The TREAT-NMD Duchenne muscular dystrophy registries: conception, design, and utilization by industry and academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations.

OBJECTIVE: To perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden. METHODS: Clinical assessments, targeted genetic studies, neuroimaging with MRI, [18F]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with 123I FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS). RESULTS: Four patients living in Sweden but with different ethnical backgrounds were included. Their clinical features were variable. Biallelic VPS13A mutations were confirmed in all patients, including 3 novel mutations. All tested patients had either low or absent chorein levels. One patient had progressive caudate atrophy. Investigation using FDG-PET revealed severe bilateral striatal hypometabolism, and DaTscan SPECT displayed presynaptic dopaminergic deficiency in 3 patients. MRS demonstrated reduced N-acetylaspartate/creatine (Cr) ratio and mild elevation of both choline/Cr and combined glutamate and glutamine/Cr in the striatum in 1 case. One patient died during sleep, and another was treated with deep brain stimulation, which transiently attenuated feeding dystonia but not his gait disorder or chorea. CONCLUSIONS: Larger longitudinal neuroimaging studies with different modalities, particularly MRS, are needed to determine their potential role as biomarkers for ChAc.

Increased serum inflammatory markers in the absence of clinical and skeletal muscle inflammation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Muscle wasting and cachexia are common occurrences in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: The current study aimed to investigate markers of inflammation in the circulation and skeletal muscle that might be associated with development of muscle wasting. METHODS: Three groups of patients with mild, moderate and severe COPD and matched healthy controls were recruited. Serum levels of C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), IL-6, IL-8, TNF-alpha, cortisol, insulin-like growth factor 1 (IGF-1), leptin and ghrelin were analysed. Skeletal muscle inflammation was investigated microscopically using a panel of antibodies and standard staining for inflammatory cell infiltration. RESULTS: All COPD patients were clinically stable, with no sign of inflammation and normal CRP values. Compared to controls, significantly increased hs-CRP levels were observed in all COPD patient groups. Significant rises in IL-6 levels were first observed in moderate COPD, while IL-8 levels were significantly elevated at the late severe stage. Circulating levels of TNF-alpha, cortisol, IGF-1, leptin and ghrelin were similar to control levels. No microscopic signs of skeletal muscle inflammation were observed. CONCLUSION: Our results identify hs-CRP as an early marker of inflammation that is significantly increased in the circulation even in mild COPD. Serum interleukin levels appear to be increased with disease progress. These changes were manifested in the absence of any clinical signs of disease exacerbation, evidence of skeletal muscle inflammation or hormonal changes.

Correction to: Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

The original version of this article [1] unfortunately included an error to an author's name. Author Jordi Díaz-Manera was erroneously presented as Jorge Alberto Diaz Manera. The correct author name has been included in the author list of this Correction article.

Eight years after an international workshop on myotonic dystrophy patient registries: case study of a global collaboration for a rare disease.

BACKGROUND: Myotonic Dystrophy is the most common form of muscular dystrophy in adults, affecting an estimated 10 per 100,000 people. It is a multisystemic disorder affecting multiple generations with increasing severity. There are currently no licenced therapies to reverse, slow down or cure its symptoms. In 2009 TREAT-NMD (a global alliance with the mission of improving trial readiness for neuromuscular diseases) and the Marigold Foundation held a workshop of key opinion leaders to agree a minimal dataset for patient registries in myotonic dystrophy. Eight years after this workshop, we surveyed 22 registries collecting information on myotonic dystrophy patients to assess the proliferation and utility the dataset agreed in 2009. These registries represent over 10,000 myotonic dystrophy patients worldwide (Europe, North America, Asia and Oceania). RESULTS: The registries use a variety of data collection methods (e.g. online patient surveys or clinician led) and have a variety of budgets (from being run by volunteers to annual budgets over €200,000). All registries collect at least some of the originally agreed data items, and a number of additional items have been suggested in particular items on cognitive impact. CONCLUSIONS: The community should consider how to maximise this collective resource in future therapeutic programmes.

Increased prevalence of celiac disease in idiopathic inflammatory myopathies.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are often associated with other immune-mediated diseases or malignancy. Some studies have reported a high frequency of celiac disease in IIM. The aim of this study was to investigate the prevalence of celiac disease, systemic inflammatory diseases, and malignancy in a cohort of IIM patients, and estimate the incidence of IIM in the county of Östergötland, Sweden. MATERIAL AND METHODS: We reviewed medical records and analyzed sera from 106 patients, fulfilling pathological criteria of inflammatory myopathy, for the presence of IgA antibodies against endomysium and gliadin. Antibody-positive patients were offered further investigation with small bowel biopsy or investigation for the presence of antibodies against antitissue transglutaminase (t-TG). The patients were classified according to Bohan and Peter or Griggs criteria. The presence of celiac disease, systemic inflammatory, and malignant diseases was documented. RESULTS: Four of 88 patients classified as IIM (4.5%) had biopsy-confirmed celiac disease, which is higher than the prevalence in the general population, detected with a similar screening procedure (0.53%). Thirty-three patients (38%) had a systemic inflammatory disease and five (5.7%) a malignancy. The incidence of confirmed IIM in the county of Östergötland was 7.3 per million/year. CONCLUSIONS: The results highlight the high frequency of associated inflammatory and malignant diseases and confirm an increased prevalence of celiac disease in IIM.

Surface electromyography and peak torque of repetitive maximum isokinetic plantar flexions in relation to aspects of muscle morphology.

This study investigates the relationships between surface electromyography (EMG [Mean frequency of the power spectrum (MNF)]) and peak torque variables obtained during 100 maximum concentric plantar flexions with the right limb at 60 degrees s(-1) and different muscle morphological variables. Surface EMG was recorded from the right gastrocnemius lateralis and muscle biopsies were taken from the same site as the EMG electrodes were positioned. Muscle fibre area and fibre type composition were determined on serial muscle cross sections using both histochemistry (myofibrillar adenosine triphosphatase) and immunohistochemistry (monoclonal antibodies against specific myosin heavy chain isoforms). Forty-three female and nine male students participated in the study. Gastrocnemius lateralis contained predominantly type I fibres (50%) and type IIA fibres (40%) in both sexes and large individual differences were found. Principal component analysis (PCA) was used for the intercorrelation analyses, and projection to latent structures (PLS) was used for the multivariate regression analysis. MNF correlated positively with different fibre areas and with the proportion of type I fibres. Fibre areas and sex were the most important factors in the regression of maximum peak torque. High proportion of type I fibres and sex were the most important regressors of peak torque endurance normalised for lean body mass. More studies are needed to understand the complex interrelationships between intrinsic muscle properties and the frequency content of the surface EMG before theoretical models can be formulated that incorporate both fibre areas and fibre type proportions.

Childhood onset tubular aggregate myopathy associated with de novo STIM1 mutations.

We investigated three unrelated patients with tubular-aggregate myopathy and slowly progressive muscle weakness manifesting in the first years of life. All patients showed type 1 muscle fiber predominance and hypotrophy of type 2 fibers. Tubular aggregates were abundant. In all three patients mutations were identified in the gene STIM1, and the mutations were found to be de novo in all patients. In one of the patients the mutation was identified by exome sequencing. Two patients harbored the previously described mutation c.326A>G p.(His109Arg), while the third patient had a novel mutation c.343A>T p.(Ile115Phe). Taking our series together with previously published cases, the c.326A>G p.(His109Arg) seems to be a hotspot mutation that is characteristically related to early onset muscle weakness.

Classification and diagnostic investigation in inflammatory myopathies: a study of 99 patients.

OBJECTIVE: Insights into the pathogenesis of inflammatory myopathies have led to new diagnostic methods. The aims of our study were (1) to evaluate the consequences of using the classification of Amato/European Neuromuscular Centre Workshop (ENMC) compared to that of Bohan and Peter; and (2) to evaluate any diagnostic benefit in using an extended pathological investigation. METHODS: From a consecutive retrospective database, we evaluated 99 patients for classification. Patients with inclusion body myositis (IBM) were classified according to Griggs, et al. In addition to routine stainings and immunohistochemistry, a multilevel serial sectioning procedure was performed on paraffin-embedded material, to identify scarce pathological findings. RESULTS: Classification according to Bohan and Peter could be performed for 83 of the 99 patients, whereas only 60 patients met the Amato/ENMC criteria, the latter resulting in the following diagnostic groups: IBM (n = 18), nonspecific myositis (n = 14), polymyositis (n = 12), dermatomyositis (n = 10), dermatomyositis sine dermatitis (n = 5), and immune-mediated necrotizing myopathy (n = 1). Most of the Amato/ENMC diagnostic groups harbored patients from several of the Bohan and Peter groups, which included a substantial group lacking proximal muscle weakness. The serial sectioning procedure was essential for classification of 9 patients (15%), and led to a more specific diagnosis for 13 patients (22%) according to Amato/ENMC. CONCLUSION: The classification of Amato/ENMC was more restrictive, forming groups based on clinical criteria and specified myopathological findings, which clearly differed from the groups of the Bohan and Peter classification. An extended pathological investigation increased the diagnostic yield of a muscle biopsy and highlights the quantity and specificity of certain pathological findings.

Extensive inflammatory cell infiltration in human skeletal muscle in response to an ultraendurance exercise bout in experienced athletes.

The impact of a 24-h ultraendurance exercise bout on systemic and local muscle inflammatory reactions was investigated in nine experienced athletes. Blood and muscle biopsies were collected before (Pre), immediately after the exercise bout (Post), and after 28 h of recovery (Post28). Circulating blood levels of leukocytes, creatine kinase (CK), C-reactive protein (CRP), and selected inflammatory cytokines were assessed together with the evaluation of the occurrence of inflammatory cells (CD3(+), CD8(+), CD68(+)) and the expression of major histocompatibility complex class I (MHC class I) in skeletal muscle. An extensive inflammatory cell infiltration occurred in all athletes, and the number of CD3(+), CD8(+), and CD68(+) cells were two- to threefold higher at Post28 compared with Pre (P < 0.05). The inflammatory cell infiltration was associated with a significant increase in the expression of MHC class I in muscle fibers. There was a significant increase in blood leukocyte count, IL-6, IL-8, CRP, and CK at Post. At Post28, total leukocytes, IL-6, and CK had declined, whereas IL-8 and CRP continued to increase. Increases in IL-1ß and TNF-α were not significant. There were no significant associations between the magnitude of the systemic and local muscle inflammatory reactions. Signs of muscle degenerative and regenerative events were observed in all athletes with various degrees of severity and were not affected by the 24-h ultraendurance exercise bout. In conclusion, a low-intensity but very prolonged single-endurance exercise bout can generate a strong inflammatory cell infiltration in skeletal muscle of well-trained experienced ultraendurance athletes, and the amplitude of the local reaction is not proportional to the systemic inflammatory response.

Subacute neuronopathy in a young man: a possible association with tetracycline treatment.

A young man with subacute neuronopathy following tetracycline treatment is described. The symptoms started as a sensory dorsal root affection but by time also involved motor nerves. He developed a severe sensory ataxia with pseudoathetotic movements. Other possible aetiologies were scrutinized and excluded. Tetracycline induced neuronopathy is hitherto not reported in the literature. We propose a possible association between treatment with tetracycline and the development of sensory neuronopathy in this patient.

Expression of apoptosis related proteins in normal and diseased muscle: a possible role for Bcl-2 in protection of striated muscle.

The unique absence of major histocompatibility complex class I antigen (MHC-I) expression in normal muscle is one possible mechanism protecting striated muscle. In order to define their possible involvement in protection of normal muscle, we investigated the expression of molecules involved in muscle fibre death and survival mechanisms (Bcl-2, Fas, Fas-ligand and TRAIL), focusing on disorders with possible involvement of cytotoxic T cells. We studied muscle biopsies from 20 healthy volunteers, from 10 patients affected by polymyositis and 10 by Duchenne muscular dystrophy. By using immunohistochemistry, Western blot and real-time PCR we detected a constitutional expression of Bcl-2 in healthy muscle, whereas the expression was weaker in disease processes. Fas-L and TRAIL were not detected in muscle fibres, and Fas only in muscle affected by disease. Our findings indicate that the major apoptotic protein Bcl-2 might have a hitherto unrecognized role in the protection of normal muscle.

A case report of plasmapheresis treatment in a patient with paraneoplastic cerebellar degeneration and high anti-yo antibody titers.

A patient with paraneoplastic cerebellar degeneration due to anti-Purkinje cell antibodies (anti-Yo) arising from ovarian carcinoma with metastases was treated with three plasmapheresis (PP) series (a total of 22 PP treatments) over one year and was monitored by repeated otoneurological testing, balance tests and clinical investigations. Blood samples for antibody titers were checked on several occasions. Initially there was a weak clinical response and significantly improved test results regarding the caloric response, as well as a possible effect on visual suppression of the vestibulo-ocular reflex after caloric ear irrigation. After the first series of PP treatment, new metastases were found. A half year later there was a progressive course with increasing general symptoms. Serology tests showed continuously high titers of anti-Yo antibody, although somewhat lower after PP. We thus report a minor and short-lived effect of PP, possibly inhibited by the natural course of metastatic disease.

Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on molecular expression in muscle tissue of patients with inflammatory myopathies.

OBJECTIVES: The study was conducted with the aim of achieving an improved understanding of the molecular mechanisms of high-dose intravenous immunoglobulin (IVIG) in inflammatory myopathies by investigating the effects on muscle function and immunological molecules in skeletal muscle of polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM) patients. METHODS: Thirteen treatment-resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM, were treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index in Myositis and serum creatinine kinase (CK) levels were determined, and muscle biopsies were performed before treatment and after the third IVIG infusion. Immunological molecules were also studied in biopsies taken 24-48 h after the first infusion. RESULTS: Improved muscle function was observed in three patients (1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages, major histocompatibility complex (MHC) class I antigen on muscle fibres, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression and membranolytic attack complex (MAC) deposits on capillaries were present to an equal degree in biopsies before and after IVIG treatment. No correlation between the clinical response and molecular changes was found. CONCLUSIONS: The clinical effects of high-dose IVIG on muscle function in patients with refractory inflammatory active myositis did not correspond to effects on any of the investigated molecules in our study. T cells, macrophages, phenotypical changes in muscle fibres and endothelial cell activation were still present after treatment. These observations question a role for IVIG as an immune-modulating therapy in patients with inflammatory myopathies.

Subclinical myositis is common in primary Sjögren's syndrome and is not related to muscle pain.

OBJECTIVE: Although muscle pain is common in primary Sjögren's syndrome (SS), the underlying mechanisms are mainly unknown. We studied all patients with SS at our rheumatology unit with respect to muscle pain in general and to fibromyalgia (FM), and correlated clinical data to muscle biopsy findings. METHODS: We investigated 48 patients with SS according to the modified European diagnostic criteria. The ACR criteria for FM were used to subgroup the patients. Muscle biopsy was performed in 36 patients. Light microscope morphology and immunohistochemical expression of MHC class I, MHC class II, and membrane attack complex (MAC) were studied. RESULTS: We found 44% of patients complained of muscle pain; 27% fulfilled the ACR criteria for FM, whereas 17% had other forms of myalgia. Muscle pain could not be related to histopathological findings. Signs of inflammation were found in 26 of 36 biopsies (72%), and inflammation combined with degeneration/regeneration (i.e., histological signs of polymyositis) in 17 biopsies (47%). However, only 5 patients (14%) had clinical as well as histological signs of polymyositis. Eight muscle biopsies (22%) showed histological features of inclusion body myositis (IBM). However, no patient had clinical symptoms suggestive of this disease. Abnormal expression of MHC class I, MHC class II, and MAC was found in 18 (50%), 16 (44%), and 27 (75%) patients, respectively. CONCLUSION: Muscle pain, especially FM, is common in SS. Histopathological signs of myositis are very common in SS. However, muscle symptoms are not related to histological signs of muscle inflammation. IBM-like findings may represent vacuolar myopathic degeneration due to previous subclinical muscle inflammation rather than a specific clinical entity.

Myosin storage myopathy associated with a heterozygous missense mutation in MYH7.

Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.