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Jan J.g.m. Verschuuren - One of the best experts on this subject based on the ideXlab platform.

  • Studying the role of dystrophin-associated proteins in influencing Becker Muscular Dystrophy disease severity.
    Neuromuscular disorders : NMD, 2015
    Co-Authors: J.c. Van Den Bergen, B.h.a. Wokke, Margriet Hulsker, Jan J.g.m. Verschuuren, Annemieke Aartsma-rus
    Abstract:

    Becker Muscular Dystrophy is characterized by a variable disease course. Many factors have been implicated to contribute to this diversity, among which the expression of several components of the dystrophin associated glycoprotein complex. Together with dystrophin, most of these proteins anchor the muscle fiber cytoskeleton to the extracellular matrix, thus protecting the muscle from contraction induced injury, while nNOS is primarily involved in inducing vasodilation during muscle contraction, enabling adequate muscle oxygenation. In the current study, we investigated the role of three components of the dystrophin associated glycoprotein complex (beta-dystroglycan, gamma-sarcoglycan and nNOS) and the dystrophin homologue utrophin on disease severity in Becker patients. Strength measurements, data about disease course and fresh muscle biopsies of the anterior tibial muscle were obtained from 24 Becker patients aged 19 to 66. The designation of Becker Muscular Dystrophy in this study was based on the mutation and not on the clinical severity. Contrary to previous studies, we were unable to find a relationship between expression of nNOS, beta-dystroglycan and gamma-sarcoglycan at the sarcolemma and disease severity, as measured by muscle strength in five muscle groups and age at reaching several disease milestones. Unexpectedly, we found an inverse correlation between utrophin expression at the sarcolemma and age at reaching disease milestones.

  • dystrophin levels and clinical severity in Becker Muscular Dystrophy patients
    Journal of Neurology Neurosurgery and Psychiatry, 2014
    Co-Authors: J.c. Van Den Bergen, B.h.a. Wokke, Margriet Hulsker, H B Ginjaar, Anneke A M Janson, S G Van Duinen, J C Van Deutekom, A Aartsmarus, Hermien E Kan, Jan J.g.m. Verschuuren
    Abstract:

    Objective Becker Muscular Dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne Muscular Dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45–47 deletion. Methods Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration. Results 33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%–78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45–47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45–47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients’ age. Conclusions Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45–47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.

  • clinical characterisation of Becker Muscular Dystrophy patients predicts favourable outcome in exon skipping therapy
    Journal of Neurology Neurosurgery and Psychiatry, 2014
    Co-Authors: J.c. Van Den Bergen, B.h.a. Wokke, Margriet Hulsker, C S M Straathof, Annemieke Aartsmarus, S Schade M Van Westrum, Luuk Dekker, A J Van Der Kooi, M De Visser, Jan J.g.m. Verschuuren
    Abstract:

    Objective Duchenne and Becker Muscular Dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. Methods Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. Results Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6–67). Nine patients were wheelchair users (26–56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. Conclusions This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a ‘skipped’ DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD.

  • dystrophin quantification and clinical correlations in Becker Muscular Dystrophy implications for clinical trials
    Brain, 2011
    Co-Authors: Karen Anthony, Sebahattin Cirak, S Torelli, Giorgio Tasca, L Feng, Virginia Arechavalagomeza, Annarita Armaroli, Michela Guglieri, C S M Straathof, Jan J.g.m. Verschuuren
    Abstract:

    Duchenne Muscular Dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne Muscular Dystrophy phenotype to that of the milder disorder, Becker Muscular Dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker Muscular Dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne Muscular Dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker Muscular Dystrophy. Furthermore, grouping the patients by deletion, patients with Becker Muscular Dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne Muscular Dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker Muscular Dystrophy with deletions relevant for on-going exon skipping trials in Duchenne Muscular Dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne Muscular Dystrophy.

  • Becker Muscular Dystrophy patients with deletions around exon 51 a promising outlook for exon skipping therapy in duchenne patients
    Neuromuscular Disorders, 2010
    Co-Authors: A Heldermanvan Den T J M Enden, Jan J.g.m. Verschuuren, C S M Straathof, Annemieke Aartsmarus, J Den T Dunnen, Berit M Verbist, E Bakker, H B Ginjaar
    Abstract:

    Theoretically, 13% of patients with Duchenne Muscular Dystrophy may benefit from antisense-mediated skipping of exon 51 to restore the reading frame, which results in the production of a shortened dystrophin protein. We give a detailed description with longitudinal follow up of three patients with Becker Muscular Dystrophy with in-frame deletions in the DMD gene encompassing exon 51. Their internally deleted, but essentially functional, dystrophins are identical to those that are expected as end products in DMD patients treated with the exon 51 skipping therapy. The mild phenotype encourages further development of exon 51 skipping therapy.

Kevin M. Flanigan - One of the best experts on this subject based on the ideXlab platform.

  • Genetics and Emerging Treatments for Duchenne and Becker Muscular Dystrophy
    Pediatric Clinics of North America, 2015
    Co-Authors: Nicolas Wein, Lindsay Alfano, Kevin M. Flanigan
    Abstract:

    Abstract Mutations in the DMD gene result in Duchenne or Becker Muscular Dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne Muscular Dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker Muscular Dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades.

  • a phase 1 2a follistatin gene therapy trial for Becker Muscular Dystrophy
    Molecular Therapy, 2015
    Co-Authors: Kevin M. Flanigan, Zarife Sahenk, Jerry R. Mendell, Vinod Malik, A M Gomez, Linda Lowes, L Alfano
    Abstract:

    Becker Muscular Dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intraMuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 1011 vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 1011 vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

  • nonsense mutation associated Becker Muscular Dystrophy interplay between exon definition and splicing regulatory elements within the dmd gene
    Human Mutation, 2011
    Co-Authors: Kevin M. Flanigan, Jerry R. Mendell, Diane M Dunn, Andrew Von Niederhausern, Payam Soltanzadeh, Michael T Howard, Jacinda B Sampson, Kathryn J Swoboda, Mark B Bromberg, Laura E Taylor
    Abstract:

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the

  • nonsense mutation associated Becker Muscular Dystrophy interplay between exon definition and splicing regulatory elements within the dmd gene
    Human Mutation, 2011
    Co-Authors: Kevin M. Flanigan, Jerry R. Mendell, Diane M Dunn, Payam Soltanzadeh, Michael T Howard, Jacinda B Sampson, Kathryn J Swoboda, Mark B Bromberg, Andrew Von Niederhausern, Laura E Taylor
    Abstract:

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.

Jerry R. Mendell - One of the best experts on this subject based on the ideXlab platform.

  • Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy.
    Journal of neuromuscular diseases, 2015
    Co-Authors: Samiah Al-zaidy, Zarife Sahenk, Louise R. Rodino-klapac, Brian K. Kaspar, Jerry R. Mendell
    Abstract:

    Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intraMuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker Muscular Dystrophy as well as the future directions for clinical gene therapy trials using follistatin.

  • a phase 1 2a follistatin gene therapy trial for Becker Muscular Dystrophy
    Molecular Therapy, 2015
    Co-Authors: Kevin M. Flanigan, Zarife Sahenk, Jerry R. Mendell, Vinod Malik, A M Gomez, Linda Lowes, L Alfano
    Abstract:

    Becker Muscular Dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intraMuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 1011 vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 1011 vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

  • nonsense mutation associated Becker Muscular Dystrophy interplay between exon definition and splicing regulatory elements within the dmd gene
    Human Mutation, 2011
    Co-Authors: Kevin M. Flanigan, Jerry R. Mendell, Diane M Dunn, Andrew Von Niederhausern, Payam Soltanzadeh, Michael T Howard, Jacinda B Sampson, Kathryn J Swoboda, Mark B Bromberg, Laura E Taylor
    Abstract:

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the

  • nonsense mutation associated Becker Muscular Dystrophy interplay between exon definition and splicing regulatory elements within the dmd gene
    Human Mutation, 2011
    Co-Authors: Kevin M. Flanigan, Jerry R. Mendell, Diane M Dunn, Payam Soltanzadeh, Michael T Howard, Jacinda B Sampson, Kathryn J Swoboda, Mark B Bromberg, Andrew Von Niederhausern, Laura E Taylor
    Abstract:

    Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.

John Vissing - One of the best experts on this subject based on the ideXlab platform.

  • effects of sildenafil on cerebrovascular reactivity in patients with Becker Muscular Dystrophy
    Neurotherapeutics, 2017
    Co-Authors: Ulrich Lindberg, Nanna Witting, John Vissing, Stine Lundgaard Jorgensen, Egill Rostrup, Henrik Larsson, Christina Kruuse
    Abstract:

    Patients suffering from Becker Muscular Dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

  • contractile properties are disrupted in Becker Muscular Dystrophy but not in limb girdle type 2i
    Annals of Neurology, 2016
    Co-Authors: Nicoline Lokken, Gitte Hedermann, Carsten Thomsen, John Vissing
    Abstract:

    We investigated whether a linear relationship between muscle strength and cross-sectional area (CSA) is preserved in calf muscles of patients with Becker Muscular Dystrophy (BMD, n = 14) and limb-girdle type 2I Muscular Dystrophy (LGMD2I, n = 11), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat-free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile-CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466-471.

  • Becker Muscular Dystrophy with widespread muscle hypertrophy and a non sense mutation of exon 2
    Neuromuscular Disorders, 2013
    Co-Authors: Nanna Witting, Morten Duno, John Vissing
    Abstract:

    Abstract Becker Muscular Dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10–20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker Muscular Dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site.

  • endurance training improves fitness and strength in patients with Becker Muscular Dystrophy
    Brain, 2008
    Co-Authors: Marie Louise Sveen, Lars Kober, Tina D Jeppesen, Simon Hauerslev, Thomas Krag, John Vissing
    Abstract:

    Studies in a dystrophinopathy model (the mdx mouse) suggest that exercise training may be deleterious for muscle integrity, but exercise has never been studied in detail in humans with defects of dystrophin. We studied the effect of endurance training on conditioning in patients with the dystrophinopathy, Becker Muscular Dystrophy (BMD). Eleven patients with BMD and seven matched, healthy subjects cycled 50, 30 min sessions at 65% of their maximal oxygen uptake (VO(2max)) over 12 weeks, and six patients continued cycling for 1 year. VO(2max), muscle biopsies, echocardiography, plasma creatine kinase (CK), lower extremity muscle strength and self-reported questionnaires were evaluated before, after 12 weeks and 1 year of training. Endurance training for 12 weeks, improved VO(2max) by 47 +/- 11% and maximal workload by 80 +/- 19% in patients (P < 0.005). This was significantly higher than in healthy subjects (16 +/- 2% and 17 +/- 2%). CK levels did not increase with training, and number of central nuclei, necrotic fibres and fibres expressing neonatal myosin heavy chain did not change in muscle biopsies. Strength in muscles involved in cycle exercise (knee extension, and dorsi- and plantar-flexion) increased significantly by 13-40%. Cardiac pump function, measured by echocardiography, did not change with training. All improvements and safety markers were maintained after 1 year of training. Endurance training is a safe method to increase exercise performance and daily function in patients with BMD. The findings support an active approach to rehabilitation of patients with BMD.

  • cardiac involvement in patients with limb girdle Muscular Dystrophy type 2 and Becker Muscular Dystrophy
    JAMA Neurology, 2008
    Co-Authors: Marie Louise Sveen, Jens Jakob Thune, Lars Kober, John Vissing
    Abstract:

    Objective To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle Muscular Dystrophy type 2 (LGMD2A-L) and Becker Muscular Dystrophy (BMD). Design Prospective screening. Setting NeuroMuscular Clinic and Department of Cardiology at Rigshospitalet. Patients One hundred one patients with LGMD2A-I and BMD and 29 patients with LGMD2 and no molecular diagnosis. Main Outcome Measures Clinical investigation, echocardiography, and electrocardiographic findings. Results Cardiac involvement was present in 24 of 100 patients (24%) with LGMD2A-I and in 14 of 30 patients (47%) with BMD. Only a few patients with LGMD2A and unclassified LGMD2 had mild cardiac involvement, whereas 29% and 67% of patients with LGMD2I and LGMD2E, respectively, had cardiac involvement. Cardiac involvement was not correlated with age, muscle strength, or the level of dystrophic changes on muscle biopsy. Conclusions This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement.

Gail D Thomas - One of the best experts on this subject based on the ideXlab platform.

  • Functional muscle ischemia in Duchenne and Becker Muscular Dystrophy
    Frontiers in physiology, 2013
    Co-Authors: Gail D Thomas
    Abstract:

    Duchenne and Becker Muscular Dystrophy (DMD/BMD) comprise a spectrum of devastating X-linked muscle wasting disease for which there is no treatment. DMD/BMD is caused by mutations in the gene encoding dystrophin, a cytoskeletal protein that stabilizes the muscle membrane and also targets other proteins to the sarcolemma. Among these is the muscle-specific isoform of neuronal nitric oxide synthase (nNOSμ) which binds spectrin-like repeats within dystrophin's rod domain and the adaptor protein α-syntrophin. Dystrophin deficiency causes loss of sarcolemmal nNOSμ and reduces paracrine signaling of muscle-derived nitric oxide (NO) to the microvasculature, which renders the diseased muscle fibers susceptible to functional muscle ischemia during exercise. Repeated bouts of functional ischemia superimposed on muscle fibers already weakened by dystrophin deficiency result in use-dependent focal muscle injury. Genetic and pharmacologic strategies to boost nNOSμ-NO signaling in dystrophic muscle alleviate functional muscle ischemia and show promise as novel therapeutic interventions for the treatment of DMD/BMD.

  • tadalafil alleviates muscle ischemia in patients with Becker Muscular Dystrophy
    Science Translational Medicine, 2012
    Co-Authors: Elizabeth A. Martin, Evgeny Tsimerinov, Bryan L Scott, Ashley E Walker, Francine Anene, Robert Elashoff, Swaminatha V. Gurudevan, R Barresi, Barry J Byrne, Gail D Thomas
    Abstract:

    Becker Muscular Dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne Muscular Dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3′,5′-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.