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Respiratory Medicine

This page shows you the most recent publications within this specialty of the MedWorm directory. This is page number 10.

G.P.216: Allele-specific silencing of a dominant-negative mutation using siRNA or LNA antisense oligonucleotides alleviates the phenotype of a cellular model of Ullrich congenital muscular dystrophy
This study provides further insights into the comparative allele-specificity of these two pathways to target dominant mutations at the transcript level, with the goal of developing optimal compounds for in vivo application. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: V. Bolduc, Y. Zou, M. Lindow, S. Obad, C.G. Bönnemann Source Type: research

G.P.213: Investigating the molecular mechanisms underlying the progression of collagen VI-related muscular dystrophies
Ullrich congenital muscular dystrophy (UCMD) presents at birth or in infancy with progressive muscle weakness, joint contractures and respiratory failure, and is caused by mutations in the three genes coding for collagen VI. Dysfunction of the collagen VI microfibrills in the extracellular matrix perturbs the normal extracellular matrix/muscle interface, leading to yet incompletely characterized downstream effects. Review of muscle biopsies from UCMD patients show that the histological appearance changes with disease progression, suggesting changing disease-driving pathways throughout the progression of the disease. In pre...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: E. Guadagnin, J. Dastgir, L. Yang, K. Johnson, Q. Wang, Y. Hu, A. Dillmann, M. Cookson, C. Bönnemann Source Type: research

T.P.22: Two cases of late-onset Pompe disease treated with enzyme replacement therapy: Clinical outcome for 3years follow-up
We present 2 cases of Late-onset pompe disease (LOPD) treated with ERT for about 3years. Case 1: A 33-year-old man was admitted in our hospital for dyspnea. At 16years old, He felt progressive weakness of his lower limbs. At 18years old, He felt tiredness when he climbed the stairs. At 29years old, he had mild respiratory difficulty. At 33years old, he admitted in our hospital and showed proximal weakness, low forced vital capacity (FVC) and elevated creatine kinase (CK) level. On dried blood spot (DBS) test and molecular analysis, low GAA activity and two mutations (c.1309C>T, c.1316T>A) were detected. He applied non-inva...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: J.H. Lee, Y.N. Cho, H.J. Park, Y.C. Choi Source Type: research

T.P.17: Asymptomatic Pompe disease: A study of 6 patients
To describe 6 patients with asymptomatic Pompe disease (APD). Background. Pompe disease (PD) is a muscle glycogenosis due to acid alpha-glucosidase (GAA) deficiency, potentially leading to limb girdle muscle weakness and respiratory insufficiency in adults. Because of the availability of enzyme replacement therapy (ERT), and the improvement of enzymatic assessment techniques, an increasing number of patients are now diagnosed at an early stage of the disease. We studied 6 patients diagnosed with APD in France in the 1991–2013 interval. PD diagnosis was established on GAA enzyme activity levels and GAA gene analysis. All ...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: P. Laforêt, R.Y. Carlier, K. Laloui, P. Carlier, E. Salort-Campana, J. Pouget, A. Echaniz-Laguna Source Type: research

T.P.20: Effect of enzyme replacement therapy in late onset Pompe disease: Open pilot study of 60weeks follow up
In this study, we have evaluated the efficacy and adverse events of ERT for 60weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features including motor and pulmonary function was assessed, and rhGAA was infused every two weeks. Then, patients were examined at every 12weeks interval to evaluate their changes in motor and pulmonary function for 48weeks along with adverse reactions of ERT. The motor and pulmonary function of the patients demonstrated mild improvement or stabilization after 60weeks of ERT. And none of them showed deterioration in their am...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: J.S. Park, Y.E. Park, Y.C. Choi, J.H. Shin, J.M. Lee, D.S. Kim Source Type: research

T.P.15: Enzymotherapy in late onset Pompe disease patients: a 4-year longitudinal study using quantitative MRI
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...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: E. Doche, E. Salort-Campana, A. Le Troter, S. Attarian, J. Pouget, D. Bendahan Source Type: research

T.P.16: Clinical and molecular characteristics of 33 patients with Late Onset Pompe Disease (LOPD): Unusual phenotypes, novel mutations and therapeutic responses
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 andGAA sequence analysis. At follow-up patients underwent motor, respiratory, cardiac and...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: F. Montagnese, O. Musumeci, E. Barca, S. Romeo, A. Ciranni, M. Aguennouz, C. Rodolico, A. Toscano Source Type: research

G.P.189: Exercise intolerance associated with atypical facial muscle hypertrophy related to mitochondrial tRNA (Pro) gene mutation
We report a family where 7 female subjects presented with various degree of exercise intolerance since childhood. A common and original feature shared by affected members was the increased volume of the masseter muscle systematically occurring after feeding, making them looking like a hamster. Limb muscle size was not affected by effort. Patients also complained of keloid scars and for some of them of congenital cataract. The index case underwent full examination including clinical assessment, electromyography, electro-retinography, muscle biopsy, pulmonary function testing, exercise test, genetic testing. Clinical and EDX...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: Y. Péréon, A. Magot, G. Fayet, S. Mercier, J.M. Mussini, K. Auré, A. Lombès, C. Jardel Source Type: research

G.P.185: The novel non-sense mutation m.4214G>A in MT-ND1 results in mitochondrial myopathy with severe complex I deficiency
Mitochondrial DNA host a wide number of molecular defects associated with a broad spectrum of human clinical presentations ranging from tissue-specific diseases such as isolated myopathy or Leber hereditary optic neuropathy to multisystem disorders. Mutations affecting mitochondrial protein synthesis (transfer and ribosomal RNA genes) are quite frequent while molecular defects affecting genes encoding respiratory chain subunits are relatively less common. Here we discuss clinical, histological and molecular features of a patient presenting isolated myopathy secondary to mitochondrial complex I deficiency. Muscle biopsy sho...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: D. Ronchi, M. Sciacco, A. Bordoni, I. Colombo, D. Piga, F. Fortunato, M. Moggio, G.P. Comi Source Type: research

G.P.186: Gene expression profile of cybrid cells harbouring a mitochondrial DNA mutation in the MT-ATP6 gene reveals new pathogenic pathway
Mutations in the human mitochondrial MT-ATP6 gene, encoding ATP synthase subunit a, are causing different neurological disorders such as Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh’s syndrome, Charcot-Marie-Tooth neuropathy, and more recently paralysis episodes. The deleterious consequences of these MT-ATP6 mutations are still the matter of debate with respect to their cellular impact and influence of the nuclear background. To investigate the primary molecular mechanisms independently from the impact of nuclear genome, we constructed cybrids with homoplasmic levels of the MT-ATP6 m.9185T>C mutation previous...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: G. Fayet, K. Aure, P. Lesimple, C. L’Hermitte-Stead, C. Chevalier, A. Magot, R. Houlgatte, Y. Pereon, A. Lombes, F. Savagner Source Type: research

G.P.188: Autosomal recessive Kearns-Sayre syndrome in a girl with altered mitochondrial DNA transcription caused by RRM2B gene defect
We present the first child with KSS described so far with a nuclear gene defect of RRM2B, encoding the small subunit of p53-inducible ribonucleotide reductase. In the 15year-old girl, sensorineural hearing loss was noticed at the age of 11/2year leading to cochlear implants at ages 2 and 6years. Her psychomotor development was slightly retarded until the age of 10years when muscle weakness and an atactic gait became increasingly evident. At the age of 8years, the girl developed edema caused by a protein-loosing nephropathy. She now presents with ptosis, external ophthalmoplegia and retinitis pigmentosa. Muscle biopsy showe...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: E.K.G. Wilichowski, A. Abicht, H. Mayr, R. Horvath, W. Sperl, J. Gärtner Source Type: research

G.P.182: Severe and progressive mitochondrial myopathy in early childhood: novel mutations in TK2 gene
We present 3 unrelated male patients from non-consanguineous families, with normal early development until they showed a progressive hypotonia and muscular weakness with a fast motor regression between 14–24months of age. Two patients (currently 2 and 3years of age) lost the gait few months after starting the first clinical symptoms and the other at the age of 7, this patient died at 8,5years. At present, the other 2 patients are about to start treatment with deoxypyrimidine mono phosphates. All patients presented a mild increase of serum CK and lactate levels. Electromyogram showed a myopathic pattern. Muscle biopsy sho...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Nascimento, J. Dominguez, R. Mati, C. Ortez, M. Madruga, S. Emperador, J. Montoya, J. Aguirre, C. Jou, J. Colomer, C. Jimenez-Mallebrera Source Type: research

G.P.183: TK2 mutation: An expanding clinical phenotype
Conclusion We would like to highlight that the clinical phenotype for TK2 mutation is variable and can range from mild to very severe. In milder forms of this disorder, early multidisciplinary input should be sought to ensure that mobility, feeding and respiratory difficulties are all managed appropriately. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: D. Ram, M.I. Hughes Source Type: research

G.P.184: Mitochondrial DNA depletion in single fibers in a patient with novel TK2 mutations
We describe a patient with progressive muscle weakness and increased creatine kinase and lactate levels. Muscle weakness was first noted at age 1.5years and he died of respiratory failure and bronchopneumonia at age 3.5years. The muscle biopsy showed dystrophic features with ragged red fibers and numerous cytochrome c oxidase (COX)-negative fibers. qPCR analysis demonstrated depletion of mtDNA and sequence analysis of the mitochondrial thymidine kinase 2 (TK2) gene revealed two novel heterozygous variants, c.332C>T, p. (T111I) and c.156+5G>C. Quantitative analysis of mtDNA in single muscle fibers demonstrated that COX-defi...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: S. Roos, U. Lindgren, C. Ehrstedt, A.R. Moslemi, A. Oldfors Source Type: research

G.P.179: Association between resting energy expenditure and body weight change in patients with Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) patients are at risk of significant weight change relating to several factors. However, the relationship between body weight and calorie requirement during each stage of the disease is not known. The purpose of this study was to explore the appropriate nutritional management of DMD patients. Retrospective data from 28 DMD patients (mean age 20.6±3.5years) was assessed withrespect to body weight (BW), resting energy expenditure (REE), and assessment of respiratory and circulatory functions, which were conducted during annual examinations for at least 3years. Based on the annual change in B...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: S. Baba, S. Takanoha, A. Ishiyama, H. Komaki, E. Takeshita, H. Imaizumi, Y. Abe, M. Kobayashi, Y. Kumazawa, M. Sasaki Source Type: research

G.P.176: Steroid therapy and respiratory function in Duchenne muscular dystrophy
We have been monitoring the respiratory function in 95 DMD patients (aged between 6 and 24years) 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 c...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M.G. D’Angelo, A. LoMauro, M. Romei, S. Gandossini, E. Brighina, E. Marchi, N. Bresolin, A. Aliverti Source Type: research

G.P.169: Non-fatal fat embolism syndrome in Duchene muscular dystrophy
Fat Embolism Syndrome (FES) is associated with multisystem dysfunction. It has a wide spectrum of presentation and severity. Our first report of FES in Duchenne Muscular Dystrophy (DMD), onset soon after injury was associated with an early and rapid death. Since then, we have reviewed 6 boys with DMD who developed FES and survived. The boys were between 13 and 19years (mean 16.3), taking Deflazacort and were obese. All 6 boys had osteoporosis, straight spines, and good cardiac and pulmonary function. All 6 boys had a history of trauma: 4 falls (1 walking, 1 ceiling tract transfer and 2 from wheelchair seatbelt unfastened),...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: L.C. McAdam, K. MacLeod, N. Serrao, W.D. Biggar Source Type: research

G.P.163: Clinical features of Duchenne muscular dystrophy aged over 40 years
In the muscular dystrophy wards of 27 hospitals in Japan, of which 26 belong to the National Hospital Organization, and the other is the National Center of Neurology and Psychiatry, there are 733 patients diagnosed as Duchenne muscular dystrophy (DMD). Among them, 119 patients are 40years and older. To elucidate their clinical feature, we made survey of their condition and medical treatment. Questionnaire includes results of gene analysis, muscle biopsy findings, time of loss of ambulation, respiratory condition, nutrition, treatment for cardiomyopathy, steroid therapy, and history of spinal fusion. Information of 79 patie...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: T. Saito, M. Kawai, T. Matsumura, H. Fujimura, S. Sakoda Source Type: research

G.P.164: Physical ability and health in a non-steroid population of 77 adult patients with Duchenne muscular dystrophy
This study presents the result from the physical part of a questionnaire survey in the Danish adult DMD population. All Danish patients ⩾18years (n=80) with a confirmed clinical diagnosis of DMD were invited to participate in the study. The patient was interviewed in his home by two professionals from the National Danish Rehabilitation Centre for neuromuscular Diseases (RCfM) about his physical ability, health social relations and daily life using a comprehensive questionnaire. 79 patients accepted the invitation. Two patients were excluded due to previous steroid treatment. Median age of 77 patients was 27years (18–46...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: B. Werge, J. Rahbek, A. Madsen, J. Marquardt, U. Werlauff, B.F. Steffensen Source Type: research

G.O.12: Semi-automated analysis of diaphragmatic motion during deep breathing using dynamic MRI in both healthy controls and non-ambulant Duchenne muscular dystrophy
Whilst spirometry is the most common test of pulmonary function in Duchenne muscular dystrophy (DMD), cine MRI of diaphragm motion may provide a more direct and sensitive measure of diaphragm dysfunction, especially in a setting of clinical trials. As part of an on-going, natural history study in non-ambulant DMD patients, cine MRI of diaphragm motion is investigated as a potential objective biomarker of disease severity. Cine MRI is acquired during several cycles of deep-breathing in non-ambulant DMD individuals and volunteers. Data taken in the sagittal plane is analysed to assess maximal change during the respiratory cy...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: C.A. Bishop, V. Ricotti, C.D.J. Sinclair, J. Butler, R.B.M. Evans, J.M. Morrow, M.G. Hanna, P.M. Matthews, T.A. Yousry, J.S. Thornton, F. Muntoni, R.L. Janiczek Source Type: research

G.O.10: Skeletal muscle, cardiac, and pulmonary imaging biomarkers of disease activity in boys with Duchenne muscular dystrophy
With the promise of new treatments for Duchenne muscular dystrophy (DMD), there is a need for development of noninvasive biomarkers to assess pharmacologic response to study drugs. Magnetic resonance imaging (MRI) is a valuable tool for measuring the changes in the fat and water signal characteristics in dystrophic muscle. We performed a prospective imaging study of skeletal, cardiac, and respiratory muscles as part of a phase 2, placebo-controlled study of oligonucleotide GSK2401968-induced exon skipping in ambulatory boys with DMD. Muscles in the legs from the hips to the ankles were imaged using T1w, T2w, and 3-point Di...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Mankodi, R. Janiczek, M. Froeling, N. Azzabou, L. Gaur, D. Stock, R. Evers, C. Bishop, L. Yao, C. Grunseich, A. Arai, P. Carlier, K. Fischbeck Source Type: research

L.I.2: The ABC of autosomal recessive limb girdle muscular dystrophy
Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a group of heterogeneous muscle diseases that share several common denominators. Beside the same mode of inheritance, patients develop progressive weakness and wasting of their shoulder and pelvic girdle muscles whilst muscle biopsies generally show dystrophic histological features. Coming to a specific diagnosis in a patient with LGMD2 can be quite challenging. Diagnostic clues for the clinician can be the age of onset, the ethnic background, the involvement of respiratory muscles, the heart or other organ systems, the selective pattern of muscle pathology and ...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: V. Straub Source Type: research

G.P.160: Cysteine mutations cause defective tyrosine phosphorylation in MEGF10 myopathy
MEGF10 is a single transmembrane protein that is expressed in satellite cells of skeletal muscle, with 17 EGF-like domains in the extracellular region and 13 tyrosine residues in the cytoplasmic domain. Recessive mutations in MEGF10 are known to cause a congenital myopathy in humans, including the syndrome of early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Previously we reported a family with a milder phenotype who harbored the compound heterozygous missense mutations C326R and C774R. A heterozygous C774R mutation was also found in a patient with EMARDD, paired with a heterozygous nonsense mut...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: S. Mitsuhashi, H. Mitsuhashi, M.S. Alexander, H. Sugimoto, P.B. Kang Source Type: research

G.P.157: Clinical and pathological features associated with mutations in MICU1
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 lact...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A.M. Childs, K. Pysden, H. Roper, G. Chow, E.H. Niks, M. Kriek, P.F. Chinnery, D. Lewis-Smith, M. Duchen, G. Szabadkai, C. Logan, E. Sheridan, C. Sewry, F. Muntoni Source Type: research

G.P.155: A first Asian MEGF10 myopathy due to novel homozygous mutation
Recessive mutations in Multiple epidermal growth factor-like domains 10 (MEGF10) are known to cause the syndrome of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). We found a novel MEGF10 mutation by whole exome sequencing (WES) in a Japanese patient with EMRDD. The patient is a 9-year-old boy from a non-consanguineous family. There is no family history of neuromuscular disease. He was born at 39 weeks of gestational age. Although peri- and neonatal periods were uneventful, he had frequent respiratory infections in early infancy. At age 1 year and 6 months he developed respiratory failure for...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: K. Takayama, S. Mitsuhashi, S. Noguchi, Y.K. Hayashi, I. Nonaka, I. Nishino Source Type: research

G.P.129: Cine-MRI as a new tool to evaluate diaphragmatic dysfunction in Pompe disease
Severe pulmonary dysfunction is a serious threat to patients with Pompe disease, a treatable metabolic neuromuscular disorder caused by lysosomal acid α-glucosidase deficiency. This pulmonary dysfunction - which is particularly severe in the supine position – is mainly caused by diaphragmatic weakness. Standard pulmonary function tests provide only indirect information about diaphragmatic function, and they do not supply information about chest mechanics in detail. We therefore used cine-MRI to examine the dynamic performance of respiratory muscles, and compared these data with the results of simultaneously performed pu...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: S.C. Wens, P. Ciet, A. Perez-Rovira, K. Logie, E. Salamon, P. Wielopolski, M. Bruijne, M.E. Kruijshaar, H.W. Tiddens, N.A.M. van der Beek, P.A. van Doorn, A.T. van der Ploeg Source Type: research

A.P.7: Misfolding of fibronectin III 119 subdomain in titin results in hereditary myopathy with early respiratory failure
Hereditary myopathy with early respiratory failure (HMERF) is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. These protein aggregates are composed of multiple proteins including titin, áB-crystallin, actin, myotilin, desmin and others. Previous reports have described mutations in A-band titin (TTN) gene associated with HMERF. All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif o...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: C. Hedberg, A. Gomez Toledo, C.M. Gustafsson, G. Larson, A. Oldfors, B. Macao Source Type: research

A.P.8: Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure (HMERF)
Hereditary myopathy with early respiratory failure (HMERF) is an adult-onset progressive myopathy characterized by early presentation of respiratory disturbance usually during ambulant stage. The disease is caused by mutations in the exon 343 of TTN that encodes the fibronectin-3 119 domain in A-band region (ENST00000589042). Pathologically, HMERF is categorized into myofibrillar myopathy (MFM). Interestingly, cytoplasmic bodies (CBs) often localize in subsarcolemmal regions, with a necklace-like alignment in muscle fibers. Then we supposed that the necklace CBs might be useful in the diagnosis of HMERF. Here we aim to elu...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Uruha, Y.K. Hayashi, S. Mitsuhashi, S. Noguchi, I. Nonaka, I. Nishino Source Type: research

A.P.3: Unusual extraskeletal involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies
Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogenous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with respiratory and/or extraskeletal involvement. We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n=43) and particularly focused on the associated extraskeletal symptoms. We identified 14 heterozyg...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A.L. Semmler, S. Sacconi, J.E. Bach, C. Liebe, J. Bürmann, R.A. Kley, A. Ferbert, R. Anderheiden, P. Van den Bergh, J.J. Martin, P. De Jonghe, E. Neuen-Jacob, O. Müller, M. Deschauer, M. Bergmann, J.M. Schröder, M. Vorgerd, J.B. Schulz, J. Weis, W. Kre Source Type: research

A.P.4: Cytoplasmic bodies in the muscle of HMERF patients with TTN A150/FN3 119 and kinase domain mutations – An immunofluorescent analysis
Hereditary myopathy with early respiratory failure (HMERF) is an early adult-onset muscular dystrophy, with weakness predominantly in proximal and respiratory muscles. A mutation in the titin kinase domain was originally reported as one cause of the disease. However, the genetic background of HMERF has recently turned out to be more complex, with titin A150/FN3 119 domain mutations playing a central role. The HMERF muscle histopathology consists of myopathic-dystrophic changes with protein aggregation pathology, including autophagic rimmed vacuoles and myofibrillar pathology. A distinctive feature is the presence of cytopl...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Vihola, J. Palmio, G. Tasca, B. Eymard, A. Evila, S. Lange, F. Xiang, L. Edstrom, P. Hackman, M. Gautel, B. Udd Source Type: research

A.P.6 Autosomal recessive myofibrillar myopathy caused by ACTA1 mutations
Myofibrillar myopathies (MFMs) are a heterogeneous group of muscle diseases frequently associated with cardiac abnormalities and characteristic muscle histopathology. Most cases show autosomal dominant inheritance and adult onset of symptoms. Muscle biopsy findings include Z-line abnormalities, accumulation of myofibrillar degradation products and cytoplasmic aggregations of proteins. To date, the genetic cause of MFMs remains unclear in approximately 50% of cases. Here we describe a brother and a sister presenting with a myopathy with early childhood onset. The brother developed slowly progressive proximal muscle weakness...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M. Guglieri, N. Sambuughin, A. Sarkozy, R. Barresi, H. Lochmüller, K. Bushby, L.G. Goldfarb, V. Straub Source Type: research

A.P.2: Proteomic profile of cytoplasmic bodies (CB) compared to non-CB aggregates in HMERF associated with mutations in A-band titin
In conclusion, our analysis revealed that the proteomic profiles of CB and non-CB aggregates are highly similar in HMERF, especially regarding abundant over-represented proteins, and typical of MFM aggregates. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Maerkens, G. Tasca, G. Pfeffer, A. Sarkozy, J. Uszkoreit, R. Barresi, M. Vorgerd, B. Udd, R. Schröder, K. Marcus, H. Lochmüller, P. Chinnery, R.A. Kley Source Type: research

G.P.112: Pulmonary function is stable through week 120 in patients with Duchenne muscular dystrophy (DMD) treated with exon-skipping drug eteplirsen in phase 2b study
DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and premature death and affects 1:5000 male births. Clinically manifest pulmonary dysfunction often occurs when DMD patients become non-ambulant and is preceded by subclinical deterioration of pulmonary function tests (PFTs). Specifically, MIP and MEP % predicted deteriorate by approximately 4 % per year between the ages of 8–19. Eteplirsen is an investigational drug designed to enable functional dystrophin production in boys who are amenable to skipping exon 51. When dosed for up to 120weeks, stabilization of 6min walk distance was demo...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: J.R. Mendell, L.P. Lowes, L. Alfano, J. Saoud, P. Duda, E. Kaye Source Type: research

G.P.101 CAT-1004, a novel anti-Inflammatory agent under development for treatment of Duchenne muscular dystrophy
In DMD, inflammation is driven by elevated NF-κB in muscle and occurs early in life, with resident immune cells driving muscle degeneration. Corticosteroids block inflammation and delay loss of ambulation and onset of cardiac and respiratory failure, but chronic use has significant adverse effects. CAT-1004 is a novel compound that inhibits NF-κB and is in development to treat chronic inflammation in DMD. In the mdx mouse model, CAT-1004 reduced muscle inflammation and degenerating fibers, and increased regenerating muscle fibers. In the Golden Retriever Muscular Dystrophy (GRMD) model, a single dose of CAT-1004 reduced ...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: J. Milne, J. Donovan, L. Sweeney, M. Sleeper, D. Hammers, M. Jirousek, M. Curtis Source Type: research

G.P.97 Prophylactic oral bisphosphonate therapy in Duchenne muscular dystrophy: The Newcastle upon Tyne experience
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...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Sarkozy, R. Srinivasan, D. Rawlings, M. Guglieri, C. Owen, V. Straub, T. Cheetham, K. Bushby Source Type: research

G.P.82: Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle
Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. Existing animal models have been instrumental to understand the pathophysiology of DMD, but have limitations related to the type of mutation, the clinical phenotype, and the predictive value for molecular therapies. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscle...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M.C. Walter, N. Klymiuk, A. Blutke, A. Graf, S. Krause, A. Wuensch, S. Krebs, B. Kessler, V. Zakhartchenko, M. Kurome, E. Kemter, H. Nagashima, B. Schoser, N. Herbach, H. Blum, R. Wanke, A. Aartsma-Rus, H. Lochmuller, E. Wolf Source Type: research

G.P.76: Juvenile dermatomyositis involving large muscle infarction in three cases
We present peculiar muscle pathological findings in three patients suggesting large muscle infarction extending several fascicles with inflammatory changes. We investigated if there were some similarities among the three cases in clinical characteristics and pathlogies. Patient 1, 2year-old female visited a hospital in November 2012 because of persistent fever, fatigue, weight loss and striae exanthema after having a cold. Elevations of ESR, ferritin, sIL-2R, FDP, ALD, KL-6 and anti CADM-140 antibody were detected. Interstitial lung disease resistant to immune therapies was rapidly progressed and died from respiratory fail...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: R. Koichihara, H. Komaki, A. Ishiyama, Y.K. Hayashi, R.S. Tsuburaya, T. Saito, Y. Saito, E. Nakagawa, K. Sugai, M. Sasaki, I. Nonaka, I. Nishino Source Type: research

G.P.65: Obstructive sleep apnoea and subclinical impairment of respiratory function are common in sporadic inclusion body myositis
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±9.9years; disease duration 11.9±5.0years; body mass index 28.5±4.0kg/m2). Four patien...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: P.M. Rodriguez Cruz, M. Needham, P. Hollingsworth, F.L. Mastaglia, D.R. Hillman Source Type: research

G.P.47: Severe congenital myopathy with central nuclei and novel RYR1 gene mutations
We report a 17year old wheelchair-bound girl who presented at birth with severe generalized weakness, ptosis, ophthalmoplegia and profound facial and bulbar weakness. All findings have lasted throughout her life requiring tracheostomy and life-long nocturnal ventilation (at 17years FVC is 39% of predicted, and FEV1 33%) as well as placement of G-tube. Her CK has been repeatedly normal, EMG was myopathic. Muscle biopsy at 4months of age showed 91.2% fiber type I predominance and centrally placed nuclei in 10–15% of muscle fibers. EM showed focal myofribrillary disarray. DNA analysis of MTM1 and DNM2 genes revealed no muta...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: N. Chrestian, J. Dowling, K. Amburgey, T. Moraes, R. Cohn, C. Hawkins, W. Halliday, L. McAdam, D. Biggar, J. Vajsar Source Type: research

G.P.44: Clinical features of eight French patients with STIM 1 gene mutations
In conclusion, a characteristic clinical signature was evidenced in our patients associating proximal lower limb weakness, ophthalmoplegia and contractures. Such a phenotype with tubular aggregates at biopsy prompts to look for STIM1 gene mutations. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: B. Eymard, K. Ghorab, P. Laforet, F. Chevessier, J. Vallat, D. Hantai, N. Romero, J. Böhm, J. Laporte Source Type: research

G.P.42: Mild clinical phenotype in two siblings carrying myotubular myopathy
Among congenital myopathies, X-linked recessive myotubular myopathy is one of the most severe forms. The majority of patients present with severe hypotonia at birth and respiratory insufficiency and most of them die in the first year of life. However, there is phenotypic variability. Here, we report two patients carrying a missense mutation in MTM1 gene and presenting with a mild phenotype. The first boy was born on time with respiratory insufficiency and generalised hypotonia. He required ventilator support for 3weeks, and then he went home without specific care. He walked at 11month. He is now 24 and can run, practices c...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: A. Magot, V. Biancalana, S. Mercier, A. David, G. Fayet, J.M. Mussini, J. Laporte, Y. Pereon Source Type: research

G.P.43: Gene replacement therapy of myotubular myopathy: Restricting expression of MTM1 in skeletal muscle
Myotubular myopathy (XLMTM) is a fatal pediatric disease of skeletal muscle due to mutations in the MTM1 gene. Patients with XLMTM typically present with generalized muscle weakness and respiratory failure. We have previously demonstrated the efficacy of AAV-mediated MTM1 gene therapy in animal models. In order to express MTM1 preferentially in skeletal muscles after systemic gene delivery, we have constructed AAV vectors that contain the Mtm1 cDNA under the potent desmin promoter and a miRNA-208a target sequence for cardiac detargeting. We show that intravenous delivery of this vector leads to myotubularin expression in s...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: L. Buscara, R. Joubert, C. Moal, K. Poulard, S. Martin, A. Vignaud, F. Mavilio, A. Buj-Bello Source Type: research

G.P.39: An international prospective, longitudinal study of the natural history and functional status of patients with myotubular myopathy
We present here a prospective study of the pathophysiology of XLMTM to characterize the disease course by using standardized evaluations. A total of 60 patients with XLMTM, male or symptomatic female of any age, are planned to be enrolled in North America and Europe. Visit frequency and assessments are adjusted to age, ambulatory and respiratory status. Evaluations include standard liver ultrasound, clinical exam, ophthalmoplegia assessment, pulmonary function tests, strength and motor function assessment by using upper limb-specific devices and common scales, six-minute walk test, activity monitoring using the Actimyo dev...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M. Annoussamy, H. Landy, D. Ramsdell, M. Nelken, F. Muntoni, C. Bönnemann, D. Bharucha, J.J. Dowling, K. Amburgey, C. Lilien, G. Ollivier, J. Laporte, V. Biancalana, U. Schara, J.M. Cuisset, A. D’Amico, N. Deconinck, P.Y. Jeannet, A. Klein, J. Fluss, M Source Type: research

G.P.40: Skeletal muscle MRI in an X-linked myotubular myopathy patient who became ambulatory
We present the magnetic resonance imaging (MRI) findings of both upper and lower limbs in an XLMTM patient, who survived with Non-invasive Positive Pressure Ventilation (NPPV) support and ultimately became ambulatory. The patient was a 12-year old boy. His older brother, who also had XLMTM, had died during infancy. The patient presented with reduction of fetal movements, and had needed artificial respirator support at birth. He was genetically diagnosed as having XLMTM. Although he suffered repeated exacerbations of respiratory failure due to infection, the frequency of mechanical ventilation decreased after the initiation...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M. Shichiji, K. Ishigaki, T. Murakami, T. Sato, S. Kajino, M. Osawa, S. Nagata, K. Saito Source Type: research

G.P.41: Canine X-linked myotubular myopathy: A dose-finding study of systemic AAV8-MTM1 effects on muscle strength, gait, respiration, neuromuscular function and survival
Mutations in the myotubularin gene (MTM1) result in X-linked myotubular myopathy (XLMTM), a fatal pediatric disease of skeletal muscle characterized by small centrally nucleated myofibers containing abnormal mitochondrial accumulations. Patients typically present with severe hypotonia and respiratory failure. Previous local studies in Mtm1-mutant mice demonstrated potential efficacy of gene therapy to treat the disease. We recently reported that administration of adeno-associated virus serotype 8 (AAV8) vector expressing myotubularin under the muscle-specific desmin promoter, delivered systemically in myotubularin deficien...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: D.L. Mack, M. Goddard, J.M. Snyder, J. Doering, M.W. Lawlor, P. Moullier, M. O’Callaghan, A.H. Beggs, F. Mavilio, K. Poulard, V. Latournerie, A. Buj-Bello, M. Childers Source Type: research

G.P.35: Analysis of a large patient cohort with recessive truncating TTN mutations reveals novel clinical features and a diverse range of muscle pathologies
TTN encodes titin, the largest human protein. In striated muscle two titin molecules align “head to head” to span the full length of the sarcomere, providing a scaffold for sarcomere organisation, a sensing and signalling hub, and both passive and active modulation of muscle contraction. Dominant mutations in TTN are established causes of cardiomyopathy, tibial muscular dystrophy, and hereditary myopathy with early respiratory failure. More recently, several individuals with two truncating mutations have been described with increased internalised nuclei (CNM) with or without multi-minicores (MMC). Using next generation...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: E.C. Oates, K.S. Yau, A. Charlton, S. Brammah, M.A. Farrar, H. Sampaio, P.L. Lamont, D. Mowat, R.B. Fitzsimons, A. Corbett, M.M. Ryan, H.L. Teoh, G.L. O’Grady, R. Ghaoui, S. Kaur, M. Lek, K.N. North, D.G. MacArthur, M.R. Davis, N.G. Laing, N.F. Clarke Source Type: research

G.P.8: Dramatic improvement after injection augmentation in oculopharyngodistal myopathy
We examined the patient, and performed all the tests during preoperative and postoperative 1st week, 1st month and 3rd month visits. No complications occurred during or after the procedure. The method was very successful in that aspirations stopped immediately after the injection, the voice became less hoarse and speech was more understandable. Augmentation was more effective for aspiration than for voice quality. Oculopharyngodistal myopathy is a non-curable genetic disease which threatens life due to respiratory insufficiency even in ambulatory patients. Application of vocal cord injection augmentation can be a promising...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: O. Ozcan, H. Durmus, O. Tarhan, Z. Polat, F. Deymeer, Y. Parman, P. Oflazer-Serdaroglu Source Type: research

G.P.9: Adult onset distal and proximal myopathy with complete ophthalmoplegia and bulbar involvement due to de novo mutation in MYH2
We present a patient clinically classified as OPD myopathy who was found to carry a MYH2 de novo mutation. An Australian male of Italian background presented at 18years old with predominantly distal but also proximal limb weakness, ophthalmoplegia, dysphagia and facial weakness. He later developed respiratory involvement. Parents were not affected. The course of the disease was progressive, being wheelchair bound by the age of 50. He had 4 muscle biopsies done from age 20 to 46, none of which showed rimmed vacuoles. Dystrophic features, type I predominance, and abundant lobulated fibres were consistently found. Ultrastruct...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: M. Cabrera, R. Junckerstorff, P.J. Lamont, N.G. Laing Source Type: research

G.O.6: Lethal disorder of mitochondrial fission caused by mutations in DNM1L
We describe two siblings, born to non-consanguineous Filipino parents after 12years of infertility, with profound hypotonia, absent respiratory effort, hepatic dysfunction and multiple abnormalities on neuropathological studies at autopsy. The first child, a female, died at 3weeks of age and the second child, a male, died at 5days of life after withdrawal of care. Array CGH, molecular testing of SMN1, DMPK, POLG1, and metabolic studies (plasma amino acids, urine organic acids, lactate, very long chain fatty acids, transferrin isoforms) were all normal. Neuropathological examination revealed many neurons in the brain and sp...
Source: Neuromuscular Disorders - September 4, 2014 Category: Neurology Authors: G. Yoon, Z. Malam, T. Paton, C. Marshall, E. Hyatt, Z. Ivakine, D. Kemaladewi, C. Forge, K.S. Lee, C. Hawkins, R.D. Cohn Source Type: research

Propeller Health gets $14.5 million in funding, nabs Chris Hogg as COO
Propeller Health, a Wisconsin-based digital health company focusing on chronic respiratory disease, has raised $14.5 million in a Series B financing round led by Safeguard Sciences, with help from Series A investor The Social+Capital Partnership, a Palo Alto venture firm with a philanthropic flavor. The four-year-old tech start up also announced that lured Chris Hogg away from San Francisco's Practice Fusion, to run its Bay Area outpost and serve as chief operating officer. Hogg earlier founded… (Source: Health Care:Hospitals headlines)
Source: Health Care:Hospitals headlines - September 4, 2014 Category: Hospital Management Authors: Chris Rauber Source Type: research