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151. Facioscapulohumeral dystrophy natural history study: standardization of testing procedures and reliability of measurements

Author

Personius, Kirkwood E., Pandya, Shree, King, Wendy M., Tawil, Rabi, and McDermott, Michael P.

Subjects
Muscular dystrophy -- Diagnosis, Muscles -- Testing
Abstract

Background and Purpose. The natural history, of facios capulohumeral muscular dystrophy (FSHD) has not been studied prospectively. Knowledge of the natural progression of any disease provides essential information for the design of clinical trials. We present a protocol for the study of the natural history of FSHD using quantitative muscle testing (QMT) manual muscle testing (MMT), and functional testing. Subjects. Thirty-two persons with FSHD (mean age=36.1 years, SD=9.6, range=17-49) and 32 age- and gender-matched volunteer controls (mean age=35.8 years, SD=8.0, range=23-50) served as subjects. Methods. Using standardized testing procedures, we examined intrarater reliability of the MMT, QMT, and functional testing measurements in both groups. We also examined interrater reliability in 7 subjects with FSHD. Eighteen muscle groups were tested for each subject using QMT and MMT Results. Intraclass correlation coefficient (ICC) values ranged from .86 to 99 for intrarater reliability and from .86 to .99 for interrater reliability, of QMT measurements. Weighted kappa values of 81 to .98 for intrarater reliability and .50 to 1.00 for interrater reliability were obtained for MMT measurements. Intrarater ICCs for various functional testing measures ranged from .60 to.97 In addition, the comparability of the two QMT machines used in the study was demonstrated by, testing the same set of volunteer controls on each machine's linear force transducer (ICC=.89-.98). Conclusion and Discussion. We conclude that this standardized testing protocol produces reliable measurements of muscle strength and functional ability in subjects with FSHD., [Personitus KE, Pandya S, King WM, et al. Facioscapulohumeral dystrophy natural history study: standardization of testing procedures and reliability of measurements. Phys Ther. 1994;74:253-263.] Key Words: Facioscapulohumeral muscular dystrophy, Functional [...]

Published
1994

152. Additional file 5: Figure S3. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, Maarel, Silvère, Tapscott, Stephen, and Sverdrup, Francis

Abstract

BETi block DUX4 target gene expression in FSHD myoblasts. (A) The expression level of ZSCAN4 mRNA after 72 h of treatment with the BETi (+)-JQ1, I-BET762, or I-BET151 in 54-2 FSHD1 myoblasts. (B) The BETi RVX-208 inhibits ZSCAN4 and TRIM43 expression in FSHD2 MB200 myoblasts treated for 72 h with EC50s of 350 nM and 280 nM, respectively. Error bars indicate the standard deviation from the mean of three biological replicates. (PDF 53 kb)

Published
2017
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153. Additional file 4: Figure S2. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, SilvèRe Maarel, Tapscott, Stephen, and Sverdrup, Francis

Abstract

The DUX4-responsive ZSCAN4 reporter system used for screening epigenetic modifier compounds. (A) Schematic depicting the ZSCAN4 promoter luciferase reporter vector (top) that includes four tandem DUX4 binding sites (D4BS), and a control reporter in which three of the four D4BS have been mutated (bottom). (B) Activity of the ZSCAN4 reporter vectors in 54-2 FSHD1 and 54-6 control (non-FSHD) myoblasts and 6Â day differentiated myotubes. Error bars indicate the standard deviation from the mean of three biological replicates. (PDF 66Â kb)

Published
2017
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154. Additional file 7: Figure S3. of SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda, Slieker, Roderick, Balog, Judit, Lemmers, Richard, Chao-Jen Wong, Zizhen Yao, Lim, Jong-Won, Filippova, Galina, Ne, Enrico, Tawil, Rabi, Heijmans, Bas, Tapscott, Stephen, and SilvèRe Van Der Maarel

Abstract

DUX4 binding at HS16. UCSC genome track of aligned DUX4 ChIP-sequencing reads from a previously published study (GEO GSE33838 [43]) showing a peak of DUX4 binding at HS16 within the cluster control region of the PCDH cluster. Sequence in the peak region is listed highlighting the DUX4 consensus binding sequence in red. (PDF 151Â kb)

Published
2017
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155. Additional file 8: Figure S6. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, SilvèRe Maarel, Tapscott, Stephen, and Sverdrup, Francis

Abstract

Characterization of BET gene expression. (A-C) 54-2 FSHD1 and 54-6 control (non-FSHD, Normal) myoblasts were induced to differentiate into myotubes and gene expression measured. Differentiation efficiency was determined by examining the early differentiation marker MYOG and the late differentiation marker MYH2 (A). As expected, DUX4 targets were strongly induced upon differentiation of FSHD1 but not control myoblasts (B). The levels of BET family member (BRD2, BRD3, BRD4, BRDT) mRNAs are shown in (C). (D) Tracks showing ChIP-seq and RNA-seq reads mapped to the BRDT locus in DUX4-expressing muscle cells. Error bars indicate the standard deviation from the mean of three biological replicates. (PDF 117Â kb)

Published
2017
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156. Additional file 2: Figure S1. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, Maarel, Silvère, Tapscott, Stephen, and Sverdrup, Francis

Abstract

Primary screening data for the Pharmakon 1600 library. Quantitative PCR detection of DUX4 target gene MBD3L2 is plotted for each library plate (88 compounds per plate). Data for each plate is normalized to no drug controls (n = 8), which were set to 1, as described in Methods. Plate means are indicated with horizontal lines and positive control data from each plate (I-BET762, n = 8) are collectively plotted in the rightmost column (Pos Controls). (PDF 126 kb)

Published
2017
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157. Additional file 6: Figure S2. of SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda, Slieker, Roderick, Balog, Judit, Lemmers, Richard, Chao-Jen Wong, Zizhen Yao, Lim, Jong-Won, Filippova, Galina, Ne, Enrico, Tawil, Rabi, Heijmans, Bas, Tapscott, Stephen, and Maarel, Silvère Van Der

Abstract

Transcriptional expression of the PCDHγ cluster in control, FSHD1, and FSHD2 individuals. RNA expression analysis of PCDHγ cluster isoform members in primary (A) myoblast cells and (B) myotube cells. Results represent log10 relative expression by qRT-PCR analysis of the indicated gene after normalization to the internal control gene GUS1. For each gene, the value of expression in control individuals was then arbitrarily set to 1. *Bonferroni adjusted P

Published
2017
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159. Additional file 6: Figure S4. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, Maarel, Silvère, Tapscott, Stephen, and Sverdrup, Francis

Abstract

BETi and beta-2 adrenergic agonists do not suppress the transcriptional activation function of DUX4. 54-6 control (non-FSHD) myoblasts that lack DUX4 were transfected with a DUX4 expression vector and DUX4 activity monitored by measuring mRNA levels of the endogenous DUX4 target gene MBD3L2. Compounds were added 5 h after transfection, a time at which there is little detectable MBD3L2 expression, and mRNA levels assessed at 24 h after transfection. The level of MBD3L2 at 24 h is expressed as ‘Fold Activation’ over the level present at 5 h, which was set to 1. Compounds were added in a 12 point, 3-fold dilution series to cover concentrations well above those required to inhibit DUX4 expression. The data point farthest to the left for each of the compounds represents a DMSO (no drug) control. The approximate EC50s of the beta-2 adrenergic agonist clenbuterol (X) and the BETi I-BET762 (Y) for blocking DUX4 expression in FSHD myoblasts are indicated on the x-axis. (PDF 31 kb)

Published
2017
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160. Additional file 8: Figure S4. of SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda, Slieker, Roderick, Balog, Judit, Lemmers, Richard, Chao-Jen Wong, Zizhen Yao, Lim, Jong-Won, Filippova, Galina, Ne, Enrico, Tawil, Rabi, Heijmans, Bas, Tapscott, Stephen, and Maarel, Silvère Van Der

Abstract

Transcriptional expression of DUX4 target genes and the PCDHγ cluster in SMCHD1 KD 4qB cell lines. RNA expression analysis of (A) the DUX4 target genes ZSCAN4 and LEUTX in primary myotubes and the PCDHγ cluster isoform members in primary (B) myoblast and (C) myotube cells after SMCHD1 shRNA KD or control shRNA KD targeting luciferase and GFP. Results represent qRT-PCR analysis of the indicated gene after normalization to the internal control gene GUS1. For each gene, the value of expression in control shRNA samples was then arbitrarily set to 1. *Bonferroni adjusted P

Published
2017
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163. Additional file 5: Figure S1. of SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda, Slieker, Roderick, Balog, Judit, Lemmers, Richard, Chao-Jen Wong, Zizhen Yao, Lim, Jong-Won, Filippova, Galina, Ne, Enrico, Tawil, Rabi, Heijmans, Bas, Tapscott, Stephen, and SilvèRe Van Der Maarel

Abstract

Methylation of the TCEB3C cluster and ZAV macrosatellite in FSHD2 and control individuals. Relative methylation levels found in FSHD2 and control individuals by RRBS, displayed as a methylation heatmap with color scale from yellow, no/low number of methylated CpGs at the locus to dark blue, high number of methylated CpGs at (A) the TCEB3C cluster and (B) the ZAV macrosatellite in primary myoblast cells. Bisulfite sequencing of (C) the TCEB3C cluster displayed as a heatmap depicting the average methylation fraction at a specific CpG from ESME analysis, with color scale from yellow to dark blue indicating a low to high percent of methylation, and (D) the ZAV macrosatellite depicted as single molecule clones for individuals, where black circles represent a methylated cytosine and open circles an unmethylated cytocine; gender of the individual is indicated by a red line for females and blue line for males in peripheral blood mononuclear cells. (PDF 109Â kb)

Published
2017
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164. Additional file 7: Figure S5. of BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy, Oliva, Jonathan, Yates, Matthew, Zhong, Jun, Shadle, Sean, Snider, Lauren, Singh, Nikita, Tai, Shannon, Hiramuki, Yosuke, Tawil, Rabi, Maarel, Silvère, Tapscott, Stephen, and Sverdrup, Francis

Abstract

FSHD myoblasts grown continuously in low dose BETi maintain suppressed DUX4 target gene expression but do not re-establish D4Z4 repeat DNA methylation. (A) DUX4 target gene expression in MB200 FSHD2 myoblasts grown for three weeks in media containing DMSO or 100 nM (+)-JQ1 compared to gene expression in 54-6 control (non-FSHD) myoblasts. (B) Structure of the D4Z4 repeat unit showing regions analyzed by bisulfate sequencing in this study (ADS3747 and ADS1454) relative to the DUX4 open reading frame (ORF). ADS3747 spans positions 665-708 and ADS1454 spans positions 2230-2361 with respect to the start of the KpnI site. The locations of previously published methylation-sensitive restriction sites and regions analyzed by bisulfite sequencing (DR1, DR2 and DR3) are indicated. (C-D) Average percent methylation across 9 CpG sites within ADS3747 (C) or 10 CpG sites within ADS1454 (D) in 54-6 control (non-FSHD, Normal), 54-2 FSHD1, and MB200 FSHD2 myoblasts, as well as MB200 FSHD2 myoblasts grown for three weeks in media containing DMSO or 100 nM (+)-JQ1. (E) Slow recovery of DUX4 target gene expression after BETi withdrawal. MB200 FSHD2 myoblasts grown for 3 weeks in 100 nM (+)-JQ1 were split and seeded onto culture plates in the absence of drug at ~10% confluence to allow for continued growth. ZSCAN4 mRNA levels in untreated MB200 FSHD2 myoblasts (Control), MB200 FSHD2 myoblasts maintained continuously in drug (JQ1) and MB200 FSHD2 myoblasts grown for the indicated times after compound withdrawal are shown. Error bars in (A) and (E) indicate the standard deviation from the mean of three biological replicates. (PDF 122 kb)

Published
2017
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165. Additional file 9: Figure S5. of SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda, Slieker, Roderick, Balog, Judit, Lemmers, Richard, Chao-Jen Wong, Zizhen Yao, Lim, Jong-Won, Filippova, Galina, Ne, Enrico, Tawil, Rabi, Heijmans, Bas, Tapscott, Stephen, and SilvèRe Van Der Maarel

Abstract

Percent input ChIP-qPCR for representative individuals. ChIP-qPCR for all ChIP examined loci displayed as a percent of the input for one control, FSHD1, and FSHD2 individual. Please note that it is difficult to compare single copy loci, HS17-17â ˛and HS19-20, to multi-copy loci tRNA and D4Z4. (PDF 831Â kb)

Published
2017
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167. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Author

van den Boogaard, Marlinde L., Lemmers, Richard J.L.F., Balog, Judit, Wohlgemuth, Mariëlle, Auranen, Mari, Mitsuhashi, Satomi, van der Vliet, Patrick J., Straasheijm, Kirsten R., van den Akker, Rob F.P., Kriek, Marjolein, Laurense-Bik, Marlies E.Y., Raz, Vered, van Ostaijen-ten Dam, Monique M., Hansson, Kerstin B.M., van der Kooi, Elly L., Kiuru-Enari, Sari, Udd, Bjarne, van Tol, Maarten J.D., Nishino, Ichizo, Tawil, Rabi, Tapscott, Stephen J., van Engelen, Baziel G.M., and van der Maarel, Silvère M.

Published
2016
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170. MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD

Author

Wang, Leo H, primary, Friedman, Seth D, additional, Shaw, Dennis, additional, Snider, Lauren, additional, Wong, Chao-Jen, additional, Budech, Chris B, additional, Poliachik, Sandra L, additional, Gove, Nancy E, additional, Lewis, Leann M, additional, Campbell, Amy E, additional, Lemmers, Richard J F L, additional, Maarel, Silvère M, additional, Tapscott, Stephen J, additional, and Tawil, Rabi N, additional

Published
2018
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175. Preliminary Results from a Phase 2 Study to Evaluate ACE-083, a Local Muscle Therapeutic, in Patients with Facioscapulohumeral Muscular Dystrophy (S38.001)

Author

Statland, Jeffrey, primary, Amato, Anthony, additional, Bravver, Elena, additional, Campbell, Craig, additional, Elman, Lauren, additional, Johnson, Nicholas, additional, Joyce, Nanette, additional, Karam, Chafic, additional, Kissel, John, additional, Korngut, Lawrence, additional, O’Ferrall, Erin, additional, Manousakis, Georgios, additional, Pestronk, Alan, additional, Shieh, Perry B., additional, Tawil, Rabi, additional, Leneus, Ashley, additional, Miller, Barry, additional, Sherman, Matthew L., additional, Glasser, Chad E., additional, and Attie, Kenneth M., additional

Published
2018
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176. Monosomy 18p is a risk factor for facioscapulohumeral dystrophy

Author

Balog, Judit, primary, Goossens, Remko, additional, Lemmers, Richard J L F, additional, Straasheijm, Kirsten R, additional, van der Vliet, Patrick J, additional, Heuvel, Anita van den, additional, Cambieri, Chiara, additional, Capet, Nicolas, additional, Feasson, Léonard, additional, Manel, Veronique, additional, Contet, Julian, additional, Kriek, Marjolein, additional, Donlin-Smith, Colleen M, additional, Ruivenkamp, Claudia A L, additional, Heard, Patricia, additional, Tapscott, Stephen J, additional, Cody, Jannine D, additional, Tawil, Rabi, additional, Sacconi, Sabrina, additional, and van der Maarel, Silvère M, additional

Published
2018
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178. Facioscapulohumeral muscular dystrophy functional composite outcome measure

Author

Eichinger, Katy, primary, Heatwole, Chad, additional, Iyadurai, Stanley, additional, King, Wendy, additional, Baker, Lindsay, additional, Heininger, Susanne, additional, Bartlett, Amy, additional, Dilek, Nuran, additional, Martens, William B., additional, Mcdermott, Michael, additional, Kissel, John T., additional, Tawil, Rabi, additional, and Statland, Jeffrey M., additional

Published
2018
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179. Electrical Impedance Myography in Facioscapulohumeral Muscular Dystrophy

Author

Statland, Jeffrey M., Heatwole, Chad, Eichinger, Kate, Dilek, Nuran, Martens, William B, and Tawil, Rabi

Subjects
Adult, Male, Cross-Sectional Studies, Electric Impedance, Myography, Humans, Female, Prospective Studies, Middle Aged, Muscle, Skeletal, Article, Muscular Dystrophy, Facioscapulohumeral, Aged
Abstract

In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD).We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared with measures of strength, FSHD disease severity, and functional outcomes.Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics.EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54: 696-701, 2016.

Published
2016

183. 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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184. Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model

Author

de Greef, Jessica C, primary, Krom, Yvonne D, additional, den Hamer, Bianca, additional, Snider, Lauren, additional, Hiramuki, Yosuke, additional, van den Akker, Rob F P, additional, Breslin, Kelsey, additional, Pakusch, Miha, additional, Salvatori, Daniela C F, additional, Slütter, Bram, additional, Tawil, Rabi, additional, Blewitt, Marnie E, additional, Tapscott, Stephen J, additional, and van der Maarel, Silvère M, additional

Published
2017
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186. Review of the Diagnosis and Treatment of Periodic Paralysis

Author

Statland, Jeffrey M., primary, Fontaine, Bertrand, additional, Hanna, Michael G., additional, Johnson, Nicholas E., additional, Kissel, John T., additional, Sansone, Valeria A., additional, Shieh, Perry B., additional, Tawil, Rabi N., additional, Trivedi, Jaya, additional, Cannon, Stephen C., additional, and Griggs, Robert C., additional

Published
2017
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187. Deep characterization of a common D4Z4 variant identifies biallelic DUX4 expression as a modifier for disease penetrance in FSHD2

Author

Lemmers, Richard JLF, primary, van der Vliet, Patrick J, additional, Balog, Judit, additional, Goeman, Jelle J, additional, Arindrarto, Wibowo, additional, Krom, Yvonne D, additional, Straasheijm, Kirsten R, additional, Debipersad, Rashmie D, additional, Özel, Gizem, additional, Sowden, Janet, additional, Snider, Lauren, additional, Mul, Karlien, additional, Sacconi, Sabrina, additional, van Engelen, Baziel, additional, Tapscott, Stephen J, additional, Tawil, Rabi, additional, and van der Maarel, Silvère M, additional

Published
2017
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188. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells

Author

Campbell, Amy E., primary, Oliva, Jonathan, additional, Yates, Matthew P., additional, Zhong, Jun Wen, additional, Shadle, Sean C., additional, Snider, Lauren, additional, Singh, Nikita, additional, Tai, Shannon, additional, Hiramuki, Yosuke, additional, Tawil, Rabi, additional, van der Maarel, Silvère M., additional, Tapscott, Stephen J., additional, and Sverdrup, Francis M., additional

Published
2017
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190. 225th ENMC international workshop

Author

Mul, Karlien, primary, Kinoshita, June, additional, Dawkins, Hugh, additional, van Engelen, Baziel, additional, Tupler, Rossella, additional, Ferreira, Verònica Alonso, additional, Attarian, Sharam, additional, Berardinelli, Angela, additional, Bogard, Betsy, additional, Evangelista, Teresinha, additional, van der Graaf, Kees, additional, Heatwole, Chad, additional, Van der Maarel, Silvère, additional, Mah, Jean, additional, Mul, Karlien, additional, van Rens, Jacqui, additional, Richiardi, Armelle, additional, Roxburgh, Richard, additional, Sacconi, Sabrina, additional, Tawil, Rabi, additional, van der Meij-Kim, Diana, additional, Voet, Nicole, additional, and Vohánka, Stanislav, additional

Published
2017
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191. 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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192. SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes

Author

Mason, Amanda G., primary, Slieker, Roderick C., additional, Balog, Judit, additional, Lemmers, Richard J. L. F., additional, Wong, Chao-Jen, additional, Yao, Zizhen, additional, Lim, Jong-Won, additional, Filippova, Galina N., additional, Ne, Enrico, additional, Tawil, Rabi, additional, Heijmans, Bas T., additional, Tapscott, Stephen J., additional, and van der Maarel, Silvère M., additional

Published
2017
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194. p38αRegulates Expression of DUX4 in a Model of Facioscapulohumeral Muscular Dystrophy▪

Author

Rojas, L. Alejandro, Valentine, Erin, Accorsi, Anthony, Maglio, Joseph, Shen, Ning, Robertson, Alan, Kazmirski, Steven, Rahl, Peter, Tawil, Rabi, Cadavid, Diego, Thompson, Lorin A., Ronco, Lucienne, Chang, Aaron N., Cacace, Angela M., and Wallace, Owen

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the loss of repression at the D4Z4locus leading to aberrant double homeobox 4 (DUX4) expression in skeletal muscle. Activation of this early embryonic transcription factor results in the expression of its target genes causing muscle fiber death. Although progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38αas a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent, and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity, and cell death across patient-derived FSHD1 and FSHD2 lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/βinhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/βinhibitors as effective therapeutics to treat FSHD at its root cause.

Published
2020
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195. SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.

Author

Lemmer, Richard J. L. F., van der Stoep, Nienke, van der Vliet, Patrick J., Moore, Steven A., Granado, David San Leon, Johnson, Katherine, Topf, Ana, Straub, Volker, Evangelista, Teresinha, Mozaffar, Tahseen, Kimonis, Virginia, Shaw, Natalie D., Selvatici, Rita, Ferlini, Alessandra, Voermans, Nicol, van Engelen, Baziel, Sacconi, Sabrina, Tawil, Rabi, Lamers, Meindert, and van der Maarel, Silvère M.

Abstract

Background Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended AT Pase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype-phenotype relationships. Methods Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a threedimensional model of the AT Pase domain of SMCHD1. Results DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended AT Pase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1. Conclusions The localisation of missense variants within the AT Pase domain of SMCHD1 may contribute to the differences in phenotypic outcome. [ABSTRACT FROM AUTHOR]

Published
2019
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198. Long Exercise Test in Periodic Paralysis: A Bayesian Analysis.

Author

Simmons, Daniel B., Lanning, Julie, Cleland, James C., Puwanant, Araya, Twydell, Paul T., Griggs, Robert C., Tawil, Rabi, and Logigian, Eric L.

Subjects
ELECTROMYOGRAPHY, EVOKED potentials (Electrophysiology), EXERCISE tests, LONGITUDINAL method, PROBABILITY theory, HEALTH self-care, SELF-evaluation, RECEIVER operating characteristic curves, SKELETAL muscle
Abstract

Introduction: The long exercise test (LET) is used to assess the diagnosis of periodic paralysis (PP), but LET methodology and normal "cutoff" values vary.Methods: To determine optimal LET methodology and cutoffs, we reviewed LET data (abductor digiti minimi motor response amplitude, area) from 55 patients with PP (32 genetically definite) and 125 controls. Receiver operating characteristic curves were constructed, and area under the curve (AUC) was calculated to compare (1) peak-to-nadir versus baseline-to-nadir methodologies and (2) amplitude versus area decrements. Using bayesian principles, we calculated optimal cutoff decrements that achieved 95% posttest probability of PP for various pretest probabilities (PreTPs).Results: AUC was highest for peak-to-nadir methodology and equal for amplitude and area decrements. For PreTP ≤ 50%, optimal decrement cutoffs (peak-to-nadir) were > 40% (amplitude) or > 50% (area).Discussion: For confirmation of PP, our data endorse the diagnostic utility of peak-to-nadir LET methodology using 40% amplitude or 50% area decrement cutoffs for PreTP ≤50%. Muscle Nerve 59:47-54, 2019. [ABSTRACT FROM AUTHOR]

Published
2019
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200. Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.

Author

Sansone, Valeria A, Sansone, Valeria A, Burge, James, McDermott, Michael P, Smith, Patty C, Herr, Barbara, Tawil, Rabi, Pandya, Shree, Kissel, John, Ciafaloni, Emma, Shieh, Perry, Ralph, Jeffrey W, Amato, Antony, Cannon, Steve C, Trivedi, Jaya, Barohn, Richard, Crum, Brian, Mitsumoto, Hiroshi, Pestronk, Alan, Meola, Giovanni, Conwit, Robin, Hanna, Michael G, Griggs, Robert C, Muscle Study Group, Sansone, Valeria A, Sansone, Valeria A, Burge, James, McDermott, Michael P, Smith, Patty C, Herr, Barbara, Tawil, Rabi, Pandya, Shree, Kissel, John, Ciafaloni, Emma, Shieh, Perry, Ralph, Jeffrey W, Amato, Antony, Cannon, Steve C, Trivedi, Jaya, Barohn, Richard, Crum, Brian, Mitsumoto, Hiroshi, Pestronk, Alan, Meola, Giovanni, Conwit, Robin, Hanna, Michael G, Griggs, Robert C, and Muscle Study Group

Abstract

ObjectiveTo determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis.MethodsTwo multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase.ResultsThe median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined).ConclusionsDCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis.Classification of evidenceThese studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

Published
2016

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