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51. New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy

Author

Houlden, Henry, Groves, Mike, Miedzybrodzka, Zosia, Roper, Helen, Willis, Tracey, Winer, John, Cole, Gaynor, and Reilly, Mary M.

Subjects
Axons -- Abnormalities, Peripheral nerve diseases -- Genetic aspects, Peripheral nerve diseases -- Development and progression, Peripheral nerve diseases -- Research, Gene mutations -- Analysis, Health, Psychology and mental health
Published
2007

56. Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9

Author

Murphy, Lindsay B., primary, Schreiber‐Katz, Olivia, additional, Rafferty, Karen, additional, Robertson, Agata, additional, Topf, Ana, additional, Willis, Tracey A., additional, Heidemann, Marcel, additional, Thiele, Simone, additional, Bindoff, Laurence, additional, Laurent, Jean‐Pierre, additional, Lochmüller, Hanns, additional, Mathews, Katherine, additional, Mitchell, Claudia, additional, Stevenson, John Herbert, additional, Vissing, John, additional, Woods, Lacey, additional, Walter, Maggie C., additional, and Straub, Volker, additional

Published
2020
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59. Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Author

Guglieri, Michela, Bushby, Kate, McDermott, Michael P., Hart, Kimberly A., Tawil, Rabi, Martens, William B., Herr, Barbara E., McColl, Elaine, Speed, Chris, Wilkinson, Jennifer, Kirschner, Janbernd, King, Wendy M., Eagle, Michelle, Brown, Mary W., Willis, Tracey, Griggs, Robert C., Straub, Volker, van Ruiten, Henriette, Childs, Anne-Marie, and Ciafaloni, Emma

Subjects
GLUCOCORTICOIDS, RESEARCH, STEROIDS, RESEARCH methodology, EVALUATION research, DUCHENNE muscular dystrophy, COMPARATIVE studies, RANDOMIZED controlled trials, RESEARCH funding, QUESTIONNAIRES, PREDNISONE
Abstract

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.Trial Registration: ClinicalTrials.gov Identifier: NCT01603407. [ABSTRACT FROM AUTHOR]

Published
2022
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60. genetic diagnosis; limb-girdle weakness; neuromuscular disease; next-generation sequencing; targeted exome analysisweakness

Author

Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R., England, Eleina M., Laricchia, Kristen M., Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B., Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G., Akay, Ela, Alonso-Pérez, Jorge, Baets, Jonathan, Barisic, Nina, Bastian, Alexandra, Borell, Sabine, Chamova, Teodora, Claeys, Kristl, Colomer, Jaume, Coppens, Sandra, Deconinck, Nicolas, de Ridder, Willem, Díaz-Manera, Jordi, Domínguez-González, Cristina, Duncan, Alexis, Durmus, Hacer, Fahmy, Nagia A., Farrugia, Maria Elena, Fernández-Torrón, Roberto, Gonzalez- Quereda, Lidia, Haberlova, Jana, von der Hagen, Maja, Hahn, Andreas, Jakovčević, Antonia, Jerico Pascual, Ivonne, Kapetanovic, Solange, Kenina, Viktorija, Kirschner, Janbernd, Klein, Andrea, Kölbel, Heike, Kostera-Pruszczyk, Anna, Kulshrestha, Richa, Lähdetie, Jaana, Layegh, Mahsa, Longman, Cheryl, López de Munain, Adolfo, Loscher, Wolfgang, Lusakowska, Anna, Maddison, Paul, Magot, Armelle, Majumdar, Anirban, Martí, Pilar, Martínez Arroyo, Amaia, Mazanec, Radim, Mercier, Sandra, Mongini, Tiziana, Muelas, Nuria, Nascimento, Andrés, Nafissi, Shahriar, Omidi, Shirin, Ortez, Carlos, Paquay, Stéphanie, Pereon, Yann, Perić, Stojan, Ponzalino, Valentina, Rakočević Stojanović, Vidosava, Remiche, Gauthier, Rodríguez Sainz, Aida, Rudnik, Sabine, Sanchez Albisua, Iciar, Santos, Manuela, Schara, Ulrike, Shatillo, Andriy, Sertić, Jadranka, Stephani, Ulrich, Strang- Karlsson, Sonja, Sznajer, Yves, Tanev, Ani, Tournev, Ivailo, Van den Bergh, Peter, Van Parijs, Vinciane, Vílchez, Juan, Vill, Katharina, Vissing, John, Wallgren-Pettersson, Carina, Wanschitz, Julia, Willis, Tracey, Witting, Nanna, Zulaica, Miren, and Straub, Volker

Subjects
genetic diagnosis, limb-girdle weakness, neuromuscular disease, next-generation sequencing, targeted exome analysis
Abstract

Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers ; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases ; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes. .

Published
2020

61. Global FKRP Registry:observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9

Author

Murphy, Lindsay B., Schreiber-Katz, Olivia, Rafferty, Karen, Robertson, Agata, Topf, Ana, Willis, Tracey A., Heidemann, Marcel, Thiele, Simone, Bindoff, Laurence, Laurent, Jean Pierre, Lochmüller, Hanns, Mathews, Katherine, Mitchell, Claudia, Stevenson, John Herbert, Vissing, John, Woods, Lacey, Walter, Maggie C., Straub, Volker, Murphy, Lindsay B., Schreiber-Katz, Olivia, Rafferty, Karen, Robertson, Agata, Topf, Ana, Willis, Tracey A., Heidemann, Marcel, Thiele, Simone, Bindoff, Laurence, Laurent, Jean Pierre, Lochmüller, Hanns, Mathews, Katherine, Mitchell, Claudia, Stevenson, John Herbert, Vissing, John, Woods, Lacey, Walter, Maggie C., and Straub, Volker

Abstract

Objective: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle–Eye–Brain Disease and Walker–Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. Methods: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. Results: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). Interpretation: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.

Published
2020

63. Prediagnosis pathway benchmarking audit in patients with Duchenne muscular dystrophy.

Author

Gowda, Vasantha Lakshmi, Fernandez, Miguel, Prasad, Manish, Childs, Anne-Marie, Hughes, Imelda, Tirupathi, Sandya, Engelbert Lourens De Goede, Christian Gaudentius, O'Rourke, Declan, Parasuraman, Deepak, Willis, Tracey, Saberian, Samira, Davidson, Ian, and De Goede, Christian Gaudentius Engelbert Lourens

Subjects
DUCHENNE muscular dystrophy, DELAYED diagnosis, MEDICAL personnel, FAMILY history (Medicine), DIAGNOSIS of Duchenne muscular dystrophy, DISEASE progression, RESEARCH, RESEARCH methodology, RETROSPECTIVE studies, EVALUATION research, BENCHMARKING (Management), MEDICAL protocols, COMPARATIVE studies, AGE factors in disease
Abstract

Objective: To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement.Design: A multicentre retrospective national audit.Setting: Nine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria.Patients: Patients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122).Main Outcome Measures: Mean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded.Results: Overall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively.Conclusions: Majority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored. [ABSTRACT FROM AUTHOR]

Published
2022
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66. Natural history of limb girdle muscular dystrophy R9 over 6 years:searching for trial endpoints

Author

Murphy, Alexander P, Morrow, Jasper, Dahlqvist, Julia R, Stojkovic, Tanya, Willis, Tracey A, Sinclair, Christopher D J, Wastling, Stephen, Yousry, Tarek, Hanna, Michael S, James, Meredith K, Mayhew, Anna, Eagle, Michelle, Lee, Laurence E, Hogrel, Jean-Yves, Carlier, Pierre G, Thornton, John S, Vissing, John, Hollingsworth, Kieren G, Straub, Volker, Murphy, Alexander P, Morrow, Jasper, Dahlqvist, Julia R, Stojkovic, Tanya, Willis, Tracey A, Sinclair, Christopher D J, Wastling, Stephen, Yousry, Tarek, Hanna, Michael S, James, Meredith K, Mayhew, Anna, Eagle, Michelle, Lee, Laurence E, Hogrel, Jean-Yves, Carlier, Pierre G, Thornton, John S, Vissing, John, Hollingsworth, Kieren G, and Straub, Volker

Abstract

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years.Methods: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups.Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies.Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

Published
2019

68. Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study

Author

Bourke, John P, primary, Watson, Gillian, additional, Muntoni, Francesco, additional, Spinty, Stefan, additional, Roper, Helen, additional, Guglieri, Michela, additional, Speed, Chris, additional, McColl, Elaine, additional, Chikermane, Ashish, additional, Jayawant, Sandeep, additional, Adwani, Satish, additional, Willis, Tracey, additional, Wilkinson, Jennifer, additional, Bryant, Andrew, additional, Chadwick, Thomas, additional, Wood, Ruth, additional, and Bushby, Kate, additional

Published
2018
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71. Additional file 3: of Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Author

Hind, Daniel, Parkin, James, Whitworth, Victoria, Saleema Rex, Young, Tracey, Hampson, Lisa, Sheehan, Jennie, Maguire, Chin, Cantrill, Hannah, Scott, Elaine, Epps, Heather, Main, Marion, Geary, Michelle, McMurchie, Heather, Pallant, Lindsey, Woods, Daniel, Freeman, Jennifer, Lee, Ellen, Eagle, Michelle, Willis, Tracey, Muntoni, Francesco, and Baxter, Peter

Abstract

Land-based therapy manual. (PDG 256 kb)

Published
2017
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72. Additional file 2: of Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Author

Hind, Daniel, Parkin, James, Whitworth, Victoria, Saleema Rex, Young, Tracey, Hampson, Lisa, Sheehan, Jennie, Maguire, Chin, Cantrill, Hannah, Scott, Elaine, Epps, Heather, Main, Marion, Geary, Michelle, McMurchie, Heather, Pallant, Lindsey, Woods, Daniel, Freeman, Jennifer, Lee, Ellen, Eagle, Michelle, Willis, Tracey, Muntoni, Francesco, and Baxter, Peter

Abstract

Hydrotherapy manual. (PDF 136 kb)

Published
2017
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73. Additional file 1: of Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Author

Hind, Daniel, Parkin, James, Whitworth, Victoria, Saleema Rex, Young, Tracey, Hampson, Lisa, Sheehan, Jennie, Maguire, Chin, Cantrill, Hannah, Scott, Elaine, Epps, Heather, Main, Marion, Geary, Michelle, McMurchie, Heather, Pallant, Lindsey, Woods, Daniel, Freeman, Jennifer, Lee, Ellen, Eagle, Michelle, Willis, Tracey, Muntoni, Francesco, and Baxter, Peter

Abstract

CONSORT. (DOCX 24 kb)

Published
2017
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74. Mobility shift of beta-dystroglycan as a marker ofGMPPBgene-related muscular dystrophy

Author

Sarkozy, Anna, primary, Torelli, Silvia, additional, Mein, Rachael, additional, Henderson, Matt, additional, Phadke, Rahul, additional, Feng, Lucy, additional, Sewry, Caroline, additional, Ala, Pierpaolo, additional, Yau, Michael, additional, Bertoli, Marta, additional, Willis, Tracey, additional, Hammans, Simon, additional, Manzur, Adnan, additional, Sframeli, Maria, additional, Norwood, Fiona, additional, Rakowicz, Wojtek, additional, Radunovic, Aleksandar, additional, Vaidya, Sujit S, additional, Parton, Matt, additional, Walker, Mark, additional, Marino, Silvia, additional, Offiah, Curtis, additional, Farrugia, Maria Elena, additional, Mamutse, Godwin, additional, Marini-Bettolo, Chiara, additional, Wraige, Elizabeth, additional, Beeson, David, additional, Lochmüller, Hanns, additional, Straub, Volker, additional, Bushby, Kate, additional, Barresi, Rita, additional, and Muntoni, Francesco, additional

Published
2018
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76. Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy

Author

Morís, Germán, primary, Wood, Libby, additional, FernáNdez-Torrón, Roberto, additional, González Coraspe, José Andrés, additional, Turner, Chris, additional, Hilton-Jones, David, additional, Norwood, Fiona, additional, Willis, Tracey, additional, Parton, Matt, additional, Rogers, Mark, additional, Hammans, Simon, additional, Roberts, Mark, additional, Househam, Elizabeth, additional, Williams, Maggie, additional, Lochmüller, Hanns, additional, and Evangelista, Teresinha, additional

Published
2017
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77. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy

Author

Guglieri, Michela, primary, Bushby, Kate, additional, McDermott, Michael P., additional, Hart, Kimberly A., additional, Tawil, Rabi, additional, Martens, William B., additional, Herr, Barbara E., additional, McColl, Elaine, additional, Wilkinson, Jennifer, additional, Kirschner, Janbernd, additional, King, Wendy M., additional, Eagle, Michele, additional, Brown, Mary W., additional, Willis, Tracey, additional, Hirtz, Deborah, additional, Shieh, Perry B., additional, Straub, Volker, additional, Childs, Anne-Marie, additional, Ciafaloni, Emma, additional, Butterfield, Russell J., additional, Horrocks, Iain, additional, Spinty, Stefan, additional, Flanigan, Kevin M., additional, Kuntz, Nancy L., additional, Baranello, Giovanni, additional, Roper, Helen, additional, Morrison, Leslie, additional, Mah, Jean K., additional, Manzur, Adnan Y., additional, McDonald, Craig M., additional, Schara, Ulrike, additional, von der Hagen, Maja, additional, Barohn, Richard J., additional, Campbell, Craig, additional, Darras, Basil T., additional, Finkel, Richard S., additional, Vita, Giuseppe, additional, Hughes, Imelda, additional, Mongini, Tiziana, additional, Pegoraro, Elena, additional, Wicklund, Matthew, additional, Wilichowski, Ekkehard, additional, Bryan Burnette, W., additional, Howard, James F., additional, McMillan, Hugh J., additional, Thangarajh, Mathula, additional, and Griggs, Robert C., additional

Published
2017
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78. Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation

Author

Hind, Daniel, primary, Parkin, James, additional, Whitworth, Victoria, additional, Rex, Saleema, additional, Young, Tracey, additional, Hampson, Lisa, additional, Sheehan, Jennie, additional, Maguire, Chin, additional, Cantrill, Hannah, additional, Scott, Elaine, additional, Epps, Heather, additional, Main, Marion, additional, Geary, Michelle, additional, McMurchie, Heather, additional, Pallant, Lindsey, additional, Woods, Daniel, additional, Freeman, Jennifer, additional, Lee, Ellen, additional, Eagle, Michelle, additional, Willis, Tracey, additional, Muntoni, Francesco, additional, and Baxter, Peter, additional

Published
2017
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79. Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial

Author

Hind, Daniel, primary, Parkin, James, additional, Whitworth, Victoria, additional, Rex, Saleema, additional, Young, Tracey, additional, Hampson, Lisa, additional, Sheehan, Jennie, additional, Maguire, Chin, additional, Cantrill, Hannah, additional, Scott, Elaine, additional, Epps, Heather, additional, Main, Marion, additional, Geary, Michelle, additional, McMurchie, Heather, additional, Pallant, Lindsey, additional, Woods, Daniel, additional, Freeman, Jennifer, additional, Lee, Ellen, additional, Eagle, Michelle, additional, Willis, Tracey, additional, Muntoni, Francesco, additional, and Baxter, Peter, additional

Published
2017
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80. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness

Author

Lukacs, Zoltan, primary, Nieves Cobos, Paulina, additional, Wenninger, Stephan, additional, Willis, Tracey A., additional, Guglieri, Michela, additional, Roberts, Marc, additional, Quinlivan, Rosaline, additional, Hilton-Jones, David, additional, Evangelista, Teresinha, additional, Zierz, Stephan, additional, Schlotter-Weigel, Beate, additional, Walter, Maggie C., additional, Reilich, Peter, additional, Klopstock, Thomas, additional, Deschauer, Marcus, additional, Straub, Volker, additional, Müller-Felber, Wolfgang, additional, and Schoser, Benedikt, additional

Published
2016
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82. Mobility shift of beta-dystroglycan as a marker of gene-related muscular dystrophy.

Author

Sarkozy, Anna, Torelli, Silvia, Mein, Rachael, Henderson, Matt, Phadke, Rahul, Feng, Lucy, Sewry, Caroline, Ala, Pierpaolo, Yau, Michael, Bertoli, Marta, Willis, Tracey, Hammans, Simon, Manzur, Adnan, Sframeli, Maria, Norwood, Fiona, Rakowicz, Wojtek, Radunovic, Aleksandar, Vaidya, Sujit S, Parton, Matt, and Walker, Mark

Subjects
DYSTROGLYCAN, GENES, GLYCOSYLATION, CONGENITAL disorders, MUSCULAR dystrophy
Abstract

Background: Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.Methods: We describe clinical, genetic and biochemical findings of 21 patients with GMPPB-associated dystroglycanopathy.Results: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal N-linked glycosylation of β-DG.Conclusions: Our data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in GMPPB. [ABSTRACT FROM AUTHOR]

Published
2018
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83. .

Author

Zoltan, Lukacs, primary, Nieves Cobos, Paulina, additional, Wenninger, Stephan, additional, Willis, Tracey A., additional, Guglieri, Michela, additional, Roberts, Marc, additional, Quinlivan, Rosaline, additional, Hilton-Jones, David, additional, Evangelista, Teresinha, additional, Zierz, Stephan, additional, Schlotter-Weigel, Beate, additional, Walter, Maggie C, additional, Reilich, Peter, additional, Klopstock, Thomas, additional, Deschauer, Marcus, additional, Straub, Volker, additional, Müller-Felber, Wolfgang, additional, and Schoser, Benedikt, additional

Published
2016
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84. Quantitative magnetic resonance imaging in limb-girdle muscular dystrophy 2I:a multinational cross-sectional study

Author

Willis, Tracey A, Hollingsworth, Kieren G, Coombs, Anna, Sveen, Marie-Louise, Andersen, Soren, Stojkovic, Tanya, Eagle, Michelle, Mayhew, Anna, de Sousa, Paulo Loureiro, Dewar, Liz, Morrow, Jasper M, Sinclair, Christopher D J, Thornton, John S, Bushby, Kate, Lochmuller, Hanns, Hanna, Michael G, Hogrel, Jean-Yves, Carlier, Pierre G, Vissing, John, Straub, Volker, Willis, Tracey A, Hollingsworth, Kieren G, Coombs, Anna, Sveen, Marie-Louise, Andersen, Soren, Stojkovic, Tanya, Eagle, Michelle, Mayhew, Anna, de Sousa, Paulo Loureiro, Dewar, Liz, Morrow, Jasper M, Sinclair, Christopher D J, Thornton, John S, Bushby, Kate, Lochmuller, Hanns, Hanna, Michael G, Hogrel, Jean-Yves, Carlier, Pierre G, Vissing, John, and Straub, Volker

Abstract

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.

Published
2014

85. UK Facioscapulohumeral Muscular Dystrophy (FSHD) Patient Registry

Author

Wood, Libby, primary, Evangelista, Teresinha, additional, Norwood, Fiona, additional, Orrell, Richard, additional, Pohlschmidt, Marita, additional, Busby, Mark, additional, Graham, Andrew, additional, Hilton-Jones, David, additional, Longman, Cheryl, additional, Lunt, Peter, additional, Roberts, Mark, additional, Watt, Stuart, additional, Watt, Suzanne, additional, Willis, Tracey, additional, and Lochmüller, Hanns, additional

Published
2014
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86. Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I:A Multicentre Longitudinal Study

Author

Willis, Tracey A, Hollingsworth, Kieren G, Coombs, Anna, Sveen, Marie-Louise, Andersen, Søren Peter, Stojkovic, Tanya, Eagle, Michelle, Mayhew, Anna, de Sousa, Paulo L, Dewar, Liz, Morrow, Jasper M, Sinclair, Christopher D J, Thornton, John S, Bushby, Kate, Lochmüller, Hanns, Hanna, Michael G, Hogrel, Jean-Yves, Carlier, Pierre G, Vissing, John, Straub, Volker, Willis, Tracey A, Hollingsworth, Kieren G, Coombs, Anna, Sveen, Marie-Louise, Andersen, Søren Peter, Stojkovic, Tanya, Eagle, Michelle, Mayhew, Anna, de Sousa, Paulo L, Dewar, Liz, Morrow, Jasper M, Sinclair, Christopher D J, Thornton, John S, Bushby, Kate, Lochmüller, Hanns, Hanna, Michael G, Hogrel, Jean-Yves, Carlier, Pierre G, Vissing, John, and Straub, Volker

Published
2013

88. Quantitative Magnetic Resonance Imaging in Limb-Girdle Muscular Dystrophy 2I: A Multinational Cross-Sectional Study

Author

Willis, Tracey A., primary, Hollingsworth, Kieren G., additional, Coombs, Anna, additional, Sveen, Marie-Louise, additional, Andersen, Soren, additional, Stojkovic, Tanya, additional, Eagle, Michelle, additional, Mayhew, Anna, additional, de Sousa, Paulo Loureiro, additional, Dewar, Liz, additional, Morrow, Jasper M., additional, Sinclair, Christopher D. J., additional, Thornton, John S., additional, Bushby, Kate, additional, Lochmuller, Hanns, additional, Hanna, Michael G., additional, Hogrel, Jean-Yves, additional, Carlier, Pierre G., additional, Vissing, John, additional, and Straub, Volker, additional

Published
2014
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89. Quantitative Muscle MRI as an Assessment Tool for Monitoring Disease Progression in LGMD2I: A Multicentre Longitudinal Study

Author

Willis, Tracey A., primary, Hollingsworth, Kieren G., additional, Coombs, Anna, additional, Sveen, Marie-Louise, additional, Andersen, Søren, additional, Stojkovic, Tanya, additional, Eagle, Michelle, additional, Mayhew, Anna, additional, de Sousa, Paulo L., additional, Dewar, Liz, additional, Morrow, Jasper M., additional, Sinclair, Christopher D. J., additional, Thornton, John S., additional, Bushby, Kate, additional, Lochmüller, Hanns, additional, Hanna, Michael G., additional, Hogrel, Jean-Yves, additional, Carlier, Pierre G., additional, Vissing, John, additional, and Straub, Volker, additional

Published
2013
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97. Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X).

Author

Fullston, Tod, Brueton, Louise, Willis, Tracey, Philip, Sunny, MacPherson, Lesley, Finnis, Merran, Gecz, Jozef, and Morton, Jenny

Subjects
INTELLECTUAL disabilities, LISSENCEPHALY, AMINO acids, GENETIC mutation, GENETICS
Abstract

Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C>G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121–123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C>G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations. [ABSTRACT FROM AUTHOR]

Published
2010
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98. Identification of a Mechanism by Which the Methylmercury Antidotes N-Acetylcysteine and Dimercaptopropanesulfonate Enhance Urinary Metal Excretion: Transport by the Renal Organic Anion Transporter-1

Author

Koh, Albert S., Simmons-Willis, Tracey A., Pritchard, John B., Grassl, Steven M., and Ballatori, Nazzareno

Abstract

N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevisoocytes expressing rat Oat1 showed increased uptake of [14C]MeHg when complexed with either NAC or DMPS but not when complexed withl-cysteine, glutathione, dimercaptosuccinate, penicillamine, or γ-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparentKmvalues for Oat1-mediated transport were 31 ± 2 μM for MeHg-NAC and 9 ± 2 μM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [14C]MeHg-NAC and [14C]MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p-aminohippurate (PAH), and wastrans-stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [3H]PAH from Oat1-expressing oocytes wastrans-stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [3H]PAH uptake was competitively inhibited by NAC (Kiof 2.0 ± 0.3 mM) and DMPS (Kiof 0.10 ± 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals.

Published
2002
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99. Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1.

Author

S, Koh Albert, A, Simmons-Willis Tracey, B, Pritchard John, M, Grassl Steven, and Nazzareno, Ballatori

Abstract

N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevis oocytes expressing rat Oat1 showed increased uptake of [(14)C]MeHg when complexed with either NAC or DMPS but not when complexed with L-cysteine, glutathione, dimercaptosuccinate, penicillamine, or gamma-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparent K(m) values for Oat1-mediated transport were 31 +/- 2 microM for MeHg-NAC and 9 +/- 2 microM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [(14)C]MeHg-NAC and [(14)C]MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p-aminohippurate (PAH), and was trans-stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [(3)H]PAH from Oat1-expressing oocytes was trans-stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [(3)H]PAH uptake was competitively inhibited by NAC (K(i) of 2.0 +/- 0.3 mM) and DMPS (K(i) of 0.10 +/- 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals.

Published
2002

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