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102. Diabetes, metformin and cancer risk in myotonic dystrophy type I.

Author

Alsaggaf, Rotana, Pfeiffer, Ruth M., Wang, Youjin, St. George, Diane Marie M., Zhan, Min, Wagner, Kathryn R., Amr, Sania, Greene, Mark H., and Gadalla, Shahinaz M.

Subjects
MYOTONIA atrophica, MUSCLE weakness, TYPE 2 diabetes, CANCER, DIABETES, CORNEAL dystrophies
Abstract

Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well‐established agent for the management of T2D, is thought to have cancer‐preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age‐, sex‐ and clinic‐matched cohort of 12,318 DM1‐free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18–10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06–3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91–1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72–1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1. What's new? Recent evidence suggests that myotonic dystrophy type I (DM1), an inherited nucleotide repeat disorder, is a cancer predisposition syndrome. However, the underlying pathological mechanisms and cancer‐predisposing risk factors remain unknown. Here, type 2 diabetes (T2D) and metformin were investigated for potential associations with cancer risk in DM1 patients. T2D was found to be more prevalent in DM1 patients than controls. DM1 patients with T2D were at increased risk of developing cancer. By contrast, cancer risk was not elevated in DM1‐T2D patients taking metformin. Further investigation of metformin use and cancer in DM1 patients could yield important insights into DM1‐related cancer prevention. [ABSTRACT FROM AUTHOR]

Published
2020
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103. Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy.

Author

Wagner, Kathryn R., Abdel-Hamid, Hoda Z., Mah, Jean K., Campbell, Craig, Guglieri, Michela, Muntoni, Francesco, Takeshima, Yasuhiro, McDonald, Craig M., Kostera-Pruszczyk, Anna, Karachunski, Peter, Butterfield, Russell J., Mercuri, Eugenio, Fiorillo, Chiara, Bertini, Enrico S., Tian, Cuixia, Statland, Jeffery, Sadosky, Alesia B., Purohit, Vivek S., Sherlock, Sarah P., and Palmer, Jeffrey P.

Subjects
*DUCHENNE muscular dystrophy, *TREATMENT effectiveness, *PHARMACOKINETICS
Abstract

• Domagrozumab at 5, 20, and 40 mg/kg was generally safe and well tolerated. • Primary endpoint of mean change from baseline in 4SC time at week 49 was not met. • Efficacy measures did not support a significant treatment effect with domagrozumab. • Nonsignificant increase in muscle volume was observed with domagrozumab vs placebo. We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619 [ABSTRACT FROM AUTHOR]

Published
2020
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105. A Transition Toolkit for Duchenne Muscular Dystrophy

Author

Trout, Christina J., primary, Case, Laura E., additional, Clemens, Paula R., additional, McArthur, Alexandra, additional, Noritz, Garey, additional, Ritzo, Marie, additional, Wagner, Kathryn R., additional, Vroom, Elizabeth, additional, and Kennedy, Annie, additional

Published
2018
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107. Cardiac Management of the Patient With Duchenne Muscular Dystrophy

Author

Buddhe, Sujatha, primary, Cripe, Linda, additional, Friedland-Little, Joshua, additional, Kertesz, Naomi, additional, Eghtesady, Pirooz, additional, Finder, Jonathan, additional, Hor, Kan, additional, Judge, Daniel P., additional, Kinnett, Kathi, additional, McNally, Elizabeth M., additional, Raman, Subha, additional, Thompson, W. Reid, additional, Wagner, Kathryn R., additional, and Olson, Aaron K., additional

Published
2018
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112. Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

Author

Kornegay, Joe N., Bogan, Daniel J., Bogan, Janet R., Dow, Jennifer L., Wang, Jiahui, Fan, Zheng, Liu, Naili, Warsing, Leigh C., Grange, Robert W., Ahn, Mihye, Balog-Alvarez, Cynthia J., Cotten, Steven W., Willis, Monte S., Brinkmeyer-Langford, Candice, Zhu, Hongtu, Palandra, Joe, Morris, Carl A., Styner, Martin A., Wagner, Kathryn R., and Human Nutrition, Foods, and Exercise

Subjects
musculoskeletal system
Abstract

Background Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/−) whippets. A total of four GRippets (dystrophic and Mstn +/−), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3 years of age. Conclusions Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors. Published version

Published
2016

113. Reduced representation optical methylation mapping (R2OM2)

Author

Grunwald, Assaf, primary, Sharim, Hila, additional, Gabrieli, Tslil, additional, Michaeli, Yael, additional, Torchinsky, Dmitry, additional, Juhasz, Matyas, additional, Wagner, Kathryn R, additional, Pevsner, Jonathan, additional, Reifenberger, Jeff, additional, Hastie, Alex R, additional, Cao, Han, additional, Weinhold, Elmar, additional, and Ebenstein, Yuval, additional

Published
2017
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115. Genetic disruption of Smad7 impairs skeletal muscle growth and regeneration

Author

Cohen, Tatiana V, Kollias, Helen D, Liu, Naili, Ward, Christopher W, and Wagner, Kathryn R

Subjects
Male, Mice, Knockout, integumentary system, Cell Differentiation, Muscle Development, Smad7 Protein, Myoblasts, Muscle, Animals, Regeneration, Female, Muscle Strength, Muscle, Skeletal, Cells, Cultured, Cell Proliferation
Abstract

Smad7 is an intracellular antagonist of transforming growth factor-β signalling pathways and modulates muscle growth in vivo. Loss of Smad7 results in decreased muscle mass, reduced force generation, fibre type switching from glycolytic towards oxidative type and delayed recovery from injury. Upregulated Smad2/3 signalling in Smad7(-/-) muscle results in reduced myoblast proliferation and differentiation. Smad7 is an important regulator of muscle growth and may be a potential intracellular therapeutic target for muscle disorders.The transforming growth factor-β (TGF-β) family of growth factors plays an essential role in mediating cellular growth and differentiation. Myostatin is a muscle-specific member of the TGF-β superfamily and a negative regulator of muscle growth. Myostatin inhibitors are currently being pursued as therapeutic options for muscle disorders. Smad7 inhibits intracellular myostatin signalling via Smad2/3, and thus presents a means of regulating myostatin and potentiating muscle growth. We investigated the functional loss of Smad7 on muscle in vivo by examining muscle growth and differentiation in mice deficient in Smad7 (Smad7(-/-) ). Smad7(-/-) mice showed reduced muscle mass, hypotrophy and hypoplasia of muscle fibres, as well as an increase in oxidative fibre types. Examination of muscle strength showed reduced force generation in vivo and ex vivo compared to wild-type controls. Analysis of muscle regeneration showed a delay in recovery, probably as a result of decreased activation, proliferation and differentiation of satellite cells, as confirmed in vitro. Additionally, myostatin expression was upregulated in Smad7(-/-) muscle. Our findings suggest that increased Smad2/3 signalling in the absence of Smad7 inhibition impedes muscle growth and regeneration. Taken together, our experiments demonstrate that Smad7 is an important mediator of muscle growth in vivo. Our studies enhance our understanding of in vivo TGF-β pathway modulation and suggest that Smad7 may be an important therapeutic target for muscle disorders.

Published
2015

116. Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

Author

Human Nutrition, Foods, and Exercise, Kornegay, Joe N., Bogan, Daniel J., Bogan, Janet R., Dow, Jennifer L., Wang, Jiahui, Fan, Zheng, Liu, Naili, Warsing, Leigh C., Grange, Robert W., Ahn, Mihye, Balog-Alvarez, Cynthia J., Cotten, Steven W., Willis, Monte S., Brinkmeyer-Langford, Candice, Zhu, Hongtu, Palandra, Joe, Morris, Carl A., Styner, Martin A., Wagner, Kathryn R., Human Nutrition, Foods, and Exercise, Kornegay, Joe N., Bogan, Daniel J., Bogan, Janet R., Dow, Jennifer L., Wang, Jiahui, Fan, Zheng, Liu, Naili, Warsing, Leigh C., Grange, Robert W., Ahn, Mihye, Balog-Alvarez, Cynthia J., Cotten, Steven W., Willis, Monte S., Brinkmeyer-Langford, Candice, Zhu, Hongtu, Palandra, Joe, Morris, Carl A., Styner, Martin A., and Wagner, Kathryn R.

Abstract

Background Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. Methods To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn +/−) whippets. A total of four GRippets (dystrophic and Mstn +/−), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Results Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, t

Published
2016

118. In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy

Author

Choudhury, Sourav R, primary, Fitzpatrick, Zachary, additional, Harris, Anne F, additional, Maitland, Stacy A, additional, Ferreira, Jennifer S, additional, Zhang, Yuanfan, additional, Ma, Shan, additional, Sharma, Rohit B, additional, Gray-Edwards, Heather L, additional, Johnson, Jacob A, additional, Johnson, Aime K, additional, Alonso, Laura C, additional, Punzo, Claudio, additional, Wagner, Kathryn R, additional, Maguire, Casey A, additional, Kotin, Robert M, additional, Martin, Douglas R, additional, and Sena-Esteves, Miguel, additional

Published
2016
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119. Clinical practice considerations in facioscapulohumeral muscular dystrophy Sydney, Australia, 21 September 2015

Author

Tawil, Rabi, primary, Mah, Jean K., additional, Baker, Scott, additional, Wagner, Kathryn R., additional, Ryan, Monique M., additional, Corbett, Alistair, additional, van Engelen, Baziel, additional, McNamara, Stephen, additional, Rasko, John, additional, Raykar, Veena, additional, Sacconi, Sabrina, additional, Tapscott, Stephen J., additional, Tawil, Rabi, additional, and Watts, Alan, additional

Published
2016
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120. Concordant but Varied Phenotypes among Duchenne Muscular Dystrophy Patient-Specific Myoblasts Derived using a Human iPSC-Based Model

Author

Choi, In Young, primary, Lim, HoTae, additional, Estrellas, Kenneth, additional, Mula, Jyothi, additional, Cohen, Tatiana V., additional, Zhang, Yuanfan, additional, Donnelly, Christopher J., additional, Richard, Jean-Philippe, additional, Kim, Yong Jun, additional, Kim, Hyesoo, additional, Kazuki, Yasuhiro, additional, Oshimura, Mitsuo, additional, Li, Hongmei Lisa, additional, Hotta, Akitsu, additional, Rothstein, Jeffrey, additional, Maragakis, Nicholas, additional, Wagner, Kathryn R., additional, and Lee, Gabsang, additional

Published
2016
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121. Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures

Author

Kornegay, Joe N., primary, Bogan, Daniel J., additional, Bogan, Janet R., additional, Dow, Jennifer L., additional, Wang, Jiahui, additional, Fan, Zheng, additional, Liu, Naili, additional, Warsing, Leigh C., additional, Grange, Robert W., additional, Ahn, Mihye, additional, Balog-Alvarez, Cynthia J., additional, Cotten, Steven W., additional, Willis, Monte S., additional, Brinkmeyer-Langford, Candice, additional, Zhu, Hongtu, additional, Palandra, Joe, additional, Morris, Carl A., additional, Styner, Martin A., additional, and Wagner, Kathryn R., additional

Published
2016
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122. Analysis of Myogenic and Candidate Disease Biomarkers in FSHD Muscle Cells

Author

Chen, Jennifer C. J., Jones, Takako I., King, Oliver D., Hanger, Kendal, Rahimov, Fedik, Homma, Sachiko, Beermann, Mary Lou, Bibat, Genila M., Miller, Jeffrey B., Kunkel, Louise M., Wagner, Kathryn R., Jones, Peter L., and Emerson, Jr., Charles P.

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities
Abstract

The UMMS Wellstone Program is a foundation and NIH-funded cooperative research center focusing on identifying biomarkers for facioscapulohumeral muscular dystrophy (FSHD) to gain insight into the molecular pathology of the disease and to develop potential therapies. FSHD is characterized by progressive wasting of skeletal muscles, with weakness often initiating in facial muscles and muscles supporting the scapula and upper arms. While the genetics associated with FSHD are complex, the major form of the disease, FSHD1, is linked to contraction of the D4Z4 repeat region located at chromosome 4q. Recently, a transcript encoded at the distal end of the repeat region, Dux4-fl, normally expressed in embryonic stem cells and germ cells, was also detected in differentiated muscle cells and biopsies from FSHD subjects, giving rise to the hypothesis that DUX4-FL function contributes to muscle weakness. We established a repository of high quality, well-characterized primary and immortalized muscle cell strains from FSHD and control subjects in affected families to provide biomaterials for cell and molecular studies to the FSHD research community. qPCR and immunostaining analyses demonstrate similar growth and differentiation characteristics in cells from FSHD and control subjects within families. We detected Dux4-fl transcript and protein in FSHD cells as recently described; interestingly, we also detected Dux4-fl in muscle cells from a subset of control individuals, suggesting that any Dux4-fl-mediated myopathy would require additional modifying elements. Microarray analysis of FSHD and control muscle cells demonstrated that several genes were upregulated in FSHD cells, including genes that were concurrently identified as downstream targets of Dux4-fl and as candidate FSHD disease genes. Future studies will further characterize the RNA and protein expression of candidate disease genes in cells from FSHD and control subjects, including nonmanifesting subjects with the D4Z4 lesion but no muscle weakness, and utilizing whole transcriptome sequencing (RNAseq) to identify additional candidates.

Published
2013
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123. Clinical Predictors of Conduction Disease Progression in Type I Myotonic Muscular Dystrophy

Author

Nazarian, Saman, Wagner, Kathryn R., Caffo, Brian S., and Tomaselli, Gordon F.

Subjects
Male, Maryland, Comorbidity, Middle Aged, Risk Assessment, Survival Analysis, Article, Survival Rate, Electrocardiography, Death, Sudden, Cardiac, Atrial Flutter, Risk Factors, Atrial Fibrillation, Disease Progression, Prevalence, Humans, Myotonic Dystrophy, Female
Abstract

Patients with type I myotonic muscular dystrophy (DM1) are at risk for sudden death due to atrioventricular conduction block. We sought to characterize the trends and predictors of time-dependent electrocardiographic (ECG) variations in patients with DM1.Seventy patients with DM1 underwent standard electrocardiography at first evaluation and routine and symptom prompted follow-up. Individual variations in ECG conduction intervals were assessed using spaghetti plots. Clinical predictors of conduction disease progression were assessed using multivariate random effects regression models of panel data clustered by patient and adjusted for heart rate.Substantial individual variability was noted in time-dependent changes in PR, QRS, and QTc intervals of patients with DM1. Changes in the QTc interval were closely associated with prolongation of the QRS interval. Age, the presence of paroxysmal atrial flutter or fibrillation, and the number of cytosine-thymine-guanine (CTG) repeats were independent positive predictors of time-dependent PR and QRS prolongation during long-term follow-up. Female sex was negatively associated with PR prolongation but positively associated with QTc prolongation. Lower left ventricular ejection fraction was associated with greater QRS interval progression during long-term follow-up but was not predictive of PR interval progression.Patients with DM1 can develop rapid changes in cardiac conduction intervals. Paroxysmal atrial flutter or fibrillation, older age, and larger CTG expansions predict greater time-dependent PR and QRS interval prolongation and warrant particular attention in the arrhythmic evaluation of this high risk patient subset.

Published
2010

126. Contemporary Cardiac Issues in Duchenne Muscular Dystrophy

Author

McNally, Elizabeth M., primary, Kaltman, Jonathan R., additional, Benson, D. Woodrow, additional, Canter, Charles E., additional, Cripe, Linda H., additional, Duan, Dongsheng, additional, Finder, Jonathan D., additional, Groh, William J., additional, Hoffman, Eric P., additional, Judge, Daniel P., additional, Kertesz, Naomi, additional, Kinnett, Kathi, additional, Kirsch, Roxanne, additional, Metzger, Joseph M., additional, Pearson, Gail D., additional, Rafael-Fortney, Jill A., additional, Raman, Subha V., additional, Spurney, Christopher F., additional, Targum, Shari L., additional, Wagner, Kathryn R., additional, and Markham, Larry W., additional

Published
2015
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127. The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development

Author

Heslop, Emma, primary, Csimma, Cristina, additional, Straub, Volker, additional, McCall, John, additional, Nagaraju, Kanneboyina, additional, Wagner, Kathryn R, additional, Caizergues, Didier, additional, Korinthenberg, Rudolf, additional, Flanigan, Kevin M, additional, Kaufmann, Petra, additional, McNeil, Elizabeth, additional, Mendell, Jerry, additional, Hesterlee, Sharon, additional, Wells, Dominic J, additional, and Bushby, Kate, additional

Published
2015
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128. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy

Author

Jones, Takako I, primary, King, Oliver D, additional, Himeda, Charis L, additional, Homma, Sachiko, additional, Chen, Jennifer C J, additional, Beermann, Mary Lou, additional, Yan, Chi, additional, Emerson, Charles P, additional, Miller, Jeffrey B, additional, Wagner, Kathryn R, additional, and Jones, Peter L, additional

Published
2015
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129. ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation.

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Sarkozy, Anna, Hicks, Debbie, Hudson, Judith, Laval, Steve H, Barresi, Rita, Hilton-Jones, David, Deschauer, Marcus, Harris, Elizabeth, Rufibach, Laura, Hwang, Esther, Bashir, Rumaisa, Walter, Maggie C, Krause, Sabine, Van den Bergh, Peter, Illa, Isabel, Pénisson-Besnier, Isabelle, De Waele, Liesbeth, Turnbull, Doug, Guglieri, Michela, Schrank, Bertold, Schoser, Benedikt, Seeger, Jürgen, Schreiber, Herbert, Gläser, Dieter, Eagle, Michelle, Bailey, Geraldine, Walters, Richard, Longman, Cheryl, Norwood, Fiona, Winer, John, Muntoni, Francesco, Hanna, Michael, Roberts, Mark, Bindoff, Laurence A, Brierley, Charlotte, Cooper, Robert G, Cottrell, David A, Davies, Nick P, Gibson, Andrew, Gorman, Gráinne S, Hammans, Simon, Jackson, Andrew P, Khan, Aijaz, Lane, Russell, McConville, John, McEntagart, Meriel, Al-Memar, Ali, Nixon, John, Panicker, Jay, Parton, Matt, Petty, Richard, Price, Christopher J, Rakowicz, Wojtek, Ray, Partha, Schapira, Anthony H, Swingler, Robert, Turner, Chris, Wagner, Kathryn R, Maddison, Paul, Shaw, Pamela J, Straub, Volker, Bushby, Kate, Lochmüller, Hanns, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Sarkozy, Anna, Hicks, Debbie, Hudson, Judith, Laval, Steve H, Barresi, Rita, Hilton-Jones, David, Deschauer, Marcus, Harris, Elizabeth, Rufibach, Laura, Hwang, Esther, Bashir, Rumaisa, Walter, Maggie C, Krause, Sabine, Van den Bergh, Peter, Illa, Isabel, Pénisson-Besnier, Isabelle, De Waele, Liesbeth, Turnbull, Doug, Guglieri, Michela, Schrank, Bertold, Schoser, Benedikt, Seeger, Jürgen, Schreiber, Herbert, Gläser, Dieter, Eagle, Michelle, Bailey, Geraldine, Walters, Richard, Longman, Cheryl, Norwood, Fiona, Winer, John, Muntoni, Francesco, Hanna, Michael, Roberts, Mark, Bindoff, Laurence A, Brierley, Charlotte, Cooper, Robert G, Cottrell, David A, Davies, Nick P, Gibson, Andrew, Gorman, Gráinne S, Hammans, Simon, Jackson, Andrew P, Khan, Aijaz, Lane, Russell, McConville, John, McEntagart, Meriel, Al-Memar, Ali, Nixon, John, Panicker, Jay, Parton, Matt, Petty, Richard, Price, Christopher J, Rakowicz, Wojtek, Ray, Partha, Schapira, Anthony H, Swingler, Robert, Turner, Chris, Wagner, Kathryn R, Maddison, Paul, Shaw, Pamela J, Straub, Volker, Bushby, Kate, and Lochmüller, Hanns

Abstract

Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.

Published
2013

131. ANO5Gene Analysis in a Large Cohort of Patients with Anoctaminopathy: Confirmation of Male Prevalence and High Occurrence of the Common Exon 5 Gene Mutation

Author

Sarkozy, Anna, primary, Hicks, Debbie, additional, Hudson, Judith, additional, Laval, Steve H., additional, Barresi, Rita, additional, Hilton-Jones, David, additional, Deschauer, Marcus, additional, Harris, Elizabeth, additional, Rufibach, Laura, additional, Hwang, Esther, additional, Bashir, Rumaisa, additional, Walter, Maggie C., additional, Krause, Sabine, additional, van den Bergh, Peter, additional, Illa, Isabel, additional, Pénisson-Besnier, Isabelle, additional, De Waele, Liesbeth, additional, Turnbull, Doug, additional, Guglieri, Michela, additional, Schrank, Bertold, additional, Schoser, Benedikt, additional, Seeger, Jürgen, additional, Schreiber, Herbert, additional, Gläser, Dieter, additional, Eagle, Michelle, additional, Bailey, Geraldine, additional, Walters, Richard, additional, Longman, Cheryl, additional, Norwood, Fiona, additional, Winer, John, additional, Muntoni, Francesco, additional, Hanna, Michael, additional, Roberts, Mark, additional, Bindoff, Laurence A., additional, Brierley, Charlotte, additional, Cooper, Robert G., additional, Cottrell, David A., additional, Davies, Nick P., additional, Gibson, Andrew, additional, Gorman, Gráinne S., additional, Hammans, Simon, additional, Jackson, Andrew P., additional, Khan, Aijaz, additional, Lane, Russell, additional, McConville, John, additional, McEntagart, Meriel, additional, Al-Memar, Ali, additional, Nixon, John, additional, Panicker, Jay, additional, Parton, Matt, additional, Petty, Richard, additional, Price, Christopher J., additional, Rakowicz, Wojtek, additional, Ray, Partha, additional, Schapira, Anthony H., additional, Swingler, Robert, additional, Turner, Chris, additional, Wagner, Kathryn R., additional, Maddison, Paul, additional, Shaw, Pamela J., additional, Straub, Volker, additional, Bushby, Kate, additional, and Lochmüller, Hanns, additional

Published
2013
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133. Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy.

Author

Wang, Leo H., Leung, Doris G., Wagner, Kathryn R., Lowry, Sarah J., McDermott, Michael P., Eichinger, Katy, Higgs, Kiley, Walker, Michaela, Lewis, Leann, Martens, William B., Mul, Karlien, Sansone, Valeria A., Shieh, Perry, Elsheikh, Bakri, LoRusso, Samantha, Butterfield, Russell J., Johnson, Nicholas, Preston, Matthew R., Messina, Carmelo, and Carraro, Elena

Subjects
*FACIOSCAPULOHUMERAL muscular dystrophy, *LEAN body mass, *DUAL-energy X-ray absorptiometry, *MASS measurement, *NEUROMUSCULAR diseases
Abstract

• There is moderate correlation between upper extremity lean tissue mass as measured by DEXA scans and their corresponding strengths measured by quantitative muscle testing. • There is moderate correlation between lower extremity lean tissue mass and corresponding strength measured by quantitative muscle testing and manual muscle testing. • There is moderate correlation between bilateral lower extremity lean tissue mass and 6-minute walk test, 10-meter walk/run, and timed-up-and-go. Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD. [ABSTRACT FROM AUTHOR]

Published
2023
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137. A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

Author

Homma, Sachiko, primary, Chen, Jennifer CJ, additional, Rahimov, Fedik, additional, Beermann, Mary Lou, additional, Hanger, Kendal, additional, Bibat, Genila M, additional, Wagner, Kathryn R, additional, Kunkel, Louis M, additional, Emerson, Charles P, additional, and Miller, Jeffrey Boone, additional

Published
2011
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143. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy

Author

Wagner, Kathryn R., primary, Fleckenstein, James L., additional, Amato, Anthony A., additional, Barohn, Richard J., additional, Bushby, Katharine, additional, Escolar, Diana M., additional, Flanigan, Kevin M., additional, Pestronk, Alan, additional, Tawil, Rabi, additional, Wolfe, Gil I., additional, Eagle, Michelle, additional, Florence, Julaine M., additional, King, Wendy M., additional, Pandya, Shree, additional, Straub, Volker, additional, Juneau, Paul, additional, Meyers, Kathleen, additional, Csimma, Cristina, additional, Araujo, Tracey, additional, Allen, Robert, additional, Parsons, Stephanie A., additional, Wozney, John M., additional, LaVallie, Edward R., additional, and Mendell, Jerry R., additional

Published
2008
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