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Charles A. Thornton - One of the best experts on this subject based on the ideXlab platform.
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transcriptome alterations in Myotonic Dystrophy frontal cortex
Cell Reports, 2021Co-Authors: Brittney A Otero, Takashi Kimura, Charles A. Thornton, Kiril Poukalov, Ryan P Hildebrandt, Kenji Jinnai, Harutoshi Fujimura, Katharine A Hagerman, Jacinda B Sampson, John W DayAbstract:Myotonic Dystrophy (DM) is caused by expanded CTG/CCTG repeats, causing symptoms in skeletal muscle, heart, and central nervous system (CNS). CNS issues are debilitating and include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Here, we generate RNA-seq transcriptomes from DM and unaffected frontal cortex and identify 130 high-confidence splicing changes, most occurring only in cortex, not skeletal muscle or heart. Mis-spliced exons occur in neurotransmitter receptors, ion channels, and synaptic scaffolds, and GRIP1 mis-splicing modulates kinesin association. Optical mapping of expanded CTG repeats reveals extreme mosaicism, with some alleles showing >1,000 CTGs. Mis-splicing severity correlates with CTG repeat length across individuals. Upregulated genes tend to be microglial and endothelial, suggesting neuroinflammation, and downregulated genes tend to be neuronal. Many gene expression changes strongly correlate with mis-splicing, suggesting candidate biomarkers of disease. These findings provide a framework for mechanistic and therapeutic studies of the DM CNS.
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Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy.
PLoS genetics, 2016Co-Authors: Stacey D. Wagner, Charles A. Thornton, Adam J. Struck, Riti Gupta, Dylan R. Farnsworth, Amy E. Mahady, Katy Eichinger, Eric T. Wang, J. Andrew BerglundAbstract:Alternative splicing is a regulated process that results in expression of specific mRNA and protein isoforms. Alternative splicing factors determine the relative abundance of each isoform. Here we focus on MBNL1, a splicing factor misregulated in the disease Myotonic Dystrophy. By altering the concentration of MBNL1 in cells across a broad dynamic range, we show that different splicing events require different amounts of MBNL1 for half-maximal response, and respond more or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assess how cis-elements mediate the MBNL1 dose-dependent splicing response. A framework was developed to estimate MBNL concentration using splicing responses alone, validated in the cell-based model, and applied to Myotonic Dystrophy patient muscle. Using this framework, we evaluated the ability of individual and combinations of splicing events to predict functional MBNL concentration in human biopsies, as well as their performance as biomarkers to assay mild, moderate, and severe cases of DM.
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mexiletine is an effective antimyotonia treatment in Myotonic Dystrophy type 1
Neurology, 2010Co-Authors: Eric L Logigian, Richard T. Moxley, William B Martens, Michael P Mcdermott, Nuran Dilek, Allen W Wiegner, Alexander T Pearson, C A Barbieri, Christine Annis, Charles A. ThorntonAbstract:# {#article-title-2} To the Editor: Logigian et al.1 conclude that mexiletine is safe and effective for the treatment of myotonia in patients with Myotonic Dystrophy type 1 (DM1). Unfortunately, the limited duration crossover trial conducted in just 30 patients cannot assure the cardiac safety of this potent sodium channel blocker if extensively used in the DM1 population. Conduction abnormalities leading to life-threatening arrhythmias are common in DM1.2,3 Mexiletine, like all sodium blockers, not only inhibits the skeletal muscle channel but also …
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hypothesis neoplasms in Myotonic Dystrophy
Cancer Causes & Control, 2009Co-Authors: Christine M Mueller, Charles A. Thornton, Richard T. Moxley, James E Hilbert, William B Martens, Mark H GreeneAbstract:Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic Dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic Dystrophy type 1 (DM1) and Myotonic Dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
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Myotonic Dystrophy rna mediated muscle disease
Current Opinion in Neurology, 2007Co-Authors: Thurman M Wheeler, Charles A. ThorntonAbstract:Purpose of reviewThe aim of this review is to highlight recent progress in elucidating the disease mechanism in Myotonic Dystrophy type 1 and type 2.Recent findingsResearch on Myotonic Dystrophy has led to the recognition of a novel RNA-mediated disease process. In Myotonic Dystrophy it is the RNA r
William B Martens - One of the best experts on this subject based on the ideXlab platform.
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Myotonic Dystrophy health index correlations with clinical tests and patient function
Muscle & Nerve, 2016Co-Authors: Chad Heatwole, Katy Eichinger, James E Hilbert, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Eric L Logigian, Elizabeth Luebbe, William B MartensAbstract:Introduction The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with Myotonic Dystrophy type-1 (DM1). Methods We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. Results MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. Conclusions Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.
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Myotonic Dystrophy health index initial evaluation of a disease specific outcome measure
Muscle & Nerve, 2014Co-Authors: Chad Heatwole, James E Hilbert, William B Martens, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Elizabeth Luebbe, Mark Heatwole, Michael P McdermottAbstract:Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). Methods: Initially we partnered with 278 Myotonic Dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test–retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test–retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. Muscle Nerve 49: 906–914, 2014
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correlates of tumor development in patients with Myotonic Dystrophy
Journal of Neurology, 2012Co-Authors: Maya Das, Richard T. Moxley, James E Hilbert, William B Martens, Mark H Greene, Lisa Letren, Shahinaz M GadallaAbstract:Patients with Myotonic Dystrophy (DM) have recently been reported to be at increased risk of tumor development, but clinical associations related to this observation are unknown. We calculated the odds ratios (ORs) and 95 % confidence intervals (CI) of self-reported tumor development by patients’ demographic and clinical characteristics to evaluate factors associated with tumor development in DM patients, using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members. Of the 911 participants, 47.5 % were male and 85.7 % had DM type 1 (DM1). Compared to DM1, patients with DM type 2 (DM2) were older at registry enrollment (median age 55 vs. 44 years, p < 0.0001) and at DM diagnosis (median age 48 vs. 30 years, p < 0.0001); and more likely to be females (p = 0.001). At enrollment, 95 (10.4 %) DM patients reported a history of benign or malignant tumor. Tumors were associated with female gender (OR 1.9, 95 % CI 1.2–3.1, p = 0.007) and DM1 (OR 2.1, 95 % CI 1.1–4.1, p = 0.03). In a subgroup analysis of patients with blood-based DNA testing results (397 DM1, 54 DM2), repeat expansion size was not associated with tumor risk in DM1 (p = 0.26) or DM2 (p = 0.34). In conclusion, female gender and DM1 subtype, but not DNA repeat expansion size, were associated with increased risk of tumors in DM. Follow-up studies are warranted to determine if oncogenes associated with dystrophia Myotonica-protein kinase are altered in DM, and to determine if repeat expansion size, as in our study, is not associated with tumor development.
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mexiletine is an effective antimyotonia treatment in Myotonic Dystrophy type 1
Neurology, 2010Co-Authors: Eric L Logigian, Richard T. Moxley, William B Martens, Michael P Mcdermott, Nuran Dilek, Allen W Wiegner, Alexander T Pearson, C A Barbieri, Christine Annis, Charles A. ThorntonAbstract:# {#article-title-2} To the Editor: Logigian et al.1 conclude that mexiletine is safe and effective for the treatment of myotonia in patients with Myotonic Dystrophy type 1 (DM1). Unfortunately, the limited duration crossover trial conducted in just 30 patients cannot assure the cardiac safety of this potent sodium channel blocker if extensively used in the DM1 population. Conduction abnormalities leading to life-threatening arrhythmias are common in DM1.2,3 Mexiletine, like all sodium blockers, not only inhibits the skeletal muscle channel but also …
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hypothesis neoplasms in Myotonic Dystrophy
Cancer Causes & Control, 2009Co-Authors: Christine M Mueller, Charles A. Thornton, Richard T. Moxley, James E Hilbert, William B Martens, Mark H GreeneAbstract:Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic Dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic Dystrophy type 1 (DM1) and Myotonic Dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
Nicholas E Johnson - One of the best experts on this subject based on the ideXlab platform.
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consensus based care recommendations for congenital and childhood onset Myotonic Dystrophy type 1
Neurology: Clinical Practice, 2019Co-Authors: Nicholas E Johnson, Eugenio Zapata Aldana, Nathalie Angeard, Tetsuo Ashizawa, Kiera N Berggren, Chiara Marinibettolo, Tina Duong, Anne Berit Ekstrom, V Sansone, Cuixia TianAbstract:Purpose of review Myotonic Dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital Myotonic Dystrophy) or in the pediatric age range (childhood-onset Myotonic Dystrophy). These children have a range of disabilities that reduce the lifespan and cause significant morbidity. Currently, there are no agreed upon recommendations for caring for these children. Recent findings The Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset Myotonic Dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the development of clinical care recommendations for this population. Summary Children with Myotonic Dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with Myotonic Dystrophy.
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consensus based care recommendations for adults with Myotonic Dystrophy type 1
Neurology: Clinical Practice, 2018Co-Authors: Tetsuo Ashizawa, Richard T. Moxley, Nicholas E Johnson, Shree Pandya, Giovanni Meola, William J Groh, Cynthia Gagnon, Laurie Gutmann, Mark T Rogers, Ericka SimpsonAbstract:Purpose of review Myotonic Dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments. Described as “one of the more variable diseases found in medicine,” Myotonic Dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family. Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics. Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies.
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Myotonic Dystrophy health index correlations with clinical tests and patient function
Muscle & Nerve, 2016Co-Authors: Chad Heatwole, Katy Eichinger, James E Hilbert, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Eric L Logigian, Elizabeth Luebbe, William B MartensAbstract:Introduction The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with Myotonic Dystrophy type-1 (DM1). Methods We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. Results MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. Conclusions Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.
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Myotonic Dystrophy health index initial evaluation of a disease specific outcome measure
Muscle & Nerve, 2014Co-Authors: Chad Heatwole, James E Hilbert, William B Martens, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Elizabeth Luebbe, Mark Heatwole, Michael P McdermottAbstract:Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). Methods: Initially we partnered with 278 Myotonic Dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test–retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test–retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. Muscle Nerve 49: 906–914, 2014
Chad Heatwole - One of the best experts on this subject based on the ideXlab platform.
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Myotonic Dystrophy health index correlations with clinical tests and patient function
Muscle & Nerve, 2016Co-Authors: Chad Heatwole, Katy Eichinger, James E Hilbert, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Eric L Logigian, Elizabeth Luebbe, William B MartensAbstract:Introduction The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with Myotonic Dystrophy type-1 (DM1). Methods We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. Results MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. Conclusions Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients.
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Myotonic Dystrophy health index initial evaluation of a disease specific outcome measure
Muscle & Nerve, 2014Co-Authors: Chad Heatwole, James E Hilbert, William B Martens, Nicholas E Johnson, Rita K Bode, Jeanne Dekdebrun, Nuran Dilek, Elizabeth Luebbe, Mark Heatwole, Michael P McdermottAbstract:Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). Methods: Initially we partnered with 278 Myotonic Dystrophy type-1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test–retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test–retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient-reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. Muscle Nerve 49: 906–914, 2014
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splicing biomarkers of disease severity in Myotonic Dystrophy
Annals of Neurology, 2013Co-Authors: Masayuki Nakamori, Katy Eichinger, Krzysztof Sobczak, Araya Puwanant, Steve Welle, Shree Pandya, Jeannne Dekdebrun, Chad Heatwole, Michael P Mcdermott, Tian ChenAbstract:Objective To develop RNA splicing biomarkers of disease severity and therapeutic response in Myotonic Dystrophy type 1 (DM1) and type 2 (DM2).
Richard T. Moxley - One of the best experts on this subject based on the ideXlab platform.
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consensus based care recommendations for adults with Myotonic Dystrophy type 1
Neurology: Clinical Practice, 2018Co-Authors: Tetsuo Ashizawa, Richard T. Moxley, Nicholas E Johnson, Shree Pandya, Giovanni Meola, William J Groh, Cynthia Gagnon, Laurie Gutmann, Mark T Rogers, Ericka SimpsonAbstract:Purpose of review Myotonic Dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments. Described as “one of the more variable diseases found in medicine,” Myotonic Dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family. Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics. Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies.
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correlates of tumor development in patients with Myotonic Dystrophy
Journal of Neurology, 2012Co-Authors: Maya Das, Richard T. Moxley, James E Hilbert, William B Martens, Mark H Greene, Lisa Letren, Shahinaz M GadallaAbstract:Patients with Myotonic Dystrophy (DM) have recently been reported to be at increased risk of tumor development, but clinical associations related to this observation are unknown. We calculated the odds ratios (ORs) and 95 % confidence intervals (CI) of self-reported tumor development by patients’ demographic and clinical characteristics to evaluate factors associated with tumor development in DM patients, using data from the National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members. Of the 911 participants, 47.5 % were male and 85.7 % had DM type 1 (DM1). Compared to DM1, patients with DM type 2 (DM2) were older at registry enrollment (median age 55 vs. 44 years, p < 0.0001) and at DM diagnosis (median age 48 vs. 30 years, p < 0.0001); and more likely to be females (p = 0.001). At enrollment, 95 (10.4 %) DM patients reported a history of benign or malignant tumor. Tumors were associated with female gender (OR 1.9, 95 % CI 1.2–3.1, p = 0.007) and DM1 (OR 2.1, 95 % CI 1.1–4.1, p = 0.03). In a subgroup analysis of patients with blood-based DNA testing results (397 DM1, 54 DM2), repeat expansion size was not associated with tumor risk in DM1 (p = 0.26) or DM2 (p = 0.34). In conclusion, female gender and DM1 subtype, but not DNA repeat expansion size, were associated with increased risk of tumors in DM. Follow-up studies are warranted to determine if oncogenes associated with dystrophia Myotonica-protein kinase are altered in DM, and to determine if repeat expansion size, as in our study, is not associated with tumor development.
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mexiletine is an effective antimyotonia treatment in Myotonic Dystrophy type 1
Neurology, 2010Co-Authors: Eric L Logigian, Richard T. Moxley, William B Martens, Michael P Mcdermott, Nuran Dilek, Allen W Wiegner, Alexander T Pearson, C A Barbieri, Christine Annis, Charles A. ThorntonAbstract:# {#article-title-2} To the Editor: Logigian et al.1 conclude that mexiletine is safe and effective for the treatment of myotonia in patients with Myotonic Dystrophy type 1 (DM1). Unfortunately, the limited duration crossover trial conducted in just 30 patients cannot assure the cardiac safety of this potent sodium channel blocker if extensively used in the DM1 population. Conduction abnormalities leading to life-threatening arrhythmias are common in DM1.2,3 Mexiletine, like all sodium blockers, not only inhibits the skeletal muscle channel but also …
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hypothesis neoplasms in Myotonic Dystrophy
Cancer Causes & Control, 2009Co-Authors: Christine M Mueller, Charles A. Thornton, Richard T. Moxley, James E Hilbert, William B Martens, Mark H GreeneAbstract:Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic Dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic Dystrophy type 1 (DM1) and Myotonic Dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
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Myotonic Dystrophy with no trinucleotide repeat expansion.
Annals of neurology, 1994Co-Authors: Charles A. Thornton, Robert C. Griggs, Richard T. MoxleyAbstract:We report 3 patients from 2 families with Myotonic Dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the Myotonic Dystrophy gene. Characteristic features of Myotonic Dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with Myotonic Dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the Myotonic Dystrophy gene does not exclude the diagnosis of Myotonic Dystrophy.
