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153. Clinical research activity in the Newcastle MRC Centre for Neuromuscular Disease

Author

Peel, A., primary, Davis, B., additional, Maddison, J., additional, Boyd, C., additional, Straub, V., additional, Lochmüller, H., additional, Guglieri, M., additional, Turnbull, D.M., additional, Trenell, M.I., additional, Horvath, R., additional, McFarland, R., additional, Gorman, G.S., additional, Miller, J., additional, and Bushby, K., additional

Published
2017
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154. The MYO-SEQ project: application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

Author

Johnson, K., primary, Bertoli, M., additional, Phillips, L., additional, Blain, A., additional, Ensini, M., additional, Bushby, K., additional, Lochmüller, H., additional, Töpf, A., additional, Lek, M., additional, Xu, L., additional, Mullen, T., additional, Valkanas, E., additional, MacArthur, D.G., additional, and Straub, V., additional

Published
2017
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155. Myotonic dystrophy trial readiness

Author

Nikolenko, N., primary, Jimenez-Moreno, A.C., additional, Gomes, T., additional, Wood, L., additional, Moat, D., additional, Newman, J., additional, Fernandez-Torrón, R., additional, Roos, A., additional, Atalaia, A., additional, Monckton, D.G., additional, Turner, C., additional, and Lochmüller, H., additional

Published
2017
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157. Respiratory involvement in Facioscapulohumeral Dystrophy

Author

Moreira, S., primary, Wood, L., additional, Marini-Bettolo, C., additional, Guglieri, M., additional, McMacken, G., additional, Bailey, G., additional, Mayhew, A., additional, Muni, R., additional, Eglon, G., additional, Smith, D., additional, Williams, M., additional, Lochmüller, H., additional, and Evangelista, T., additional

Published
2017
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161. Telethonin gene mutations detected by next generation sequencing

Author

Hudson, J., primary, Cameron, S., additional, Graham, E., additional, Evangelista, T., additional, Straub, V., additional, Guglieri, M., additional, Barresi, R., additional, Lochmüller, H., additional, Norwood, F., additional, Bushby, K., additional, and Marini-Bettolo, C., additional

Published
2017
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162. The TREAT-NMD DMD global database: Analysis of more than 7,000 duchenne muscular dystrophy mutations

Author

Bladen, C.L. Salgado, D. Monges, S. Foncuberta, M.E. Kekou, K. Kosma, K. Dawkins, H. Lamont, L. Roy, A.J. Chamova, T. Guergueltcheva, V. Chan, S. Korngut, L. Campbell, C. Dai, Y. Wang, J. Barišić, N. Brabec, P. Lahdetie, J. Walter, M.C. Schreiber-Katz, O. Karcagi, V. Garami, M. Viswanathan, V. Bayat, F. Buccella, F. Kimura, E. Koeks, Z. van den Bergen, J.C. Rodrigues, M. Roxburgh, R. Lusakowska, A. Kostera-Pruszczyk, A. Zimowski, J. Santos, R. Neagu, E. Artemieva, S. Rasic, V.M. Vojinovic, D. Posada, M. Bloetzer, C. Jeannet, P.-Y. Joncourt, F. Díaz-Manera, J. Gallardo, E. Karaduman, A.A. Topaloğlu, H. El Sherif, R. Stringer, A. Shatillo, A.V. Martin, A.S. Peay, H.L. Bellgard, M.I. Kirschner, J. Flanigan, K.M. Straub, V. Bushby, K. Verschuuren, J. Aartsma-Rus, A. Béroud, C. Lochmüller, H.

Abstract

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). © 2015 The Authors.

Published
2015

163. Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

Author

Best, A. F., Hilbert, J. E., Wood, L., Martens, W. B., Nikolenko, N., Marini‐Bettolo, C., Lochmüller, H., Rosenberg, P. S., Moxley, R. T., Greene, M. H., and Gadalla, S. M.

Subjects
MYOTONIA atrophica, CANCER-related mortality, FAMILY history (Medicine), GENETIC testing, CANCER patient medical care
Abstract

Background and purpose: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non‐muscular manifestations and the usual delays in the diagnosis of DM1. Method: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first‐degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer‐related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. Results: A total of 467 deaths and 337 cancers were reported amongst 1737 first‐degree DM1 relatives. Mortality risk amongst relatives reported as DM1‐unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1‐affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. Conclusion: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease‐specific clinical care and surveillance. [ABSTRACT FROM AUTHOR]

Published
2019
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167. The risk of re-identification versus the need to identify individuals in rare disease research

Author

Hansson, M.G., Lochmüller, H., Riess, O., Schaefer, F., Orth, M., Rubinstein, Y., Molster, C., Dawkins, H., Taruscio, D., Posada, M., Woods, S., Hansson, M.G., Lochmüller, H., Riess, O., Schaefer, F., Orth, M., Rubinstein, Y., Molster, C., Dawkins, H., Taruscio, D., Posada, M., and Woods, S.

Abstract

There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.

Published
2016

169. Psycho-organic symptoms as early manifestation of adult onset POMT1-related limb girdle muscular dystrophy : case report

Author

Haberlova, J., Mitrović, Z., Žarković, Kamelija, Lovrić, D., Barić, V., Berlengi, Lada, Bilić, Karlo, Fumić, Ksenija, Kranz, K., Huebner, A., von der Hagen, M., Barresi, R., Bushby, K, Straub, V., Barić, Ivo, and Lochmüller, H.

Subjects
fungi, psycho-organic symptoms, POMT1 mutations, limb girdle muscular dystrophy, Walker-Warburg-syndrome
Abstract

We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced α-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits.

Published
2014
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171. RD-Connect: Data sharing and analysis for rare disease research within the integrated platform and through GA4GH beacon and matchmaker exchange

Author

Roos, A., primary, Beltran, S., additional, Piscia, D., additional, Laurie, S., additional, Protasio, J., additional, Cañada, A., additional, Fernández, J., additional, Kaliyaperumal, R., additional, Lair, S., additional, Sernadela, P., additional, Girdea, M., additional, Thompson, R., additional, Straub, V., additional, Roos, M., additional, T'Hoen, P., additional, Valencia, A., additional, Salgado, D., additional, Béroud, C., additional, Gut, I., additional, and Lochmüller, H., additional

Published
2016
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172. Beevor's sign: a potential clinical marker forGNEmyopathy

Author

Preethish-Kumar, V., primary, Pogoryelova, O., additional, Polavarapu, K., additional, Gayathri, N., additional, Seena, V., additional, Hudson, J., additional, Nishino, I., additional, Prasad, C., additional, Lochmüller, H., additional, and Nalini, A., additional

Published
2016
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176. Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations

Author

Natera-de Benito, D., primary, Bestué, M., additional, Vilchez, J.J., additional, Evangelista, T., additional, Töpf, A., additional, García-Ribes, A., additional, Trujillo-Tiebas, M.J., additional, García-Hoyos, M., additional, Ortez, C., additional, Camacho, A., additional, Jiménez, E., additional, Dusl, M., additional, Abicht, A., additional, Lochmüller, H., additional, Colomer, J., additional, and Nascimento, A., additional

Published
2016
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178. Deep RNA profiling identified clock and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Author

Scotton, C., primary, Bovolenta, M., additional, Schwartz, E., additional, Falzarano, M. S., additional, Martoni, E., additional, Passarelli, C., additional, Armaroli, A., additional, Osman, H., additional, Rodolico, C., additional, Messina, S., additional, Pegoraro, E., additional, D'Amico, A., additional, Bertini, E., additional, Gualandi, F., additional, Neri, M., additional, Selvatici, R., additional, Boffi, P., additional, Maioli, M. A., additional, Lochmüller, H., additional, Straub, V., additional, Bushby, K., additional, Castrignanò, T., additional, Pesole, G., additional, Sabatelli, P., additional, Merlini, L., additional, Braghetta, P., additional, Bonaldo, P., additional, Bernardi, P., additional, Foley, R., additional, Cirak, S., additional, Zaharieva, I., additional, Muntoni, F., additional, Capitanio, D., additional, Gelfi, C., additional, Kotelnikova, E., additional, Yuryev, A, additional, Lebowitz, M., additional, Zhang, X., additional, Hodge, B., additional, Esser, K. A., additional, and Ferlini, A., additional

Published
2016
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179. International charter of principles for sharing bio-specimens and data

Author

Mascalzoni, D., Dove, E.S., Rubinstein, Y., Dawkins, H.J.S., Kole, A., McCormack, P., Woods, S., Riess, O., Schaefer, F., Lochmüller, H., Knoppers, B.M., Hansson, M., Mascalzoni, D., Dove, E.S., Rubinstein, Y., Dawkins, H.J.S., Kole, A., McCormack, P., Woods, S., Riess, O., Schaefer, F., Lochmüller, H., Knoppers, B.M., and Hansson, M.

Abstract

There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues.

Published
2015

180. The TREAT-NMD DMD Global Database: Analysis of more than 7,000 Duchenne Muscular Dystrophy mutations

Author

Bladen, C.L., Salgado, D., Monges, S., Foncuberta, M.E., Kekou, K., Kosma, K., Dawkins, H., Lamont, L., Roy, A.J., Chamova, T., Guergueltcheva, V., Chan, S., Korngut, L., Campbell, C., Dai, Y., Wang, J., Barišić, N., Brabec, P., Lahdetie, J., Walter, M.C., Schreiber-Katz, O., Karcagi, V., Garami, M., Viswanathan, V., Bayat, F., Buccella, F., Kimura, E., Koeks, Z., van den Bergen, J.C., Rodrigues, M., Roxburgh, R., Lusakowska, A., Kostera-Pruszczyk, A., Zimowski, J., Santos, R., Neagu, E., Artemieva, S., Rasic, V.M., Vojinovic, D., Posada, M., Bloetzer, C., Jeannet, P-Y, Joncourt, F., Díaz-Manera, J., Gallardo, E., Karaduman, A.A., Topaloğlu, H., El Sherif, R., Stringer, A., Shatillo, A.V., Martin, A.S., Peay, H.L., Bellgard, M.I., Kirschner, J., Flanigan, K.M., Straub, V., Bushby, K., Verschuuren, J., Aartsma-Rus, A., Beroud, C., Lochmüller, H., Bladen, C.L., Salgado, D., Monges, S., Foncuberta, M.E., Kekou, K., Kosma, K., Dawkins, H., Lamont, L., Roy, A.J., Chamova, T., Guergueltcheva, V., Chan, S., Korngut, L., Campbell, C., Dai, Y., Wang, J., Barišić, N., Brabec, P., Lahdetie, J., Walter, M.C., Schreiber-Katz, O., Karcagi, V., Garami, M., Viswanathan, V., Bayat, F., Buccella, F., Kimura, E., Koeks, Z., van den Bergen, J.C., Rodrigues, M., Roxburgh, R., Lusakowska, A., Kostera-Pruszczyk, A., Zimowski, J., Santos, R., Neagu, E., Artemieva, S., Rasic, V.M., Vojinovic, D., Posada, M., Bloetzer, C., Jeannet, P-Y, Joncourt, F., Díaz-Manera, J., Gallardo, E., Karaduman, A.A., Topaloğlu, H., El Sherif, R., Stringer, A., Shatillo, A.V., Martin, A.S., Peay, H.L., Bellgard, M.I., Kirschner, J., Flanigan, K.M., Straub, V., Bushby, K., Verschuuren, J., Aartsma-Rus, A., Beroud, C., and Lochmüller, H.

Abstract

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

Published
2015

181. Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK

Author

Figueroa Bonaparte, Sebastián, Hudson, J, Barresi, R, Polvikoski, T, Williams, T, Töpf, A, Harris, E, Hilton-Jones, D, Petty, R, Willis, T A, Longman, C, Dougan, C F, Parton, M J, Hanna, M G, Quinlivan, R, Farrugia, M E, Guglieri, M, Bushby, K, Straub, V, Lochmüller, H, Evangelista, T, and Universitat Autònoma de Barcelona

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Population, DNA Mutational Analysis, Cell Cycle Proteins, CLINICAL NEUROLOGY, Genetic analysis, 03 medical and health sciences, Exon, 0302 clinical medicine, NEUROMUSCULAR, Valosin Containing Protein, medicine, Dementia, Humans, 10. No inequality, education, Genetics, MOTOR NEURON DISEASE, Adenosine Triphosphatases, education.field_of_study, Hereditary inclusion body myopathy, business.industry, DEMENTIA, MOLECULAR BIOLOGY, PostScript, medicine.disease, United Kingdom, 3. Good health, Distal Myopathies, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Biological Variation, Population, Frontotemporal Dementia, Mutation (genetic algorithm), Mutation testing, Surgery, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Hereditary inclusion body myopathy (IBM) with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD) (IBMPFD) is a rare autosomal dominant disorder due to mutations in the valosin-containing protein gene ( VCP ).1 Pathogenic VCP variants have also been associated with amyotrophic lateral sclerosis2 and other phenotypes including dilated cardiomyopathy and Parkinson's disease. We describe phenotypic and genetic findings of 42 individuals from 21 families with VCP mutations. As our service is the reference laboratory for the UK, we calculated the UK's point prevalence based on the 2011 Census as the number of cases per population. In total, 42 individuals were identified, 23 men and 19 women from 21 kinships (see online supplementary tables S1A, B). Based on our data, the expected point prevalence of IBMPFD in the UK is 0.066/100 000 population. Eighteen unrelated patients harbour a previously described mutation. In addition, three patients from two families harbour two novel variants (c.604G>T, p.G202W in exon 6 and c.1316C>G, p.A439G in exon 11) that are predicted to be pathogenic by in silico analysis (Alamut interpretation software V.2.4) and segregate with disease. Three previously described mutations were identified in exon 5 of the VCP gene. The mutation p.R155H (c.464G>A) was found in 11 families. The mutation p.R191Q (c.572G>A) was found in three unrelated patients, p.R155C (c.463C>T) in two families, and p.R93C (c.277C>T) in two unrelated patients (see online supplementary material genetic analysis and mutation analysis). The mean age of disease onset was …

Published
2015

182. Urodynamik

Author

Leisner, B., Koch, J., Mayr, B., Moser, E. A., Faber, P., Deck, H. J., Herberger, J., Schmidt, H., Heidenreich, J., Grüneberger, A., Geier, G., Eberhard, J., Krajnović, P., Oberhofer, S., Zubec, Z., Würth, K., Dreher, E., Eduah, S. B., Adam, P., v. Fischer, B., Heidenreich, J., Faber, P., Deck, H. J., Herberger, J., Deck, H. J., Schmidt-Rimpler, J., Faber, P., Heidenreich, J., Articus, M., Staufer, F., Lochmüller, H., Lienhard, P., Furrer, M., Eberhard, J., Kümper, H. J., Richter, K., Pickart, M., Koch, J., Heinz, F., Heidenreich, J., Faber, P., Deck, H. J., Jonas, U., Petri, E., Adam, P. J., v. Fischer, B., Dreher, E., Koutifaris, B., Nestoridis, N., Christodoulakos, G., Kalogirou, D., Altmann, P., Petri, E., Jonas, U., Tammen, H., Krieglsteiner, P., Achhammer, I., Graatz, B., Parache, J., Gonzales Chavez, G., Zerolo, J. M., Fdez Robayana, F., Ojeda, A., and Cotter, A.

Published
1979
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183. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14

Author

Cossins, J, Belaya, K, Hicks, D, Salih, M, Finlayson, S, Carboni, N, Liu, W, Maxwell, S, Zoltowska, K, Farsani, G, Laval, S, Seidhamed, M, Donnelly, P, Bentley, D, McGowan, S, Müller, J, Palace, J, Lochmüller, H, and Beeson, D

Subjects
Male, N-linked glycosylation, medicine.medical_specialty, Adolescent, Blotting, Western, DNA Mutational Analysis, Molecular Sequence Data, Neuromuscular transmission, Biology, N-Acetylglucosaminyltransferases, Bioinformatics, Neuromuscular junction, ALG2, Young Adult, 03 medical and health sciences, 0302 clinical medicine, ALG14, Internal medicine, medicine, Humans, Age of Onset, Child, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Acetylcholine receptor, Myasthenic Syndromes, Congenital, 0303 health sciences, Base Sequence, Muscle weakness, DPAGT1, Original Articles, Congenital myasthenic syndrome, Scientific Commentaries, medicine.disease, Pedigree, RAPSN, medicine.anatomical_structure, Endocrinology, Child, Preschool, congenital myasthenic syndrome, Female, Neurology (clinical), mutation, medicine.symptom, 030217 neurology & neurosurgery
Abstract

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation. © 2013 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain.

Published
2013

186. Eight novel UK families further expand current knowledge on GMPPB-gene related dystroglycanopathies

Author

Sarkozy, A., primary, Torelli, S., additional, Barresi, R., additional, Bertoli, M., additional, Sframeli, M., additional, Mein, R., additional, Yau, M., additional, Sewry, C., additional, Phadke, R., additional, Feng, L., additional, Ala, P., additional, Manzur, A., additional, Bushby, K., additional, Lochmüller, H., additional, Willis, T., additional, Norwood, F., additional, Rakowicz, R., additional, and Muntoni, F., additional

Published
2015
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189. TREAT-NMD (translational research in Europe, assessment and treatment for neuromuscular disorders)

Author

Aartsma-Rus, A., primary, Hoffman, E., additional, Bucella, F., additional, Flanigan, K., additional, Kirschner, J., additional, Kole, A., additional, Mercuri, E., additional, Nishino, I., additional, North, K., additional, Pereda Alonso, A., additional, Rahbek, J., additional, Sejersen, T., additional, Wood, M., additional, Lynn, S., additional, Robertson, A., additional, Lochmüller, H., additional, Straub, V., additional, and Bushby, K., additional

Published
2015
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191. Pain and quality of life in the UK FSHD patient registry

Author

Evangelista, T., primary, Wood, L., additional, Pohlschmidt, M., additional, Longman, C., additional, Roberts, M., additional, Hilton-Jones, D., additional, Lunt, P., additional, Wills, T., additional, Orrell, R., additional, Norwood, F., additional, Williams, M., additional, Smith, D., additional, Hudson, J., additional, and Lochmüller, H., additional

Published
2015
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195. NeurOmics: EU-funded-omics research for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases

Author

Turner, C., primary, Brice, A., additional, Bushby, K., additional, Riess, O., additional, Hanna, M., additional, van Ommen, G., additional, Muntoni, F., additional, Klockgether, T., additional, Wirth, B., additional, Lochmüller, H., additional, Timmerman, V., additional, Schoells, L., additional, Straub, V., additional, and Tabrizi, S., additional

Published
2015
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199. Targeted exon skipping to correct exon duplications in the dystrophin gene

Author

Greer, K.L., Lochmüller, H., Flanigan, K., Fletcher, S., Wilton, S.D., Greer, K.L., Lochmüller, H., Flanigan, K., Fletcher, S., and Wilton, S.D.

Abstract

Duchenne muscular dystrophy is a severe muscle-wasting disease caused by mutations in the dystrophin gene that ablate functional protein expression. Although exonic deletions are the most common Duchenne muscular dystrophy lesion, duplications account for 10–15% of reported disease-causing mutations, and exon 2 is the most commonly duplicated exon. Here, we describe the in vitro evaluation of phosphorodiamidate morpholino oligomers coupled to a cell-penetrating peptide and 2′-O-methyl phosphorothioate oligonucleotides, using three distinct strategies to reframe the dystrophin transcript in patient cells carrying an exon 2 duplication. Differences in exon-skipping efficiencies in vitro were observed between oligomer analogues of the same sequence, with the phosphorodiamidate morpholino oligomer coupled to a cell-penetrating peptide proving the most effective. Differences in exon 2 excision efficiency between normal and exon 2 duplication cells, were apparent, indicating that exon context influences oligomer-induced splice switching. Skipping of a single copy of exon 2 was induced in the cells carrying an exon 2 duplication, the simplest strategy to restore the reading frame and generate a normal dystrophin transcript. In contrast, multiexon skipping of exons 2–7 to generate a Becker muscular dystrophy-like dystrophin transcript was more challenging and could only be induced efficiently with the phosphorodiamidate morpholino oligomer chemistry.

Published
2014

200. Mapping the differences in care for 5,000 Spinal Muscular Atrophy patients, a survey of 24 national registries in North America, Australasia and Europe

Author

Bladen, Cl, Thompson, R, Jackson, Jm, Garland, C, Wegel, C, Ambrosini, A, Pisano, P, Walter, Mc, Schreiber, O, Lusakowska, A, Jedrzejowska, M, Kostera Pruszczyk, A, Van Der Pol, L, Wadman, Ri, Gredal, O, Karaduman, A, Topaloglu, H, Yilmaz, O, Matyushenko, V, Rasic, Vm, Kosac, A, Karcagi, V, Garami, M, Herczegfalvi, A, Monges, S, Moresco, A, Chertkoff, L, Chamova, T, Guergueltcheva, V, Butoianu, N, Craiu, D, Korngut, L, Campbell, C, Haberlova, J, Strenkova, J, Alejandro, M, Jimenez, A, Ortiz, Gg, Enriquez, Gvg, Rodrigues, M, Roxburgh, R, Dawkins, H, Youngs, L, Lahdetie, J, Angelkova, N, Saugier Veber, P, Cuisset, J, Bloetzer, C, Jeannet, P, Klein, A, Nascimento, A, Tizzano, E, Salgado, D, Mercuri, Eugenio Maria, Sejersen, T, Kirschner, J, Rafferty, K, Straub, V, Bushby, K, Verschuuren, J, Beroud, C, Lochmüller, H., Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365), Bladen, Cl, Thompson, R, Jackson, Jm, Garland, C, Wegel, C, Ambrosini, A, Pisano, P, Walter, Mc, Schreiber, O, Lusakowska, A, Jedrzejowska, M, Kostera Pruszczyk, A, Van Der Pol, L, Wadman, Ri, Gredal, O, Karaduman, A, Topaloglu, H, Yilmaz, O, Matyushenko, V, Rasic, Vm, Kosac, A, Karcagi, V, Garami, M, Herczegfalvi, A, Monges, S, Moresco, A, Chertkoff, L, Chamova, T, Guergueltcheva, V, Butoianu, N, Craiu, D, Korngut, L, Campbell, C, Haberlova, J, Strenkova, J, Alejandro, M, Jimenez, A, Ortiz, Gg, Enriquez, Gvg, Rodrigues, M, Roxburgh, R, Dawkins, H, Youngs, L, Lahdetie, J, Angelkova, N, Saugier Veber, P, Cuisset, J, Bloetzer, C, Jeannet, P, Klein, A, Nascimento, A, Tizzano, E, Salgado, D, Mercuri, Eugenio Maria, Sejersen, T, Kirschner, J, Rafferty, K, Straub, V, Bushby, K, Verschuuren, J, Beroud, C, Lochmüller, H., and Mercuri, Eugenio Maria (ORCID:0000-0002-9851-5365)

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterised by the degeneration of motor neurons and progressive muscle weakness. It is caused by homozygous deletions in the survival motor neuron gene on chromosome 5. SMA shows a wide range of clinical severity, with SMA type I patients often dying before 2 years of age, whereas type III patients experience less severe clinical manifestations and can have a normal life span. Here, we describe the design, setup and utilisation of the TREAT-NMD national SMA patient registries characterised by a small, but fully standardised set of registry items and by genetic confirmation in all patients. We analyse a selection of clinical items from the SMA registries in order to provide a snapshot of the clinical data stratified by SMA subtype, and compare these results with published recommendations on standards of care. Our study included 5,068 SMA patients in 25 countries. A total of 615 patients were ventilated, either invasively (178) or non-invasively (437), 439 received tube feeding and 455 had had scoliosis surgery. Some of these interventions were not available to patients in all countries, but differences were also noted among high-income countries with comparable wealth and health care systems. This study provides the basis for further research, such as quality of life in ventilated SMA patients, and will inform clinical trial planning.

Published
2014

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