory and non-ambulatory cohorts as well as those on or not on ventilation support (VS) and (2) to determine if FCVpp is a viable outcome marker for progression of disease. Retrospective chart reviews of patients with confirmed MDC1A were performed at 6 international neuromuscular centers: Belgium (1), Germany (1), United Kingdom (2), and United States (2) with additional data points provided by the CMD International Registry. Serial FVCpp were plotted using linear mixed effects models with random coefficients for between-subject variability. Covariate analysis evaluated the impact of ambulatory status and use of VS. Two hundred and seventy two FVC measurements were recorded in 59 MDC1A patients. Fifteen patients were ambulatory. A total of 21 patients were on VS. The FVCpp slope for each covariate was ambulatory −0.4 ± 0.5 (±SE), non- ambulatory −2.0 ± 0.32, not on VS −1.1 ± 0.4, and on VS −1.6 ± 0.5. Patients with MDC1A experience a longitudinal decline in FVCpp. The decline can be characterized as an annual rate thus providing a viable outcome measure with which to monitor current practice patterns, therapeutic interventions, and inform clinical trial design.

Mutations in the mitofusin 2 gene (MFN2), encoding an outer mitochondrial membrane protein of the dynamin family GTPase, cause mainly Charcot–Marie–Tooth 2A (CMT2A), hereditary motor and sensory neuropathy type VI (HMSN VI) and axonal neuropathy with spastic paraparesis. Hereby, we report eight genetically confirmed patients with MFN2 defects. The mean current age of the patients is 14.5 years, (range 4–28), three are male and five female. A dominant familial inheritance was confirmed in two cases while six are sporadic. All patients were submitted to neurological, electrophysiological, ophthalmological and cranial MRI evaluation.. Symptoms started in all patients within the two first years of life with falls, and difficulties to walk consisting in: flat foot (4), equinovarus foot position (3), stepage (7) and spastic paraparesis (1). Distal upper limb involvement was observed in all patients, being severe in four. Two patients developed diaphragmatic paresis and one vocal cord paresis. Learning difficulties were observed in four and one manifested disartic episodes that lasted several days. Two patients were chair bound at 12 years old requiring nocturnal non invasive ventilatory support (BIPAP). The remaining of the patients were able to walk with orthesis (DAFOS). Axonal neuropathy was identified in all the patients. We also discuss cranial MRI, visual evocated potentials (VEP), genetic and ophthalmological findings. Early onset mitofusin deficiency constitutes a severe and disabling condition. Because several organs may be involved, systemic evaluation and follow up is required, especially when respiratory function is compromised.

The interpretation of muscle biopsies in the collagen VI-related myopathies can be challenging, given that specific structural abnormalities are not present, the pathology is often not overtly dystrophic and the immunohistochemical studies of collagen VI can be difficult to interpret when basal lamina defects are subtle. The muscle histopathology finding of cores is classically associated with the core myopathies but can be seen in other conditions including collagen VI-related myopathies. A comprehensive retrospective review of muscle biopsies was performed in 15 collagen VI-related myopathy patients, comparing histological findings to those seen in muscle biopsies of 14 RYR1 or SEPN1-related core myopathy patients. Clinical notes were reviewed (ARF), and only cases with molecularly confirmed diagnoses were included. Biopsy review was independently performed (RP), blinded to the biopsy findings originally reported (CS). Cores and/or minicores were present in the muscle biopsies of 12/15 (80%) of molecularly confirmed collagen VI-related myopathy patients studied. Both large and small neonatal myosin positive fibres were present in collagen VI-myopathy patients in contrast to the presence of only tiny neonatal myosin positive fibres seen in RYR1-related core myopathy patients. We conclude that cores are a common muscle histopathology finding in molecularly confirmed collagen VI-related myopathy patients. It is, therefore, important to include collagen VI-related myopathies in the differential diagnosis when cores are seen on muscle biopsy, especially given their clinical overlap with congenital myopathies and the invariable and often insidious decline in respiratory function in patients with this congenital muscular dystrophy subtype which must be addressed. These histopathology findings in conjunction with clinical and muscle imaging findings may assist in refining the challenging diagnostic pathway for the collagen VI-related myopathies.

Limb-girdle muscular dystrophy type 2G (LGMD2G) is a disorder caused by mutations in the TCAP gene that encodes for the striated muscle specific protein telethonin. LGMD2G is extremely rare and was initially identified in the Brazilian population. Recently, a small number of LGMD2G patients have been diagnosed in populations with diverse genetic backgrounds indicating a wider geographical distribution of this disorder. Here we describe a 49 year old male patient presenting a classical LGMD phenotype. He was born from non-consanguineous healthy parents of Indian descent. He had normal motor milestones but became noticeable slower in his early teens and presented scapular winging and Achilles tendon contractures. He eventually became wheelchair bound by age 47. There has been no cardiac involvement so far and the respiratory function is only mildly reduced with nocturnal hypoventilation. CK levels were 2541 iU/L. A muscle biopsy showed well preserved fascicular architecture with mild myopathic features. Immunohistochemistry with an antibody directed to the C-terminal portion of telethonin showed complete absence of labelling. However, an antibody directed against full-length telethonin showed some labelling on sections and a single band of ∼10 kDa on Western blot. Sequence analysis of the TCAP gene revealed a novel homozygous non-sense c.244C>T (p.Gln82X) mutation in exon 2, predicted to generate a truncated protein of molecular mass consistent with the Western blot findings. Double labelling for telethonin and filamin C showed overlap in a cross-striated pattern, consistent with the Z-disc localization of both proteins, indicating that the mutant telethonin is retained at the Z-disc. Our results suggest that the mutant protein is correctly incorporated in the sarcomere allowing sufficient binding to titin such that functional rather than structural defects may be the mechanism that leads to LGMD2G.

Duchenne muscular dystrophy (DMD) is an X-linked condition characterized by progressive muscle weakness. Glucocorticoids (GC) are a key pharmacological intervention that is associated with prolonged ambulation, reduction of scoliosis and better-preserved respiratory function. However long-term GC therapy, in particular daily regimens, is a significant risk factor for osteoporosis and vertebral fractures. While bisphosphonates (BP) are recommended in case of fractures, prophylactic use of BP remains controversial. Here we summarize our experience of prophylactic BP therapy on a group of DMD patients on daily GC on follow up at the paediatric neuromuscular clinic in Newcastle upon Tyne. Patients were offered prophylactic BP (oral Risedronate) under the guidance of the local paediatric endocrinology team from January 2008. Patients were reviewed 6 monthly for tolerability, side effects, bone pain, frequency of fractures and impact on bone mineral density (BMD) determined by yearly DXA analysis. Vitamin D supplementation (800–1000 IU/L daily) was provided and insufficiencies/deficiencies were treated. Out of a total of 52 patients included in this study, 9 stopped treatment because of side effects (in particular abdominal or joint pain and flu like symptoms). 43 boys continued BP therapy for an average of 24 months (range 12–54 months). Median lumbar spine adjusted BMD (BMAD) Z-scores remained stable during treatment, being 0.11 at baseline and 0.21 at the 3rd year follow up. Z-scores for total body mineral content (minus head) were stable during the period of treatment. 7 patients suffered long bone fracture during therapy and 3 had vertebral fractures (VF), the majority having been on GC for >36 months at the time of fracture. Patients who suffered VF all had lumbar spine BMAD Z-scores

To examine the occurrence of respiratory dysfunction in sporadic inclusion body myositis (IBM) and its relationship to peripheral muscle strength and ventilation during sleep. Anthropometric, muscle strength, dyspnoea, daytime sleepiness and dysphagia data were collected. Spirometry, respiratory muscle strength and arterial blood gas tensions were measured. Ventilation during sleep was assessed by dual channel (oximetry, nasal pressure) home monitoring. Sixteen patients with biopsy-proven IBM were studied (10 males, 6 females; age 68.1 ± 9.9 years; disease duration 11.9 ± 5.0 years; body mass index 28.5 ± 4.0 kg/m2). Four patients reported excessive daytime sleepiness (Epworth Sleepiness Scale ⩾10); 8 had at least mild dysphagia (Dysphagia Outcome Severity Scale ⩽5); forced vital capacity was 45 mmHg) in one. Sleep study was performed in 15 patients and revealed sleep hypoxemia (⩾2% of total sleep time at or below a saturation

We have been monitoring the respiratory function in 95 DMD patients (aged between 6 and 24 years) who were evaluated once or twice a year in relation to age and clinical conditions, making a total of 429 evaluations. During every evaluation, forced vital capacity, nocturnal oxygen saturation and the abdominal percentage contribution to tidal volume (an index of the action of the diaphragm) were respectively measured with spirometry, pulse oximetry and opto-electronic plethysmography. 46 patients underwent therapy with steroid while the remaining 49 never assumed steroid. No differences (p = 0.122) were found in forced vital capacity, nocturnal saturation and the action of the diaphragm between the 231 evaluations of the steroid group and the 198 evaluations of the sham group. Steroid therapy seems not to have any effects on the respiratory function decline in DMD patients.

Pompe disease is a rare metabolic myopathy due to mutations in the gene encoding acid alpha-glucosidase (GAA) involved in glycogen degradation. Two clinical presentations can occur: infantile form and late-onset form. Herein, we describe a cohort of 33 late-onset Pompe disease (LOPD) patients diagnosed at our centre from 1997 to date. Our aim is to present clinical and functional data collected in this long time lapse and to describe unusual clinical and genetic features. LOPD diagnosis was made with muscle GAA residual activity assay and GAA sequence analysis. At follow-up patients underwent motor, respiratory, cardiac and muscle MRI evaluations. Motor performances were tested with Walton Gardner-Medwin, MRC, GSGC, 6MWT. Respiratory function was assessed through FVC% in upright and supine position 19 males, 14 females. The onset symptom was asymptomatic hyperckemia in 13 patients (39%), proximal weakness in 19 (57%) and respiratory failure in 1 (3%). Atypical clinical features were observed in 4 patients: a 66year-old female with a severe distal muscle weakness; a 70-year-old male with mesial temporal sclerosis; a 46-years-old male with severe hearing loss and a 52-year-old male with leukoencephalopathy. The median age at diagnosis was 38years, median diagnostic delay 8.3years. GAA sequence analysis showed the common IVS1–13T>G mutation in all patients associated, in 25 patients, with a second mutation. Two brothers were IVS1–13T>G homozygous and 1 patient had a new mutation (c.2395C>G). In the remaining 8 no second mutation was found. 17 patients started enzyme replacement therapy (ERT). Our study confirms LOPD clinical and genetic heterogeneity. The atypical features encountered may contribute to expand the clinical aspects of the disease highlighting its multisystemic nature. Early diagnosis allows, when indicated, earlier ERT initiation even if, in our cohort, treatment responses were variable and not clearly correlated with diagnostic delay.

To investigate the effects of trainings including two different types of exercises for upper extremity (aerobic and strengthening) on respiratory function and quality of life in children with Duchenne Muscular Dystrophy (DMD). 24 children (8–15 years of age) with DMD whose upper extremity functional status were between Grade1–3 according to the Brooke Upper Extremity Functional Classification included in the study. Children were divided into 2 groups randomly as study (N = 12) and control group (N = 12). T-Shirt wearing time (s) which is one of the timed performance tests were recorded. Peak Expiratory Flow (PEF) were recorded by using Microlife PF 100 – Asthma Management System, Peak Expiratory Flow (Microlife AG, Switzerland) electronic respiratory muscle strength measuring device. Quality of life of children were assessed with The Pediatric Quality of Life Inventory (PedsQL)-Neuromuscular Module Turkish version (child and parent forms). Children in the study group received 45-min exercise sessions with electronic arm ergometer, 3 days a week for 8 weeks. Strengthening exercises for upper extremity were given as home program to control group during 8-weeks. Assessments were repeated after trainings. The time elapsed for T-Shirt wearing decreased after training in study group (mean ages 9.50 ± 1.38 years) compared to control group (mean ages 9.3 ± 1.4 years) (z = −2.281; p 0.05). There were negative, strong correlation between PEF-T-Shirt wearing time (r = −0.629; p

Ullrich congenital muscular dystrophy (UCMD) is the second most common CMD in Japan. Mutations in either COL6A1 , COL6A2 , or COL6A3 gene, each encoding a subunit of collagen VI (COL6) are known to cause UCMD. To date, there is no cure for this disease and only limited information on the rate of disease progression. To characterize the natural history of UCMD, questionnaire-based nationwide survey was conducted from October 2010 to February 2011. We enrolled 33 patients (age at survey, 11.0 ± 6.6 years (mean ± SD)) with COL6 deficiency on immunohistochemistry in skeletal muscle: 5with complete and 28 with sarcolemma specific COL6 deficiency. Sequence analysis of COL6 genes was performed using genomic DNA from 32 patients, 19 (59.4%) of whom carried identifiable mutations. We analyzed the information on perinatal and developmental abnormalities, clinical manifestations, data of Cobb angle and % vital capacity (%VC). Age at muscle biopsy was 3.2 ± 2.0 years. Creatine kinase level was 315 ± 110 (IU/L) ( n = 31). Twenty-five (81%) of 31 patients walked independently by age 1.7 ± 0.5 years but lost this ability by age 8.8 ± 2.9 years ( n = 11). Six patients never walked independently. %VC was decreased exponentially with age, resulting in severe respiratory dysfunction before pubescence. Noninvasive ventilation was initiated at age 11.2 ± 3.6 years ( n = 13). Cobb angle over 30° was noted at age 9.9 ± 5.3 years ( n = 17). The maximum progression rate was 16.2 ± 10.0°/year ( n = 13). Scoliosis surgery was performed in 3 patients at respective ages 5, 9 and 10 years. Postoperative %VC was relatively well maintained in the youngest patient. The natural history of walking ability, respiratory function and scoliosis in UCMD patients was characterized. Although the age of onset varied, scoliosis, as well as restrictive respiratory dysfunction, progressed rapidly within years, once they appeared.

The congenital muscular dystrophies (CMD) are a heterogeneous group of early onset degenerative diseases of muscle leading to significant and progressive weakness and eventually affecting mobility and respiratory function. There is a need for an effective outcome measure to monitor patients’ clinical progression and capture the effect of interventional clinical trials on patients’ strength and endurance. Currently, the 6-min walk test is used for this purpose, but there are limitations of this test for the CMD patient population, including the patients’ inability to complete the test because of significant weakness, contractures, and fatigue. We propose that shortening the test to 2 min would alleviate these issues without compromising reliability. In this study, we administered the 6 min walk test to 55 patients with various neuromuscular disorders including CMD, who ranged in age from 6 to 61 years, between 2010 and 2012. We compared the distance traveled in the initial 2 min with that traveled during the entire 6 min and found them to be highly correlated (Pearson’s r = .964, p

Steroid therapy in Duchenne Muscular Dystrophy (DMD) patients slows motor and respiratory function declines, while efficacy for cardiomyopathy is uncertain due to limited data. We reported the efficacy of long-term low-dose steroid therapy, at one-third the widely-used dose for DMD patients, in slowing respiratory failure and scoliosis progression without major side effects. Herein, we prospectively evaluated our low-dose steroid regimen for cardiomyopathy in DMD patients. Clinical longitudinal data were available for 12 steroid-treated (12–24, mean 18.9, years) and 14 non-steroid-treated (11–32, mean 19.6, years) non-ambulant DMD patients. Our regimen was started when patients recognized clear motor function declines. The initial dose was 0.5 mg/kg of prednisolone (PSL) every other day (0.25 mg/kg/day). Ages at ambulation loss, cardiomyopathy onset and starting NIV (non-invasive ventilation) were analyzed. The mean age at steroid therapy start was rather late, 9 (7–11) years. No apparent steroid side effects occurred. There was no statistically significant difference in loss of ambulation between the two groups. Among those over age 20 years, five of six non-treated patients needed NIV, before the middle teens in four, while only one of five steroid-treated patients started NIV. Respiratory decline tended to be slower in the steroid-treated group. Ten of 14 non-steroid-treated and five of 12 steroid-treated patients had cardiomyopathy, but the difference did not reach statistical significance. Steroid-treated patients tended to have less cardiomyopathy but most onsets were before the middle teen years. One patient with mild cardiomyopathy, detected before steroid therapy, showed rapid cardiomyopathy worsening within a few years while on PSL and died at age 12 years. Our results indicate that even low-dose steroids may slow respiratory failure and cardiomyopathy progression, but can cause severe cardiomyopathy at an early stage in some patients.

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.