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Sample records for dystrophy type 2c

  1. Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

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    Maruyama Koichi

    2010-03-01

    Full Text Available Abstract Background Limb-girdle muscular dystrophy type 2C (LGMD2C is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD. Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD. Methods We enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA. Results In 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of γ-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a γ-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%. Taking into consideration the DMD incidence for the overall population (1/3,500 males, the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million. Conclusions To the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.

  2. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D.

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    Abdallah Fayssoil

    Full Text Available Type 2C and 2D limb girdle muscular dystrophies (LGMD are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D.We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax, cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke and mortality as outcomes of interest for the present analysis.A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC was 31% of predicted value [20-40]. Median maximal inspiratory pressure (MIP was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF was 55% [45-64] with 38% of patients with LVEF <50%. Over a median follow-up of 6 years, we observed 38% respiratory events, 14% cardiac events and 20% mortality. Among baseline characteristics, LVEF and left ventricular end diastolic diameter (LVEDD were associated with mortality, whilst respiratory parameters (VC, MIP, MEP and the need for home mechanical ventilation (HMV were associated with respiratory events.In our cohort of severely respiratory impaired type 2C and 2D LGMD, respiratory morbidity was high. Cardiac dysfunction was frequent in particular in LGMD 2C and had an impact on long-term mortality.ClinicalTrials.gov NCT02501083.

  3. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    Science.gov (United States)

    2016-08-26

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  4. Genetics Home Reference: lattice corneal dystrophy type I

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    ... corneal dystrophy type I lattice corneal dystrophy type I Enable Javascript to view the expand/collapse boxes. ... All Close All Description Lattice corneal dystrophy type I is an eye disorder that affects the clear, ...

  5. Cardiac manifestations of myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Petri, Helle; Vissing, John; Witting, Nanna

    2012-01-01

    To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conduction abnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involvement and cytosine-thymine-guanine (CTG)-repeat, neuromuscular involvement, age and gende...... in patients with myotonic dystrophy type 1 (MD1)....

  6. Skin features in myotonic dystrophy type 1: an observational study.

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    Campanati, A; Giannoni, M; Buratti, L; Cagnetti, C; Giuliodori, K; Ganzetti, G; Silvestrini, M; Provinciali, L; Offidani, A

    2015-05-01

    Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1.

  7. Dysphagia is present but mild in myotonic dystrophy type 2

    NARCIS (Netherlands)

    R. Ensink; S. Knuijt; Baziel van Engelen; J. van Vliet; A. Tieleman; Bert de Swart

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  8. Dysphagia is present but mild in myotonic dystrophy type 2.

    NARCIS (Netherlands)

    Tieleman, A.A.; Knuijt, S.; Vliet, J. van; Swart, B.J.M. de; Ensink, R.J.H.; Engelen, B.G.M. van

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  9. Dysphagia is present but mild in myotonic dystrophy type 2

    NARCIS (Netherlands)

    Swart, Bert de; Tieleman, A.; Knuijt, S.; Vliet, J. van; Ensink, R.; Engelen, Baziel van

    2009-01-01

    The phenotype of myotonic dystrophy type 2 (DM2) shows similarities as well as differences to that of myotonic dystrophy type 1 (DM1). Dysphagia, a predominant feature in DM1, has not yet been examined in DM2. In a recent nationwide questionnaire survey of gastrointestinal symptoms in DM2, 12 out of

  10. Meretoja's Syndrome: Lattice Corneal Dystrophy, Gelsolin Type

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    Abreu, C.; Neves, M.; Oliveira, L.; Beirão, M.

    2017-01-01

    Lattice corneal dystrophy gelsolin type was first described in 1969 by Jouko Meretoja, a Finnish ophthalmologist. It is caused by an autosomal dominant mutation in gelsolin gene resulting in unstable protein fragments and amyloid deposition in various organs. The age of onset is usually after the third decade of life and typical diagnostic triad includes progressive bilateral facial paralysis, loose skin, and lattice corneal dystrophy. We report a case of a 53-year-old female patient referred to our Department of Ophthalmology by severe dry eye and incomplete eyelid closure. She had severe bilateral facial paresis, significant orbicularis, and perioral sagging as well as hypoesthesia of extremities and was diagnosed with Meretoja's syndrome at the age of 50, confirmed by the presence of gelsolin mutation. At our observation she had bilateral diminished tear film break-up time and Schirmer test, diffuse keratitis, corneal opacification, and neovascularization in the left eye. She was treated with preservative-free lubricants and topical cyclosporine, associated with nocturnal complete occlusion of both eyes, and underwent placement of lacrimal punctal plugs. Ocular symptoms are the first to appear and our role as ophthalmologists is essential for the diagnosis, treatment, and monitoring of ocular alterations in these patients. PMID:28250773

  11. In vivo confocal microscopy in different types of posterior polymorphous dystrophy

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    Babu Kalpana

    2007-01-01

    Full Text Available Posterior polymorphous dystrophy is a rare corneal dystrophy, usually detected by chance. This case series describes the morphologic features in the three different types of posterior polymorphous dystrophy using confocal microscopy.

  12. Immunoglobulins in granular corneal dystrophy Groenouw type I

    DEFF Research Database (Denmark)

    Møller, H U; Bojsen-Møller, M; Schrøder, H D

    1993-01-01

    Three patients with granular corneal dystrophy Groenouw type I underwent corneal grafting, and cryostat sections of the corneal buttons were examined immunohistochemically for immunoglobulins. Positive results were obtained for IgG, Kappa-, and Lambda chains with immunofluorescence technique...

  13. Myasthenia gravis and thymoma coexisting with myotonic dystrophy type 1.

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    Ekmekci, Ozgul; Karasoy, Hatice; Bademkiran, Fikret; Akkus, Dilek Evyapan; Yuceyar, Nur

    2014-01-01

    We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.

  14. Autophagy in granular corneal dystrophy type 2.

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    Choi, Seung-Il; Kim, Eung Kweon

    2016-03-01

    Autophagy is a lysosomal degradative process that is essential for cellular homeostasis and metabolic stress adaptation. Defective autophagy is involved in the pathogenesis of many diseases including granular corneal dystrophy type 2 (GCD2). GCD2 is an autosomal dominant disorder caused by substitution of histidine for arginine at codon 124 (R124H) in the transforming growth factor β-induced gene (TGFBI) on chromosome 5q31. Transforming growth factor β-induced protein (TGFBIp) is degraded by autophagy, but mutant-TGFBIp accumulates in autophagosomes and/or lysosomes, despite significant activation of basal autophagy, in GCD2 corneal fibroblasts. Furthermore, inhibition of autophagy induces cell death of GCD2 corneal fibroblasts through active caspase-3. As there is currently no pharmacological treatment for GCD2, development of novel therapies is required. A potential strategy for preventing cytoplasmic accumulation of mutant-TGFBIp in GCD2 corneal fibroblasts is to enhance mutant-TGFBIp degradation. This could be achieved by activation of the autophagic pathway. Here, we will consider the role and the potential therapeutic benefits of autophagy in GCD2, with focus on TGFBIp degradation, in light of the recently established role of autophagy in protein degradation.

  15. Isolation and characterization of canine parvovirus type 2C (CPV-2C) from symptomatic puppies.

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    Puentes, R; Eliopulos, N; Pérez, R; Franco, G; Sosa, K; Bianchi, P; Furtado, A; Hübner, S O; Esteves, P A

    2012-07-01

    Canine parvovirus type 2 (CPV-2) is a leading cause of diarrhea in puppies in several parts of the world. In this study CPV-2 was detected and recovered from puppies showing clinical disease from Montevideo, Uruguay. Samples were processed and used to infect CRFK and MDCK cells in order to isolate the virus. Out of twelve, two samples were positive for CPV-2. A genomic region of 583 bp was amplified and the molecular characterization was performed by sequencing, phylogenetic analysis and Restriction Fragment Length Polymorphism (RFLP). Two isolated viruses (UY1 and UY2) were CPV-2c-like viruses. The comparison between the cytophatic effect (CPE) of CPV-2 (vaccinal virus) and CPV-2c (isolated virus) on primary canine cells cultures and on CRFK line cells, demonstrated that CPV-2c is less citopathogenic in CRFK than in primary cultures. Our study represents the first report on isolation and characterization of canine parvovirus type 2c (CPV-2c) in cell cultures from South American dogs.

  16. Isolation and characterization of canine parvovirus type 2c (CPV-2c from symptomatic puppies

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    R Puentes

    2012-09-01

    Full Text Available Canine parvovirus type 2 (CPV-2 is a leading cause of diarrhea in puppies in several parts of the world. In this study CPV-2 was detected and recovered from puppies showing clinical disease from Montevideo, Uruguay. Samples were processed and used to infect CRFK and MDCK cells in order to isolate the virus. Out of twelve, two samples were positive for CPV-2. A genomic region of 583 bp was amplified and the molecular characterization was performed by sequencing, phylogenetic analysis and Restriction Fragment Length Polymorphism (RFLP. Two isolated viruses (UY1 and UY2 were CPV-2c-like viruses. The comparison between the cytophatic effect (CPE of CPV-2 (vaccinal virus and CPV-2c (isolated virus on primary canine cells cultures and on CRFK line cells, demonstrated that CPV-2c is less citopathogenic in CRFK than in primary cultures. Our study represents the first report on isolation and characterization of canine parvovirus type 2c (CPV-2c in cell cultures from South American dogs.

  17. Myocardial fibrosis in patients with myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Petri, Helle; Ahtarovski, Kiril; Vejlstrup, Niels;

    2014-01-01

    BackgroundMyotonic dystrophy type 1 (DM1) is associated with increased cardiac morbidity and mortality. Therefore, assessment of cardiac involvement and risk stratification for sudden cardiac death is crucial. Nevertheless, optimal screening-procedures are not clearly defined. ECG, echocardiography...

  18. Psychiatric and Cognitive Phenotype of Childhood Myotonic Dystrophy Type 1

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    Douniol, Marie; Jacquette, Aurelia; Cohen, David; Bodeau, Nicolas; Rachidi, Linda; Angeard, Nathalie; Cuisset, Jean-Marie; Vallee, Louis; Eymard, Bruno; Plaza, Monique; Heron, Delphine; Guile, Jean-Marc

    2012-01-01

    Aim: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence,…

  19. Muscle phenotype in patients with myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Andersen, Anne Grete Kielgast; Orngreen, Mette C; Preisler, Nicolai Rasmus;

    2012-01-01

    Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia...

  20. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Thune, Jens Jakob; Køber, Lars;

    2008-01-01

    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.......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...

  1. Granular corneal dystrophy Groenouw type I (GrI) and Reis-Bücklers' corneal dystrophy (R-B). One entity?

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    Møller, H U

    1989-12-01

    This paper maintains that Reis-Bücklers' corneal dystrophy and granular corneal dystrophy Groenouw type I are one and the same disease. Included are some of the technically best photographs of Reis-Bücklers' dystrophy found in the literature, and these are compared with photographs from patients with granular corneal dystrophy examined by the author. It is argued that most of the histological and ultrastructural findings on Reis Bücklers' dystrophy described in the literature are either congruent with what is found in granular corneal dystrophy or unspecific.

  2. Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha 2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease?

    Science.gov (United States)

    Taniguchi, Mariko; Kurahashi, Hiroki; Noguchi, Satoru; Sese, Jun; Okinaga, Takeshi; Tsukahara, Toshifumi; Guicheney, Pascale; Ozono, Keiichi; Nishino, Ichizo; Morishita, Shinichi; Toda, Tatsushi

    2006-04-07

    Fukuyama-type congenital muscular dystrophy (FCMD) and laminin-alpha2 deficient congenital muscular dystrophy (MDC1A) are congenital muscular dystrophies (CMDs) and they both are categorized into the same clinical entity of muscular dystrophy as Duchenne muscular dystrophy (DMD). All three disorders share a common etiologic defect in the dystrophin-glycoprotein complex, which connects muscle structural proteins with the extracellular basement membrane. To investigate the pathophysiology of these CMDs, we generated microarray gene expression profiles of skeletal muscle from patients in various clinical stages. Despite diverse pathological changes, the correlation coefficient of overall gene expression among these samples was considerably high. We performed a multi-dimensional statistical analysis, the Distillation, to extract determinant genes that distinguish CMD muscle from normal controls. Up-regulated genes were primarily extracellular matrix (ECM) components, whereas down-regulated genes included structural components of mature muscle. These observations reflect active interstitial fibrosis with less active regeneration of muscle cell components in the CMDs, characteristics that are clearly distinct from those of DMD. Although the severity of fibrosis varied among the specimens tested, ECM gene expression was consistently high without substantial changes through the clinical course. Further, in situ hybridization showed more prominent ECM gene expression on muscle cells than on interstitial tissue cells, suggesting that ECM components are induced by regeneration process rather than by 'dystrophy.' These data imply that the etiology of FCMD and MDC1A differs from that of the chronic phase of classical muscular dystrophy, and the major pathophysiologic change in CMDs might instead result from primary active fibrosis.

  3. Myotonic dystrophy type 1 (DM1): a triplet repeat expansion disorder.

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    Kumar, Ashok; Agarwal, Sarita; Agarwal, Divya; Phadke, Shubha R

    2013-06-15

    Myotonic dystrophy is a progressive multisystem genetic disorder affecting about 1 in 8000 people worldwide. The unstable repeat expansions of (CTG)n or (CCTG)n in the DMPK and ZNF9 genes cause the two known subtypes of myotonic dystrophy: (i) myotonic dystrophy type 1 (DM1) and (ii) myotonic dystrophy type 2 (DM2) respectively. There is currently no cure but supportive management helps equally to reduce the morbidity and mortality and patients need close follow up to pay attention to their clinical problems. This review will focus on the clinical features, molecular view and genetics, diagnosis and management of DM1.

  4. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    DEFF Research Database (Denmark)

    Kamsteeg, Erik-Jan; Kress, Wolfram; Catalli, Claudio

    2012-01-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-o...... testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing....

  5. Primary cataract as a key to recognition of myotonic dystrophy type 1

    NARCIS (Netherlands)

    Voermans, N.C.; Erasmus, C.E.; Ockeloen, C.W.; Engelen, B.G.M. van; Eggink, C.A.

    2015-01-01

    PURPOSE: Primary cataract is often the initial manifestation of the adult-onset type of myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults. It is caused by a CTG repeat expansion within the DMPK gene, and anticipation may cause earlier onset and more severe symptoms in

  6. Miyoshi-type distal muscular dystrophy - Clinical spectrum in 24 Dutch patients

    NARCIS (Netherlands)

    Linssen, WHJP; Notermans, NC; VanderGraaf, Y; Wokke, JHJ; VanDoorn, PA; Howeler, CJ; Busch, HFM; DeJager, AEJ; DeVisser, M

    1997-01-01

    Miyoshi-type distal muscular dystrophy has now been found to be more frequent outside Japan than was previously thought. We studied 24 Dutch patients with Miyoshi-type distal muscular dystrophy and focused on its clinical expression and natural history, muscle CT-scans and muscle biopsy findings. Ou

  7. Hypogonadism and erectile dysfunction in myotonic dystrophy type 1.

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    Peric, Stojan; Nisic, Tanja; Milicev, Milena; Basta, Ivana; Marjanovic, Ivan; Peric, Marina; Lavrnic, Dragana; Rakocevic Stojanovic, Vidosava

    2013-10-01

    Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. It affects many organs and systems besides muscle. Aim of this study was to assess frequency of erectile dysfunction (ED) and hypogonadism, the correlation between them and the impact of ED on quality of life (QoL) in patients with DM1. A series of 25 men (aged from 22 to 58 years) with a diagnosis of DM1 was analyzed. Muscular Impairment Rating Scale (MIRS) was used to assess severity of muscular involvement. Erectile function was assessed using the short form of the International Index of Erectile Function test (IIEF-5). Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were assessed. All patients completed the Serbian version of the SF-36 questionnaire as a measure of health-related QoL. ED was present in 18 (72%) of patients. Seven (28%) patients were euogonadic, 16 (64%) had compensated hypogonadism and 2 (8%) had primary hypogonadism. ED was somewhat more common in patients with hypogonadism (78% vs. 57%). Mental composite score of SF-36 was lower in patients with ED (p<0.05). Our results showed that 72% of men with DM1 had ED and hypogonadism. Studies with larger number of subjects are needed to resolve cascade of events that lays behind ED in DM1. Development of therapeutic strategies may have positive impact on QoL. Substitutive therapy with androgens may be benefitial.

  8. Meretoja’s Syndrome: Lattice Corneal Dystrophy, Gelsolin Type

    Directory of Open Access Journals (Sweden)

    I. Casal

    2017-01-01

    Full Text Available Lattice corneal dystrophy gelsolin type was first described in 1969 by Jouko Meretoja, a Finnish ophthalmologist. It is caused by an autosomal dominant mutation in gelsolin gene resulting in unstable protein fragments and amyloid deposition in various organs. The age of onset is usually after the third decade of life and typical diagnostic triad includes progressive bilateral facial paralysis, loose skin, and lattice corneal dystrophy. We report a case of a 53-year-old female patient referred to our Department of Ophthalmology by severe dry eye and incomplete eyelid closure. She had severe bilateral facial paresis, significant orbicularis, and perioral sagging as well as hypoesthesia of extremities and was diagnosed with Meretoja’s syndrome at the age of 50, confirmed by the presence of gelsolin mutation. At our observation she had bilateral diminished tear film break-up time and Schirmer test, diffuse keratitis, corneal opacification, and neovascularization in the left eye. She was treated with preservative-free lubricants and topical cyclosporine, associated with nocturnal complete occlusion of both eyes, and underwent placement of lacrimal punctal plugs. Ocular symptoms are the first to appear and our role as ophthalmologists is essential for the diagnosis, treatment, and monitoring of ocular alterations in these patients.

  9. Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

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    Dušanka Savić Pavićević

    2013-01-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling.

  10. Depression in Myotonic Dystrophy type 1: clinical and neuronal correlates

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    Samuelsson Lena

    2010-05-01

    Full Text Available Abstract Background This study was designed to investigate the prevalence and correlates of depression in Myotonic dystrophy type 1 (DM1. Methods Thirty-one patients with DM1 and 47 subjects in a clinical contrast group, consisting of other neuromuscular disorders, including Spinal muscular atrophy, Limb girdle muscle atrophy and Facioscapulohumeral dystrophy, completed Beck Depression Inventory (BDI. We aimed to establish whether different factors associated with DM1 correlated with ratings in the BDI. Results Signs of a clinical depression were prevalent in 32% of the patients with DM1, which was comparable with ratings in the clinical contrast group. The depressive condition was mild to moderate in both groups. In DM1, a longer duration of clinical symptoms was associated with lower scores on the BDI and higher educational levels were correlated with higher scores on depression. We also found a negative association with brain white matter lesions. Conclusions Findings indicate significantly more DM1 patients than normative collectives showing signs of a clinical depression. The depressive condition is however mild to moderate and data indicate that the need for intervention is at hand preferentially early during the disease process.

  11. Oropharyngeal dysphagia in myotonic dystrophy type 1: a systematic review.

    Science.gov (United States)

    Pilz, Walmari; Baijens, Laura W J; Kremer, Bernd

    2014-06-01

    A systematic review was conducted to investigate the pathophysiology of and diagnostic procedures for oropharyngeal dysphagia in myotonic dystrophy (MD). The electronic databases Embase, PubMed, and The Cochrane Library were used. The search was limited to English, Dutch, French, German, Spanish, and Portuguese publications. Sixteen studies met the inclusion criteria. Two independent reviewers assessed the methodological quality of the included articles. Swallowing assessment tools, the corresponding protocols, the studies' outcome measurements, and main findings are summarized and presented. The body of literature on pathophysiology of swallowing in dysphagic patients with MD type 1 remains scant. The included studies are heterogeneous with respect to design and outcome measures and hence are not directly comparable. More importantly, most studies had methodological problems. These are discussed in detail and recommendations for further research on diagnostic examinations for swallowing disorders in patients with MD type 1 are provided.

  12. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    NARCIS (Netherlands)

    Kamsteeg, E.J.; Kress, W.; Catalli, C.; Hertz, J.M.; Witsch-Baumgartner, M.; Buckley, M.F.; Engelen, B.G. van; Schwartz, M.; Scheffer, H.

    2012-01-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onse

  13. Endocrine function in 97 patients with myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Ørngreen, Mette Cathrine; Arlien-Søborg, P; Duno, M

    2012-01-01

    . We found that patients with DM1 have an increased risk of abnormal endocrine function, particularly calcium metabolism disorders. However, the endocrine dysfunction appears not to be of clinical significance in all of the cases. Finally, we found correlations between CTG(n) expansion size and plasma......The aim of this study was to investigate the endocrine function and its association to number of CTG repeats in patients with myotonic dystrophy type 1 (DM1). Concentration of various hormones and metabolites in venous blood was used to assess the endocrine function in 97 patients with DM1...... LH, but normal testosterone levels, indicating relative insufficiency. Numbers of CTG repeats correlated directly with plasma PTH, phosphate, LH, and tended to correlate with plasma testosterone for males. This is the largest study of endocrine dysfunction in a cohort of Caucasian patients with DM1...

  14. Delusional and psychotic disorders in juvenile myotonic dystrophy type-1.

    Science.gov (United States)

    Jacobs, Delphine; Willekens, Diane; de Die-Smulders, Christine; Frijns, Jean-Pierre; Steyaert, Jean

    2017-06-01

    We investigated the clinically derived hypothesis of a relatively high incidence of delusional and psychotic disorders in adolescents with juvenile Myotonic Dystrophy type-1 (DM1). Twenty-seven subjects of age 16-25 with juvenile DM1 and their parents were invited to have a clinical psychiatric interview, and to complete an ASEBA behavior checklist (YSR, ASR, CBCL, and ABCL). We diagnosed a Delusional Disorder in 19% of our patients and a Psychotic Disorder not otherwise specified in another 19%. These two groups of patients had a significantly worse level of clinically defined general functioning. It is clinically relevant to investigate in patients with juvenile DM the symptom of delusions and the presence of a delusional and psychotic disorder, and to consider the presence of juvenile DM in youngsters presenting with such a thought disorder. These disorders compromise the general functioning of the subjects and are often to some extent treatable. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. Deregulated microRNAs in myotonic dystrophy type 2.

    Directory of Open Access Journals (Sweden)

    Simona Greco

    Full Text Available Myotonic Dystrophy Type-2 (DM2 is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Since microRNA (miRNA expression is disrupted in Myotonic Dystrophy Type-1 and many other myopathies, miRNAs deregulation was studied in skeletal muscle biopsies of 13 DM2 patients and 13 controls. Eleven miRNAs were deregulated: 9 displayed higher levels compared to controls (miR-34a-5p, miR-34b-3p, miR-34c-5p, miR-146b-5p, miR-208a, miR-221-3p and miR-381, while 4 were decreased (miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p. To explore the relevance of DM2 miRNA deregulation, the predicted interactions between miRNA and mRNA were investigated. Global gene expression was analyzed in DM2 and controls and bioinformatic analysis identified more than 1,000 miRNA/mRNA interactions. Pathway and function analysis highlighted the involvement of the miRNA-deregulated mRNAs in multiple aspects of DM2 pathophysiology. In conclusion, the observed miRNA dysregulations may contribute to DM2 pathogenetic mechanisms.

  16. Neuroimaging study of Fukuyama type congenital muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Murasugi, Hiroko (Tokyo Women' s Medical Coll. (Japan))

    1992-11-01

    Fukuyama type congenital muscular dystrophy (FCMD) has been attracting attention in recent years because of its brain malformation and progressive muscular dystrophy. The intravitam recognition of brain malformation has been remarkably enhanced by the advent of noninvasive neuroimaging techniques such as CT and MRI. In this study, 87 cranial CT scans and 22 MRIs of the brain, carried out on 60 patients with FCMD, were systematically surveyed, and the correlation between neuroradiological findings and clinical disabilities, and, in two autopsy cases, neuropathological findings was evaluated. Four cases of lissencephalic, 29 of pachygyric, and one of polymicrogyric (suspected) brain surface, and 2 normal brain surfaces were recognized. The patients with lissencephalic brain surface were compared using Dobyns' criteria. Grading of pachygyria was judged as bilateral II in 52% of cases and bilateral I in 48%. The surface of the occipital lobe could not be confirmed with either CT or MRI. Polymicrogyria was suspected using MRI but could not confirmed with CT. Five caces of lissencephaly had never learned any meaningful words and all but one were bedridden because of poor head control. The abilities of patients were better when the grading of pachygyria was milder. Mental disability and peak motor function correlate more closely with the degree and extent of brain malformation than with muscle degeneration. The decrease in radiodensity in the white matter was remarkable in 12 out of 19 cases (63%), and was usually bilaterally symmetrical. An increase in radiodensity in the white matter with age was observed in 3 patients. The rate of myelination was slower than normal in 3 out of the 6 cases. (author).

  17. Epiretinal membrane: a treatable cause of visual disability in myotonic dystrophy type 1.

    Science.gov (United States)

    Kersten, Hannah M; Roxburgh, Richard H; Child, Nicholas; Polkinghorne, Philip J; Frampton, Chris; Danesh-Meyer, Helen V

    2014-01-01

    A wide range of ocular abnormalities have been documented to occur in patients with myotonic dystrophy type 1. The objectives of this study were to investigate the macular and optic nerve morphology using optical coherence tomography in patients with myotonic dystrophy type 1. A total of 30 myotonic dystrophy type 1 patients and 28 controls were recruited for participation. All participants underwent a thorough ophthalmologic examination, including spectral-domain optical coherence tomography of the macula and retinal nerve fibre layer. Images were reviewed by a retinal specialist ophthalmologist, masked to the diagnosis of the participants. Average macular thickness was significantly greater in the myotonic dystrophy group compared to controls [327.3 μm vs. 308.5 μm (p myotonic dystrophy patient group (p = 0.0002): 48.2 % of myotonic dystrophy patient eyes had evidence of epiretinal membrane, compared with 12.5 % of control eyes. Examination revealed that 56.7 % of myotonic dystrophy patients had an epiretinal membrane in at least one eye. Visual acuity was reduced due to the presence of epiretinal membrane in six patient eyes and none of the control eyes. The presence of an epiretinal membrane was significantly correlated with increasing age in the patient group. We report an increased prevalence of epiretinal membrane in the myotonic dystrophy type 1 group. This may be a previously under-recognised form of visual impairment in this group. Epiretinal membranes can be treated surgically. We suggest that, in addition to a comprehensive clinical examination, optical coherence tomography examination is implemented as part of an ophthalmological assessment for the myotonic dystrophy type 1 patient with reduced visual acuity.

  18. Congenital myotonic dystrophy can show congenital fiber type disproportion pathology.

    Science.gov (United States)

    Tominaga, Kayo; Hayashi, Yukiko K; Goto, Kanako; Minami, Narihiro; Noguchi, Satoru; Nonaka, Ikuya; Miki, Tetsuro; Nishino, Ichizo

    2010-04-01

    Congenital myotonic dystrophy (CDM) is associated with markedly expanded CTG repeats in DMPK. The presence of numerous immature fibers with peripheral halo is a characteristic feature of CDM muscles together with hypotrophy of type 1 fibers. Smaller type 1 fibers with no structural abnormality are a definitive criterion of congenital fiber type disproportion (CFTD). Nonetheless, we recently came across a patient who was genetically confirmed as CDM, but had been earlier diagnosed as CFTD when he was an infant. In this study, we performed clinical, pathological, and genetic analyses in infantile patients pathologically diagnosed as CFTD to evaluate CDM patients indistinguishable from CFTD. We examined CTG repeat expansion in DMPK in 28 infantile patients pathologically diagnosed as CFTD. Mutation screening of ACTA1 and TPM3 was performed, and we compared clinical and pathological findings of 20 CDM patients with those of the other cohorts. We identified four (14%) patients with CTG expansion in DMPK. ACTA1 mutation was identified in four (14%), and TPM3 mutation was found in two (7%) patients. Fiber size disproportion was more prominent in patients with ACTA1 or TPM3 mutations as compared to CFTD patients with CTG expansion. A further three patients among 20 CDM patients showed pathological findings similar to CFTD. From our results, CDM should be excluded in CFTD patients.

  19. Cardiac involvement of progressive muscular dystrophy (Becker type, Limb-girdle type and Fukuyama type) evaluated by radionuclide method

    Energy Technology Data Exchange (ETDEWEB)

    Nagamachi, Shigeki; Inoue, Kenjiro; Jinnouchi, Seishi; Hoshi, Hiroaki; Ono, Seiji; Ohnishi, Takashi; Futami, Shigemi; Watanabe, Katsushi; Hayashi, Tohru (Miyazaki Medical Coll., Kiyotake (Japan))

    1994-02-01

    Tl-201 SPECT and Tc-99m-Human serum albumin (HSA) multigated radionuclide ventriculography were performed on 11 patients with progressive muscular dystrophy (Becker type 2, Fukuyama type 2, Limb-girdle type 7) to evaluate myocardial involvement. Hypoperfusion was detected in 8 patients on Tl-201 SPECT. Decreases in both systolic function (left ventricular ejection fraction; LVEF) and diastolic function (peak filling rate; PFR) were also seen in these patients. A high incidence of myocardial involvement of these kinds of progressive muscular dystrophy was suggested. (author).

  20. Myotonic dystrophy type 1: frequency of ophthalmologic findings

    Directory of Open Access Journals (Sweden)

    Karin Suzete Ikeda

    2016-03-01

    Full Text Available ABSTRACT The purpose of the study was to evaluate the frequency of ophthalmologic abnormalities in a cohort of myotonic dystrophy type 1 (DM1 patients and to correlate them with motor function. We reviewed the pathophysiology of cataract and low intraocular pressure (IOP. Method Patients were included after clinical and laboratory diagnosis and after signed informed consent. They were evaluated by Motor Function Measure scale, Portuguese version (MFM-P and ophthalmic protocol. Results We evaluated 42 patients aged 17 to 64 years (mean 40.7 ± 12.5, 22 of which were men. IOP (n = 41 was reduced in all but one. We found cataract or positivity for surgery in 38 (90.48% and ptosis in 23 (54.76%. These signs but not IOP were significantly correlated with severity of motor dysfunction. Abnormalities in ocular motility and stereopsis were observed. Conclusion Cataract and ptosis are frequent in DM1 and associated to motor dysfunction. Reduced IOP is also common, but appears not to be related with motor impairment.

  1. [Social Cognitive Impairment in Myotonic Dystrophy Type 1].

    Science.gov (United States)

    Kobayakawa, Mutsutaka

    2016-02-01

    Myotonic dystrophy type 1 (DM 1) is a heritable, multisystem disease that affects not only the muscles but also the brain. DM 1 is often accompanied by developmental behavioral disorders, such as autism spectrum disorders. The autistic traits in DM 1 may be related to social cognitive dysfunction. The social cognitive function of patients with DM 1 was examined with respect to facial emotion recognition and theory of mind, which is the specific cognitive ability to understand the mental states of other people. With respect to facial emotion recognition, the sensitivities to disgust and anger were lower among patients with DM 1 than among healthy subjects, and this difference could not be attributed to visual impairment. To examine the theory of mind ability, the "Reading the Mind in the Eyes" test and the faux pas recognition test were used. Patients with DM 1 were found to be impaired in both tests, but the results were not attributed to visual ability and lexical comprehension. The possible causes of social cognitive dysfunction in DM 1 are the l cerebral atrophy and white matter abnormalities in the temporal, frontal, and insular cortex. Dysfunctions in these areas may affect the emotional and theory of mind abilities in DM 1, which result in the behavioral and communication disorders.

  2. Synaptic protein dysregulation in myotonic dystrophy type 1

    Science.gov (United States)

    Hernández-Hernández, Oscar; Sicot, Géraldine; Dinca, Diana M.; Huguet, Aline; Nicole, Annie; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-01-01

    The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program. PMID:25003003

  3. Evaluation of Limb-Girdle Muscular Dystrophy

    Science.gov (United States)

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  4. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    OpenAIRE

    2012-01-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age an...

  5. Does quantitative EMG differ myotonic dystrophy type 2 and type 1?

    Science.gov (United States)

    Szmidt-Salkowska, Elzbieta; Gawel, Malgorzata; Lusakowska, Anna; Nojszewska, Monika; Lipowska, Marta; Sulek, Anna; Krysa, Wioletta; Rajkiewicz, Marta; Seroka, Andrzej; Kaminska, Anna M

    2014-10-01

    Genetic testing is considered the only reliable diagnostic approach in myotonic dystrophy. However it has recently been reported that a considerable number of patients with genetically proven types of the disease have unusual phenotypic presentation. The aim of our study was to evaluate motor unit reorganization reflected by various electrophysiological abnormalities in myotonic dystrophies and to compare findings between type 1 (DM 1) and type 2 myotonic dystrophy (DM2). Quantitative electromyography (EMG) recordings in 63 patients (33 with DM1 and 30 with DM2) from the biceps brachii (BB), rectus femoris (RF), first dorsal interosseus (FDI), and tibialis anterior (TA) muscles were analyzed. Mean amplitude and size index (SI) of motor unit potentials recorded in TA and RF muscles, mean potential duration in TA, and mean SI and the number of outliers with amplitude above the normal range in BB were significantly increased in DM2 as compared to DM1. Myotonic discharges were recorded more frequently in DM1 than in DM2. EMG findings significantly differ between DM1 and DM2. The presence of high amplitude potentials in lower limb muscles in DM2 patients, atypical for myogenic muscle lesions, could be explained by muscle fiber hypertrophy observed in muscle biopsies.

  6. Progressive muscular dystrophy: Duchenne type. Controversies of the kinesitherapy treatment

    Directory of Open Access Journals (Sweden)

    Ana Valéria de Araujo Leitão

    Full Text Available The authors carried out a study of children with progressive muscular dystrophy of Duchenne type (DMD, giving special attention to physiatrical follow-up, having in mind that the practice of exercises has been debated very much in the specialized literature. The goal of this study is to try to settle the limits for the utilization of kinesitherapy which should be applied only in specific situations, such as: after skeletal muscular trauma or when the respiratory system is at risk. In this situation the physiatrical procedure would be to restrict physical activity, with early use of wheelchairs and the exclusion of the use of orthoses for orthostatism. DMD, at present, has been considered a result of duplication (60%, deletion (5 to 6% or point mutations at gen Xp21 (Zatz, 1994, that codifies a protein called Dystrophin ( Hoffman et al., 1987. Dystrophin is a cytoskeletal sarcolemmic protein that constitutes about .002% of the total protein of the muscle, present in skeletal fibers concentrated in muscle tendinous joints, which supplies mechanical reinforcement to the surface of the membrane during stretching and shortening physical activity. This protein is absent in DMD cases, wherefore, the sarcolemma undergoes a segmentary necrosis losing its contractile property during eccentric and concentric physical activity. The importance of physiatrical follow-up for DMD patients is to avoid deformities and tendon shortening, to ameliorate the patient's quality of life, to provide respiratory assistance and general couseling to members of the patient's family. The objective of this study is to try to clarify the risks and possibilities of kinesitherapy applied to DMD cases.

  7. Psychosocial impact of predictive testing for myotonic dystrophy type 1.

    Science.gov (United States)

    Prévost, Claude; Veillette, Suzanne; Perron, Michel; Laberge, Claude; Tremblay, Carmen; Auclair, Julie; Villeneuve, Josée; Tremblay, Marc; Mathieu, Jean

    2004-04-01

    In the Saguenay-Lac-Saint-Jean region (Quebec, Canada), a predictive DNA-testing program for myotonic dystrophy type 1 (DM1) has been available as a clinical service since 1988. From 1 to 12 years (median, 5 years) after receiving predictive testing, a total of 308 participants (44 carriers and 264 non-carriers) answered a questionnaire to determine the psychosocial impact of this genetic testing. The main reasons for wanting to be tested were to learn if children are at risk for DM1 or for reproductive decision making (75%) and to relieve the uncertainty for themselves (17%). The majority of participants (96.1%) remembered correctly their test result. At the time of the survey, the perception of the general well-being, the psychological distress (Psychiatric Symptom Index), and the self-esteem (Rosenberg Self-Esteem Scale) were similar in carriers, in non-carriers, and in the reference (Quebec) population. When participants indicated a change in different aspects of their lives following predictive testing, it was perceived as a change for the better by non-carriers and as a change for the worse by carriers. Nevertheless, for a majority of carriers and of non-carriers, the test result did not bring changes in their lives. All respondents believed that predictive testing should be available for the at-risk population and the vast majority of carrier and of non-carriers would recommend the use of predictive testing to their family members. Predictive testing for individuals at-risk of DM1 can be offered safely within a well-organized clinical and genetic counseling program that includes careful pre-test counseling, pre-test clinical assessment, post-test psychological support, and follow-up for those identified as carriers. Copyright 2003 Wiley-Liss, Inc.

  8. Selective disappearance of medial back muscles in a case of myotonic dystrophy type 1.

    Science.gov (United States)

    Morihara, Ryuta; Hishikawa, Nozomi; Yamashita, Toru; Deguchi, Kentaro; Kurata, Tomoko; Abe, Koji

    2015-01-01

    Here, we report a unique case of late-onset myotonic dystrophy type 1 in a 64-year-old woman, with selective disappearance of the medial lower back muscles. We compared the clinical features of this patient with those of a cohort of 29 patients with myotonic dystrophy type 1 to clarify the correlation between clinical features and lower back muscle atrophy. After classification into three subgroups according to muscle atrophy pattern, medial muscle atrophy was present in 17.2% of the patients. Affected patients were older at onset than non-affected patients, and limb muscle power and respiratory function decreased with atrophy progression.

  9. Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies

    DEFF Research Database (Denmark)

    Petri, Helle; Sveen, Marie-Louise; Thune, Jens Jakob;

    2015-01-01

    AIM: To assess the degree and progression of cardiac involvement in patients with limb-girdle type 2 (LGMD2) and Becker muscular dystrophies (BMD). METHODS: A follow-up study of 100 LGMD2 (types A-L) and 30 BMD patients assessed by electrocardiogram (ECG) and echocardiography, supplemented...

  10. Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I

    DEFF Research Database (Denmark)

    Løkken, Nicoline; Hedermann, Gitte; Thomsen, Carsten;

    2016-01-01

    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...

  11. Endocrine function over time in patients with myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Dahlqvist, Julia Rebecka; Ørngreen, M C; Witting, N

    2015-01-01

    BACKGROUND AND PURPOSE: Patients with myotonic dystrophy type 1 (DM1) have an increased incidence of endocrine dysfunction. In this study, the temporal evolution of endocrine dysfunction in patients with DM1 was investigated. METHODS: Endocrine function was assessed in 68 patients with DM1, in whom...

  12. No relevant excess prevalence of myotonic dystrophy type 2 in patients with suspected fibromyalgia syndrome

    NARCIS (Netherlands)

    Vliet, J. van; Verrips, A.; Tieleman, A.A.; Scheffer, H.; Cats, H.A.; Broeder, A.A. den; Engelen, B.G.M. van

    2016-01-01

    Myotonic dystrophy type 2 (DM2) is a rare, autosomal dominant, multisystem disorder with proximal weakness, myotonia, pain and cataract as important symptoms. Given the assumed underreporting of DM2 in the Netherlands combined with the predominant role of pain in DM2 as well as in fibromyalgia syndr

  13. Overweight Is an Independent Risk Factor for Reduced Lung Volumes in Myotonic Dystrophy Type 1

    NARCIS (Netherlands)

    Seijger, Charlotte G W; Drost, Gea; Posma, Joram M; van Engelen, Baziel G M; Heijdra, Yvonne F

    2016-01-01

    BACKGROUND: In this large observational study population of 105 myotonic dystrophy type 1 (DM1) patients, we investigate whether bodyweight is a contributor of total lung capacity (TLC) independent of the impaired inspiratory muscle strength. METHODS: Body composition was assessed using the combinat

  14. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2.

    Science.gov (United States)

    Kamsteeg, Erik-Jan; Kress, Wolfram; Catalli, Claudio; Hertz, Jens M; Witsch-Baumgartner, Martina; Buckley, Michael F; van Engelen, Baziel G M; Schwartz, Marianne; Scheffer, Hans

    2012-12-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1 of the CNBP (formerly ZNF9) gene, respectively. The length of the (CTG)n repeat expansion in DM1 correlates with disease severity and age of onset. Nevertheless, these repeat sizes have limited predictive values on individual bases. Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.

  15. Longitudinal in vivo muscle function analysis of the DMSXL mouse model of myotonic dystrophy type 1.

    Science.gov (United States)

    Decostre, Valérie; Vignaud, Alban; Matot, Béatrice; Huguet, Aline; Ledoux, Isabelle; Bertil, Emilie; Gjata, Bernard; Carlier, Pierre G; Gourdon, Geneviève; Hogrel, Jean-Yves

    2013-12-01

    Myotonic dystrophy is the most common adult muscle dystrophy. In view of emerging therapies, which use animal models as a proof of principle, the development of reliable outcome measures for in vivo longitudinal study of mouse skeletal muscle function is becoming crucial. To satisfy this need, we have developed a device to measure ankle dorsi- and plantarflexion torque in rodents. We present an in vivo 8-month longitudinal study of the contractile properties of the skeletal muscles of the DMSXL mouse model of myotonic dystrophy type 1. Between 4 and 12 months of age, we observed a reduction in muscle strength in the ankle dorsi- and plantarflexors of DMSXL compared to control mice although the strength per muscle cross-section was normal. Mild steady myotonia but no abnormal muscle fatigue was also observed in the DMSXL mice. Magnetic resonance imaging and histological analysis performed at the end of the study showed respectively reduced muscle cross-section area and smaller muscle fibre diameter in DMSXL mice. In conclusion, our study demonstrates the feasibility of carrying out longitudinal in vivo studies of muscle function over several months in a mouse model of myotonic dystrophy confirming the feasibility of this method to test preclinical therapeutics.

  16. [A genetic systemic disease: clinical description of type 1 myotonic dystrophy in adults].

    Science.gov (United States)

    Kaminsky, P; Pruna, L

    2012-09-01

    Type 1 myotonic dystrophy is an autosomal dominant inherited disorder related to the expansion of a trinucleotide (CTG) repeat in the exon 15 in the 3'-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Mutant transcripts containing an expanded CUG repeat are retained in nuclear foci and cause numerous dysfunctions by interfering with biogenesis of other mRNAs. Prominent clinical features are progressive muscular weakness and myotonia, which affect skeletal muscles but also white muscles leading to digestive, urinary and obstetrical disorders. Functional prognosis correlates with motor handicap and vital prognosis is linked to cardiac rhythm disturbances and conduction defects due to progressive subendocardial fibrosis, and to complex respiratory dysfunctions, which associate restrictive lung disease, involvement of the central inspiratory pathway, and sleep apnea. Other clinical features are lens opacity, glucose intolerance, metabolic syndrome, several endocrine disorders (gonadal deficiency, hyperparathydoidism), or immunoglobulin deficiency due to immunoglobulin G hypercatabolism. Life expectancy is reduced in myotonic dystrophy, and death is mainly caused by respiratory complications, but also by cardiac arrhythmias. Moreover, an abnormal incidence of tumors has been reported. Therefore, myotonic dystrophy does not only concern neurologists but a multidisciplinary approach is necessary, including at least pneumologist, cardiologist, and physiotherapist. General internists should also be implicated, not only in the initial diagnosis step, but also in the diagnosis of complications and their treatments.

  17. Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1.

    NARCIS (Netherlands)

    Vanlinthout, L.E.H.; Booij, L.H.D.J.; Egmond, J. van; Robertson, E.N.

    2010-01-01

    We measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies

  18. Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy.

    Science.gov (United States)

    Schneider, Ilka; Stoltenburg, Gisela; Deschauer, Marcus; Winterholler, Martin; Hanisch, Frank

    2014-05-01

    Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy.

  19. [Anesthetic management of a pediatric patient with non-Fukuyama type congenital muscular dystrophy].

    Science.gov (United States)

    O'Higashi, T; Kato, S; Shirakami, G; Hirota, K; Suzuki, S; Sasai, S

    1997-01-01

    Non-Fukuyama type congenital muscular dystrophy (n-FCMD), a subtype of progressive muscular dystrophy (PMD), is a very rare autosomal recessive disorder. N-FCMD is characterized by severe and progressive motor weakness and atrophies of proximal muscles during the infant period. A 9-year-old boy with n-FCMD underwent elective surgery for muscle release around the hip joints bilaterally. As many perioperative complications related with volatile anesthetics and muscle relaxants had been reported in the anesthetic management of PMD, these drugs were thought to be contraindicated in patients with n-FCMD. Because n-FCMD seemed to have very similar pathogenesis with PMD, caudal epidural block was chosen, supplemented with the administration of diazepam, pentazocine and nitrous oxide. The operation and anesthesia were conducted uneventfully. No complications occurred postoperatively.

  20. Structural myocardial involvement in adult patients with type 1 myotonic dystrophy

    Directory of Open Access Journals (Sweden)

    Upinder K. Dhand

    2013-03-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is the commonest muscular dystrophy in adults, affecting multiple organs in addition to skeletal muscles. Cardiac conduction system abnormalities are well recognized as an important component of DM1 phenotype; however, primary structural myocardial abnormalities, which may predispose these patients to congestive heart failure, are not as well characterized. We reviewed the retrospective analysis of the clinical and echocardiographic findings in adult patients with DM1. Among 27 patients (16 male; age 19-61 years with DM1, the echocardiogram (ECHO was abnormal in 10 (37% including one of 6 patients (16% with congenital myotonic dystrophy. Reduced left ventricular ejection fraction (LVEF ≤50% was noted in 5, diastolic dysfunction in 4, left atrial dilatation in 3, left ventricular hypertrophy in 2, apical hypokinesia in 1 and mitral valve prolapse in 3 patients. One patient had paradoxical septal movement in the setting of left bundle branch block. Echocardiographic abnormalities significantly correlated with older age; however, patients with systolic dysfunction on echocardiogram ranged in age from 27 to 52 years including 2 patients aged 27 and 34 years. We can conclude that echocardiographic abnormalities are frequent in adult patients with DM1. The incidence is similar in the classical and congenital type of DM1. Overall, echocardiographic abnormalities in DM1 correlate with increasing age; however, reduced LVEF is observed even at young age. Cardiac assessment and monitoring in adult patients with DM1 should include evaluation for primary myocardial involvement.

  1. First detection of canine parvovirus type 2c in Brazil Detecção de parvovírus canino tipo 2c no Brasil

    OpenAIRE

    André Felipe Streck; Carine Kunzler Souza; Karla Rathje Gonçalves; Luciana Zang; Luciane Dubina Pinto; Cláudio Wageck Canal

    2009-01-01

    The presence of canine parvovirus type 2 (CPV-2), 2a and 2b has been described in Brazil, however, the type 2c had not been reported until now. In the current study, seven out of nine samples from dogs with diarrhea were characterized as CPV-2c, indicating that this virus is already circulating in the Brazilian canine population.No Brasil, a presença do parvovírus canino do tipo 2 (CPV-2), 2a e 2b já havia sido descrita, contudo, ainda não havia sido verificada a presença do tipo 2c. No prese...

  2. Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy.

    Science.gov (United States)

    Reyes, Nicholas L; Banks, Glen B; Tsang, Mark; Margineantu, Daciana; Gu, Haiwei; Djukovic, Danijel; Chan, Jacky; Torres, Michelle; Liggitt, H Denny; Hirenallur-S, Dinesh K; Hockenbery, David M; Raftery, Daniel; Iritani, Brian M

    2015-01-13

    Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

  3. Measurement of the functional status of patients with different types of muscular dystrophy.

    Science.gov (United States)

    Lue, Yi-Jing; Lin, Rong-Fong; Chen, Shun-Sheng; Lu, Yen-Mou

    2009-06-01

    Muscular dystrophy (MD) comprises a group of diseases characterized by progressive muscle weakness that induces functional deterioration. Clinical management requires the use of a well-designed scale to measure patients' functional status. This study aimed to investigate the quality of the functional scales used to assess patients with different types of MD. The Brooke scale and the Vignos scale were used to grade arm and leg function, respectively. The Barthel Index was used to evaluate the function of daily living activity. We performed tests to assess the acceptability of these scales. The characteristics of the different types of MD are discussed. This was a multicenter study and included patients diagnosed with Duchenne muscular dystrophy (DMD) (classified as severely progressive MD), Becker muscular dystrophy (BMD), limb girdle muscular dystrophy (LGMD) and facioscapulohumeral muscular dystrophy (FSHD). BMD, LGMD, and FSHD were classified as slowly progressive MD. The results demonstrated that the Brooke scale was acceptable for grading arm function in DMD, but was unable to discriminate between differing levels of severity in slowly progressive MD. The floor effect was large for all types of slowly progressive MD (range, 20.0-61.9), and was especially high for BMD. The floor effect was also large for BMD (23.8%) and FSHD (50.0%) using the Vignos scale. Grades 6-8 of the Vignos scale were inapplicable because they included items involving the use of long leg braces for walking or standing, and some patients did not use long leg braces. In the Barthel Index, a ceiling effect was prominent for slowly progressive MD (58.9%), while a floor effect existed for DMD (17.9%). Among the slowly progressive MDs, FSHD patients had the best level of functioning; they had better leg function and their daily living activities were less affected than patients with other forms of slowly progressive MD. The results of this study demonstrate the acceptability of the different

  4. Measurement of the Functional Status of Patients with Different Types of Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Yi-Jing Lue

    2009-06-01

    Full Text Available Muscular dystrophy (MD comprises a group of diseases characterized by progressive muscle weakness that induces functional deterioration. Clinical management requires the use of a well-designed scale to measure patients' functional status. This study aimed to investigate the quality of the functional scales used to assess patients with different types of MD. The Brooke scale and the Vignos scale were used to grade arm and leg function, respectively. The Barthel Index was used to evaluate the function of daily living activity. We performed tests to assess the acceptability of these scales. The characteristics of the different types of MD are discussed. This was a multicenter study and included patients diagnosed with Duchenne muscular dystrophy (DMD (classified as severely progressive MD, Becker muscular dystrophy (BMD, limb girdle muscular dystrophy (LGMD and facioscapulohumeral muscular dystrophy (FSHD. BMD, LGMD, and FSHD were classified as slowly progressive MD. The results demonstrated that the Brooke scale was acceptable for grading arm function in DMD, but was unable to discriminate between differing levels of severity in slowly progressive MD. The floor effect was large for all types of slowly progressive MD (range, 20.0–61.9, and was especially high for BMD. The floor effect was also large for BMD (23.8% and FSHD (50.0% using the Vignos scale. Grades 6–8 of the Vignos scale were inapplicable because they included items involving the use of long leg braces for walking or standing, and some patients did not use long leg braces. In the Barthel Index, a ceiling effect was prominent for slowly progressive MD (58.9%, while a floor effect existed for DMD (17.9%. Among the slowly progressive MDs, FSHD patients had the best level of functioning; they had better leg function and their daily living activities were less affected than patients with other forms of slowly progressive MD. The results of this study demonstrate the acceptability of the

  5. First detection of canine parvovirus type 2c in Brazil Detecção de parvovírus canino tipo 2c no Brasil

    Directory of Open Access Journals (Sweden)

    André Felipe Streck

    2009-09-01

    Full Text Available The presence of canine parvovirus type 2 (CPV-2, 2a and 2b has been described in Brazil, however, the type 2c had not been reported until now. In the current study, seven out of nine samples from dogs with diarrhea were characterized as CPV-2c, indicating that this virus is already circulating in the Brazilian canine population.No Brasil, a presença do parvovírus canino do tipo 2 (CPV-2, 2a e 2b já havia sido descrita, contudo, ainda não havia sido verificada a presença do tipo 2c. No presente trabalho, sete de nove amostras de cães com diarréia foram caracterizadas como CPV-2c, indicando que este vírus já está circulando na população canina no Brasil.

  6. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1

    African Journals Online (AJOL)

    Enrique

    (CPRS), type 1 is a pain disorder that develops unpredictably and ... Computed tomography was done to exclude stress ... Magnetic resonance images revealed oedema in the ... with MRI every 3 months and the bone marrow .... spinal cord.

  7. Canine parvovirus type 2c infection in a kitten associated with intracranial abscess and convulsions.

    Science.gov (United States)

    Decaro, Nicola; Desario, Costantina; Amorisco, Francesca; Losurdo, Michele; Colaianni, Maria Loredana; Greco, Maria Fiorella; Buonavoglia, Canio

    2011-04-01

    A case of canine parvovirus type 2c (CPV-2c) infection in a 3-month-old feral kitten with a cerebral abscess and neurological disease is reported. The cat displayed ataxia and convulsions together with signs of gastroenteritis and profound alteration of the total and differential white blood cell counts. A parvovirus strain was detected by a TaqMan assay in the blood and faeces of the affected kitten, which was characterised as CPV by means of molecular assays but did not react with any of the CPV type-specific probes. By sequence and phylogenetic analyses of the VP2-protein gene, the CPV-2c strain displayed a non-coding mutation in the probe-binding region. Although the role of CPV-2c in this particular case is unclear, it is possible that it predisposed the kitten to the clinical signs seen. Continuous surveillance is needed to monitor future spreading of this CPV-2c mutant, and any associated clinical signs, in the dog and cat population.

  8. Reduced Toxicity of Shiga Toxin (Stx Type 2c in Mice Compared to Stx2d Is Associated with Instability of Stx2c Holotoxin

    Directory of Open Access Journals (Sweden)

    Joshua C. Bunger

    2015-06-01

    Full Text Available Shiga toxin (Stx is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC. These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a and six subtypes (b–g, but only STEC that make Stx2a, and/or Stx2c, or Stx2d are associated with severe disease. However, Stx2c is about 10-fold less toxic than Stx2d in vivo despite only two amino acid differences in the A subunit at positions 291 and 297. We made mutations at these two sites to create intermediate toxins between Stx2c and Stx2d, and determined the 50% cytotoxic dose on Vero cells before and after heat treatment, and the 50% lethal dose in mice of the toxins. We found that serine 291 was associated with increased toxicity in vivo and that either amino acid change from that in Stx2c to that in Stx2d increased heat stability. We also assessed the secondary structure of Stx2c and Stx2d by circular dichroism (CD spectroscopy. The CD studies suggest that Stx2c has a less-ordered secondary structure than Stx2d. We conclude that both amino acids at positions 291 and 297 in Stx2c contribute to its decreased stability and in vivo toxicity compared to Stx2d.

  9. Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?

    Institute of Scientific and Technical Information of China (English)

    Antonio Costantini; Erika Trevi; Maria Immacolata Pala; Roberto Fancellu

    2016-01-01

    Myotonic dystrophy type 1, also known as Steinert’s disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine (vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell me-tabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deifciency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We de-scribed two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council (MRC), the Muscular Impairment Rating Scale (MIRS), and the Modiifed Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients’ activi-ties of daily living using the Modiifed Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2–4 in the distal muscles (the MRC score before the treatment was 3–4 and 1–3, re-spectively). The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modiifed Barthel Index improved by 44%, and in patient #2 by 29%. These ifndings suggest that clinical outcomes are improved by long-term thiamine treatment.

  10. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Science.gov (United States)

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  11. Type II collagen C2C epitope in human synovial fluid and serum after knee injury

    DEFF Research Database (Denmark)

    Kumahashi, N; Swärd, P; Larsson, S

    2015-01-01

    PURPOSE: Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS: Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235...... = 0.403, P collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P ... with an immediate and sustained local degradation of type II collagen....

  12. Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

    LENUS (Irish Health Repository)

    Walsh, Richard

    2012-02-01

    Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.

  13. Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules That Reduce Toxicity

    OpenAIRE

    Childs-Disney, Jessica L.; Yildirim, Ilyas; Park, HaJeung; Lohman, Jeremy R.; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C.; Disney, Matthew D.

    2013-01-01

    Myotonic dystrophy type 2 (DM2) is an untreatable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)exp) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5’CCUG/3’GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG)exp refined to 2.35 Å. Structural analysis of the three 5’CCUG/3’GUCC repeat internal loop...

  14. Muscular Dystrophy

    Science.gov (United States)

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and muscle loss. Some forms of MD appear in infancy ... types can vary in whom they affect, which muscles they affect, and what the symptoms are. All ...

  15. Reflex sympathetic dystrophy/complex regional pain syndrome, type 1

    Directory of Open Access Journals (Sweden)

    S.H. Botha

    2004-02-01

    Full Text Available Complex regional pain syndrome (CPRS, type 1 is a pain disorder that develops unpredictably and can follow a minor injury. A 12-year-old boy presented with severe pain in the feet and could not walk or stand weight bearing. Normal X-rays showed osteopenic changes and radiolucent lines, which appeared to be stress fractures. Three-phase bone scintigraphy showed no uptake in the left lower leg on the blood pool phase or on the immediate or delayed images. This indicated typical CPRS type 1 in children. The uptake in the right foot was increased and the stress fracture and other illness could not be differentiated. Computed tomography was done to exclude stress fractures. Only osteopenic changes in both calcaneus bones were found and there was no evidence of cortical stress fractures. Magnetic resonance images revealed oedema in the calcaneus and talus bones of both feet. The patient received epidural narcotic infusion with sympathetic blockage for 1 week combined with extensive physiotherapy. The blood pool phase of the bone scan became normal within 2 weeks, and increased uptake in both feet was noticed. The patient was followed up with MRI every 3 months and the bone marrow oedema disappeared after 6 months.

  16. Distinct Fiber Type Signature in Mouse Muscles Expressing a Mutant Lamin A Responsible for Congenital Muscular Dystrophy in a Patient

    Directory of Open Access Journals (Sweden)

    Alice Barateau

    2017-04-01

    Full Text Available Specific mutations in LMNA, which encodes nuclear intermediate filament proteins lamins A/C, affect skeletal muscle tissues. Early-onset LMNA myopathies reveal different alterations of muscle fibers, including fiber type disproportion or prominent dystrophic and/or inflammatory changes. Recently, we identified the p.R388P LMNA mutation as responsible for congenital muscular dystrophy (L-CMD and lipodystrophy. Here, we asked whether viral-mediated expression of mutant lamin A in murine skeletal muscles would be a pertinent model to reveal specific muscle alterations. We found that the total amount and size of muscle fibers as well as the extent of either inflammation or muscle regeneration were similar to wildtype or mutant lamin A. In contrast, the amount of fast oxidative muscle fibers containing myosin heavy chain IIA was lower upon expression of mutant lamin A, in correlation with lower expression of genes encoding transcription factors MEF2C and MyoD. These data validate this in vivo model for highlighting distinct muscle phenotypes associated with different lamin contexts. Additionally, the data suggest that alteration of muscle fiber type identity may contribute to the mechanisms underlying physiopathology of L-CMD related to R388P mutant lamin A.

  17. Analysis of meiotic segregation, using single-sperm typing: Meiotic drive at the myotonic dystrophy locus

    Energy Technology Data Exchange (ETDEWEB)

    Leeflang, E.P.; Arnheim, N. [Univ. of Southern California, Los Angeles, CA (United States); McPeek, M.S. [Univ. of Chicago, IL (United States)

    1996-10-01

    Meiotic drive at the myotonic dystrophy (DM) locus has recently been suggested as being responsible for maintaining the frequency, in the human population, of DM chromosomes capable of expansion to the disease state. In order to test this hypothesis, we have studied samples of single sperm from three individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than 19 CTG repeats. To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size at the DM locus. Using statistical models specifically designed to study single-sperm segregation data, we find no evidence of meiotic segregation distortion. The upper limit of the two-sided 95% confidence interval for the estimate of the common segregation probability for the three donors is at or below .515 for all models considered, and no statistically significant difference from .5 is detected in any of the models. This suggests that any greater amount of segregation distortion at the myotonic dystrophy locus must result from events following sperm ejaculation. The mathematical models developed make it possible to study segregation distortion with high resolution by using sperm-typing data from any locus. 26 refs., 1 fig., 8 tabs.

  18. How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1.

    Science.gov (United States)

    Serra, Laura; Petrucci, Antonio; Spanò, Barbara; Torso, Mario; Olivito, Giusy; Lispi, Ludovico; Costanzi-Porrini, Sandro; Giulietti, Giovanni; Koch, Giacomo; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2015-01-01

    Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.

  19. A phylogenetic study of canine parvovirus type 2c in midwestern Brazil

    Directory of Open Access Journals (Sweden)

    Danúbia S. Fontana

    2013-02-01

    Full Text Available Since the late 1970s, canine parvovirus type 2 (CPV-2 has emerged as a causative agent of fatal severe acute hemorrhagic enteritis in dogs. To date, three antigenic types of CPV-2 were described worldwide (CPV-2a/b/c. This study was conducted to determine the variants of CPV-2 circulating in dogs from the Cuiabá Municipality in Midwestern Brazil. Out of 50 fecal samples, collected between 2009 and 2011, 27 tested positive for CPV-2. A 583 bp fragment of the VP2 gene was amplified by PCR, 13 representative samples were analyzed further by DNA sequencing. All strains were characterized as CPV-2c, displayed a low genetic variability although observed several amino acid substitution. These findings indicated that CPV-2c has been circulating in dogs from the Cuiabá Municipality in Midwestern Brazil.

  20. Oral motor movements and swallowing in patients with myotonic dystrophy type 1.

    Science.gov (United States)

    Ercolin, Beatriz; Sassi, Fernanda Chiarion; Mangilli, Laura Davison; Mendonça, Lucia Iracema Zanotto; Limongi, Suelly Cecilia Olivan; de Andrade, Claudia Regina Furquim

    2013-09-01

    Oropharyngeal dysphagia and esophageal motility disorders were found to be the most important causes of aspiration pneumonia in patients with myotonic dystrophy. The purpose of this report was to evaluate clinical characteristics of the oral motor movements and swallowing of individuals with myotonic dystrophy type 1 (DM1) using a standardized clinical protocol and surface electromyography (sEMG). Participants were 40 individuals divided in two groups: G1 composed of 20 adults with DM1 and G2 composed of 20 healthy volunteers paired by age and gender to the individuals in G1. Statistical analysis included one-way ANOVA with two factors for within- and between-group comparisons and Bonferroni correction for multiple comparisons. Patients with DM1 presented deficits in posture, position, and mobility of the oral motor structures, as well as compromised mastication and deglutition. The sEMG data indicated that these patients had longer muscle activations during swallowing events. The longer duration of sEMG in the group of patients with DM1 is possibly related to myotonia and/or incoordination of the muscles involved in the swallowing process or could reflect a physiological adaptation for safe swallowing.

  1. Limb-girdle muscular dystrophy type 2I is not rare in Taiwan.

    Science.gov (United States)

    Liang, Wen-Chen; Hayashi, Yukiko K; Ogawa, Megumu; Wang, Chien-Hua; Huang, Wan-Ting; Nishino, Ichizo; Jong, Yuh-Jyh

    2013-08-01

    Alpha-dystroglycanopathy is caused by the glycosylation defects of α-dystroglycan (α-DG). The clinical spectrum ranges from severe congenital muscular dystrophy (CMD) to later-onset limb girdle muscular dystrophy (LGMD). Among all α-dystroglycanopathies, LGMD type 2I caused by FKRP mutations is most commonly seen in Europe but appears to be rare in Asia. We screened uncategorized 40 LGMD and 10 CMD patients by immunohistochemistry for α-DG and found 7 with reduced α-DG immunostaining. Immunoblotting with laminin overlay assay confirmed the impaired glycosylation of α-DG. Among them, five LGMD patients harbored FKRP mutations leading to the diagnosis of LGMD2I. One common mutation, c.948delC, was identified and cardiomyopathy was found to be very common in our cohort. Muscle images showed severe involvement of gluteal muscles and posterior compartment at both thigh and calf levels, which is helpful for the differential diagnosis. Due to the higher frequency of LGMD2I with cardiomyopathy in our series, the early introduction of mutation analysis of FKRP in undiagnosed Taiwanese LGMD patients is highly recommended.

  2. Canine parvovirus--a review of epidemiological and diagnostic aspects, with emphasis on type 2c.

    Science.gov (United States)

    Decaro, Nicola; Buonavoglia, Canio

    2012-02-24

    Canine parvovirus type 2 (CPV-2) emerged in late 1970s causing severe epizootics in kennels and dog shelters worldwide. Soon after its emergence, CPV-2 underwent genetic evolution giving rise consecutively to two antigenic variants, CPV-2a and CPV-2b that replaced progressively the original type. In 2000, a new antigenic variant, CPV-2c, was detected in Italy and rapidly spread to several countries. In comparison to the original type CPV-2, the antigenic variants display increased pathogenicity in dogs and extended host range, being able to infect and cause disease in cats. Epidemiological survey indicate that the newest type CPV-2c is becoming prevalent in different geographic regions and is often associated to severe disease in adult dogs and also in dogs that have completed the vaccination protocols. However, the primary cause of failure of CPV vaccination is interference by maternally derived immunity. Diagnosis of CPV infection by traditional methods has been shown to be poorly sensitive, especially in the late stages of infections. New diagnostic approaches based on molecular methods have been developed for sensitive detection of CPV in clinical samples and rapid characterisation of the viral type. Continuous surveillance will help assess whether there is a real need to update currently available vaccines and diagnostic tests.

  3. Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.

    Science.gov (United States)

    Meyer, Alain; Lannes, Béatrice; Carapito, Raphaël; Bahram, Seiamak; Echaniz-Laguna, Andoni; Geny, Bernard; Sibilia, Jean; Gottenberg, Jacques Eric

    2015-02-01

    Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8 kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2.

  4. Occurrence of canine parvovirus type 2c in the dogs with haemorrhagic enteritis in India.

    Science.gov (United States)

    Nandi, S; Chidri, S; Kumar, Manoj; Chauhan, R S

    2010-02-01

    Canine parvovirus 2 (CPV-2) causes a highly contagious and often fatal disease in dogs. Since its sudden emergence in the early 1970s, CPV-2 has been evolving through the generation of novel genetic and antigenic variants (CPV-2a/b/c) that are unevenly distributed throughout the world. In the present study we have examined 36 clinical cases of dogs suspected of CPV collected during year 2006. A fragment of the VP2 gene of the virus was analyzed using polymerase chain reaction (PCR), restriction endonuclease (RE) and DNA sequence analysis. Out of the 36 samples analyzed, 16 were found positive for CPV-2a/2b by conventional PCR. DNA sequencing was done for 6 PCR positive samples, out of which three were characterized as CPV-2c, indicating that this CPV type 2c is currently circulating in India.

  5. Proteoglycan biosynthesis by human corneas from patients with types 1 and 2 macular corneal dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Midura, R.J.; Hascall, V.C.; MacCallum, D.K.; Meyer, R.F.; Thonar, E.J.; Hassell, J.R.; Smith, C.F.; Klintworth, G.K. (National Institute of Dental Research, Bethesda, MD (USA))

    1990-09-15

    Corneal buttons were obtained from patients with types 1 and 2 macular corneal dystrophy (MCD) and from control patients with Fuchs' dystrophy or keratoconus. Buttons were incubated for 20 h in the presence of (3H)glucosamine or (2-3H)mannose. Radiolabeled proteoglycans and lactosaminoglycan-glycoproteins (L-GPs) were purified using chromatography on Q-Sepharose, Superose 6, and octyl-Sepharose. They were identified using chondroitinase ABC, keratanase or endo-beta-galactosidase digestion, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis or Superose 6 chromatography. This study confirms previous reports that type 1 MCD corneas synthesize a normal dermatan sulfate-proteoglycan (DS-PG) and an abnormal keratan sulfate-proteoglycan (KS-PG). The data indicate that typ 1 MCD corneas synthesize L-GP instead of KS-PG. This L-GP has a core protein of similar hydrophobicity (elution from octyl-Sepharose) and nearly similar mass (42 kDa) as the core protein of the KS-PG. It has identical glycoconjugates as those of the KS-PG except that they lack sulfate. Thus, type 1 MCD fails to synthesize keratan sulfate as a result of a defect in a sulfotransferase specific for sulfating lactosaminoglycans. Further, proteoglycans synthesized by a cornea from a patient with type 2 MCD were studied. This cornea synthesized a normal ratio of KS-PG to DS-PG although net synthesis of proteoglycans was approximately 30% below normal. The KS-PG appeared normal whereas the DS-PG had dermatan sulfate chains that were approximately 40% shorter than normal.

  6. Cognition and Adaptive Skills in Myotonic Dystrophy Type 1: A Study of 55 Individuals with Congenital and Childhood Forms

    Science.gov (United States)

    Ekstrom, Anne-Berit; Hakenas-Plate, Louise; Tulinius, Mar; Wentz, Elisabet

    2009-01-01

    Aims: To investigate cognitive abilities and adaptive skills in children and adolescents with myotonic dystrophy type 1 (DM1) and correlate the findings to the cytosine-thymine-guanine (CTG) repeat expansion size. Method: Cognitive level was assessed in 55 children and adolescents with DM1 (31 males, 24 females; mean age 12y 1mo, SD 5y 1mo; range…

  7. Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1.

    Science.gov (United States)

    Vanlinthout, L E H; Booij, L H D J; van Egmond, J; Robertson, E N

    2010-06-01

    We measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies. In myotonic dystrophy type 1 patients, the dose-response curve obtained with acceleromyography was steeper and right-shifted compared with that obtained using mechanomyography. However, the effective doses to produce 95% neuromuscular block determined with both acceleromyography and mechanomyography were similar to each other and to values found in normal patients. In the three myotonic dystrophy type 1 patients with mild to moderate disease, times to recovery from block were similar to those observed in normal controls. In both patients and normal controls, neuromuscular block recovered faster with acceleromyography. However, in one patient with severe muscle wasting, recovery of neuromuscular block was prolonged. We conclude that mechanomyography and acceleromyography cannot be used interchangeably to monitor neuromuscular block in myotonic dystrophy type 1 patients.

  8. Lower limb muscle impairment in myotonic dystrophy type 1: the need for better guidelines.

    Science.gov (United States)

    Petitclerc, Émilie; Hébert, Luc J; Desrosiers, Johanne; Gagnon, Cynthia

    2015-04-01

    In myotonic dystrophy type 1 (DM1), leg muscle weakness is a major impairment. There are challenges to obtaining a clear portrait of muscle strength impairment. A systematic literature review was conducted on lower limb strength impairment in late-onset and adult phenotypes to document variables which affect strength measurement. Thirty-two articles were reviewed using the COSMIN guidelines. Only a third of the studies described a reproducible protocol. Only 2 muscle groups have documented reliability for quantitative muscle testing and only 1 total score for manual muscle testing. Variables affecting muscle strength impairment are not described in most studies. This review illustrates the variability in muscle strength assessment in relation to DM1 characteristics and the questionable validity of the results with regard to undocumented methodological properties. There is therefore a clear need to adopt a consensus on the use of a standardized muscle strength assessment protocol.

  9. MRI findings and cognitive functions in a small cohort of myotonic dystrophy type 1: Retrospective analyses.

    Science.gov (United States)

    Bajrami, Arsida; Azman, Filiz; Yayla, Vildan; Cagirici, Sultan; Keskinkiliç, Cahit; Sozer, Nejla

    2017-02-01

    Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease with common cognitive deficits and potential brain involvement in addition to the cardinal muscular and systemic symptoms. Impaired mental function associated with nonspecific pathological findings such as white-matter hyperintense lesions (WMHLs), ventricular enlargement and brain atrophy on brain MRI have been previously reported in DM1 patients. While some studies showed correlation of brain morphological changes with neuropsychological and clinical parameters including CTG repeat sizes and disease severity scales in DM1, others failed. The goal of this study was to retrospectively investigate cranial MR abnormalities, predominantly WMHLs, and their effects on clinical and cognitive deficits in a small, phenotypically or genotypically well-characterized cohort of DM1 patients.

  10. Fatigue and daytime sleepiness in patients with myotonic dystrophy type 1: to lump or split?

    Science.gov (United States)

    Laberge, Luc; Dauvilliers, Yves; Bégin, Paul; Richer, Louis; Jean, Stéphane; Mathieu, Jean

    2009-06-01

    We assessed the relationship and clinical correlates of fatigue and Excessive Daytime Sleepiness (EDS) in 200 myotonic dystrophy type 1 (DM1) patients by means of questionnaire and neuropsychological evaluation. Fatigue levels were higher in patients with EDS and daytime sleepiness levels higher in patients with excessive fatigue. However, EDS without fatigue was rarely observed. Also, DM1 patients with fatigue (with or without EDS) showed greater muscular impairment, CTG repeats, abnormalities regarding personality, depressive symptoms and lower health-related quality of life (HRQoL) than patients without these symptoms. These findings do not readily support the contention that fatigue and EDS constitute distinct clinical manifestations in DM1. Clinicians should systematically evaluate both symptoms since fatigue and EDS have a greater impact on HRQoL than fatigue alone. However, specific rating scales for fatigue in DM1 have yet to be devised.

  11. Muscle Quantitative MR Imaging and Clustering Analysis in Patients with Facioscapulohumeral Muscular Dystrophy Type 1.

    Directory of Open Access Journals (Sweden)

    Emilie Lareau-Trudel

    Full Text Available Facioscapulohumeral muscular dystrophy type 1 (FSHD1 is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest.Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ± 20.4% than in volunteers (3.6 ± 2.8% (p<0.001. In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001. However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p ≤ 0.01 and was inversely correlated with MMT score, MFM subscore D1 (p ≤ 0.01 further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy.The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients.

  12. Anticipation in myotonic dystrophy type 1 parents with small CTG expansions.

    Science.gov (United States)

    Pratte, Annabelle; Prévost, Claude; Puymirat, Jack; Mathieu, Jean

    2015-04-01

    Myotonic dystrophy type 1 is the most common form of adult muscular dystrophy and has the world's highest prevalence in the Saguenay-Lac-St-Jean region, due to a founder effect. This autosomal dominant disorder results from an unstable CTG repeat expansion in DMPK. This region of Canada has had a family screening and predictive testing program for this disorder since 1988. Heterozygotes for small expansions (50-100 CTG repeats) can be asymptomatic or minimally affected. The aim of this study was to assess anticipation for these individuals. At the time of this study, the molecular data of 40 individuals and their 76 affected children were available. We compared 76 parent-child pairs. Most offspring (92.1%) had a larger number of repeats than their parent and the median number of repeats in the offspring was 325 (range, 57-2000). The number of CTG repeats was significantly greater when the mutation was transmitted by a father (median, 425 repeats; range, 70-2000), than when it was transmitted by a mother (median, 200 repeats; range, 57-1400). The majority (65.8%) of children also had a more severe phenotype than their parent but the sex of the parent had no significant influence on the severity of the child's phenotype. No congenital phenotype was observed. These results confirm that anticipation is present even when the parent is heterozygous for a small CTG expansion. The parental sex has an impact on the size of the repeat in the next generation, larger increases being transmitted by males with a small expansion. © 2015 Wiley Periodicals, Inc.

  13. Genome-wide scan of granular corneal dystrophy, type II: confirmation of chromosome 5q31 and identification of new co-segregated loci on chromosome 3q26.3

    OpenAIRE

    Lee, Eun-Ju; Kim, Kwang Joong; Kim, Han-Na; Bok, Jeong; Jung, Sung-Chul; Kim, Eung Kweon; Lee, Jong-Young; Kim, Hyung-Lae

    2011-01-01

    Granular corneal dystrophy, type II (CGD2; Avellino corneal dystrophy) is the most common corneal dystrophy among Koreans, but its pathophysiology is still poorly understood. Many reports showed that even though the causative mutation is the same TGFBI R124H mutation, there are severe and mild phenotypes of the corneal dystrophy. We also observed the phenotype differences in our samples. For this reason, we focused our effort on the identification of unknown genetic factor related to phenotyp...

  14. A new tetragonal structure type for Li2B2C.

    Science.gov (United States)

    Pavlyuk, Volodymyr; Milashys, Viktoriya; Dmytriv, Grygoriy; Ehrenberg, Helmut

    2015-01-01

    The ternary dilithium diboron carbide, Li2B2C (tetragonal, space group P-4m2, tP10), crystallizes as a new structure type and consists of structural fragments which are typical for structures of elemental lithium and boron or binary borocarbide B13C2. The symmetries of the occupied sites are .m. and 2mm. for the B and C atoms, and -4m2 and 2mm. for the Li atoms. The coordination polyhedra around the Li atoms are cuboctahedra and 15-vertex distorted pseudo-Frank-Kasper polyhedra. The environment of the B atom is a ten-vertex polyhedron. The nearest neighbours of the C atom are two B atoms, and this group is surrounded by a deformed cuboctahedron with one centred lateral facet. Electronic structure calculations using the TB-LMTO-ASA method reveal strong B...C and B...B interactions.

  15. Myotonic dystrophy.

    Science.gov (United States)

    Thornton, Charles A

    2014-08-01

    Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over a century ago. More recently, a second form of the disease, DM type 2 was recognized, which results from repeat expansion in a different gene. Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. This article reviews the clinical presentation and pathophysiology of DM and discusses current management and future potential for developing targeted therapies.

  16. Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A.

    Science.gov (United States)

    Jaka, Oihane; Azpitarte, Margarita; Paisán-Ruiz, Coro; Zulaika, Miren; Casas-Fraile, Leire; Sanz, Raúl; Trevisiol, Nathalie; Levy, Nicolas; Bartoli, Marc; Krahn, Martin; López de Munain, Adolfo; Sáenz, Amets

    2014-09-01

    Limb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a typical LGMD2A phenotype and posterior compartment involvement on MRI. Different genetic analyses were performed, including microarray analysis. There was an apparently homozygous mutation in exon 24, c.2465G>T, p.(*822Leuext62*), and a lack of correlation in the disease segregation analyses. This suggested the presence of a genomic rearrangement. In fact, a heterozygous deletion of the entire CAPN3 gene was found. This novel deletion comprised the terminal region of the GANC gene and the entire CAPN3 gene. This finding points out the need to reconsider and adapt our current strategy of molecular diagnosis in order to detect these types of genomic rearrangements that escape standard mutation screening procedures.

  17. Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A

    Energy Technology Data Exchange (ETDEWEB)

    Speer, M.C.; Yamaoka, L.H.; Stajich, J.; Lewis, K. [and others

    1995-08-28

    The Bethlem myopathy, an autosomal-dominant myopathy, shows a distribution of proximal muscle weakness similar to that observed in dominant limb-girdle muscular dystrophy (LGMD). Yet the Bethlem myopathy differs from most limb-girdle dystrophies in two important regards. First, the Bethlem myopathy presents with joint contractures most commonly observed at the elbows, ankles, and neck. Secondly, disease onset in the Bethlem myopathy is in early childhood, while most dominant LGMDs present with adult onset. 6 refs., 1 fig.

  18. The effect of atrial preference pacing on atrial fibrillation electrophysiological substrate in Myotonic Dystrophy type 1 population

    OpenAIRE

    Russo, Vincenzo; NIGRO, GERARDO; DI MEO, FEDERICA; PAPA, ANDREA ANTONIO; CIOPPA, NADIA DELLA; PROIETTI, RICCARDO; Russo, Maria Giovanna; Calabrò, Raffaele; Politano, Luisa

    2014-01-01

    P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the poss...

  19. Muscular Dystrophy

    Science.gov (United States)

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a genetic ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most ...

  20. Muscular Dystrophy

    Science.gov (United States)

    ... Devices The Search for a Cure en español Distrofia muscular About MD Muscular dystrophy (MD) is a ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the ...

  1. Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.

    Science.gov (United States)

    Perfetti, Alessandra; Greco, Simona; Fasanaro, Pasquale; Bugiardini, Enrico; Cardani, Rosanna; Garcia-Manteiga, Jose M; Manteiga, Jose M Garcia; Riba, Michela; Cittaro, Davide; Stupka, Elia; Meola, Giovanni; Martelli, Fabio

    2014-01-01

    Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis.

  2. Validation of plasma microRNAs as biomarkers for myotonic dystrophy type 1.

    Science.gov (United States)

    Perfetti, A; Greco, S; Cardani, R; Fossati, B; Cuomo, G; Valaperta, R; Ambrogi, F; Cortese, A; Botta, A; Mignarri, A; Santoro, M; Gaetano, C; Costa, E; Dotti, M T; Silvestri, G; Massa, R; Meola, G; Martelli, F

    2016-12-01

    Non-invasive and simple to measure biomarkers are still an unmet need for myotonic dystrophy type 1 (DM1). Indeed, muscle biopsies can be extremely informative, but their invasive nature limits their application. Extracellular microRNAs are emerging humoral biomarkers and preliminary studies identified a group of miRNAs that are deregulated in the plasma or serum of small groups of DM1 patients. Here we adopted very stringent selection and normalization criteria to validate or disprove these miRNAs in 103 DM1 patients and 111 matched controls. We confirmed that 8 miRNAs out of 12 were significantly deregulated in DM1 patients: miR-1, miR-27b, miR-133a, miR-133b, miR-206, miR-140-3p, miR-454 and miR-574. The levels of these miRNAs, alone or in combination, discriminated DM1 from controls significantly, and correlated with both skeletal muscle strength and creatine kinase values. Interestingly, miR-133b levels were significantly higher in DM1 female patients. Finally, the identified miRNAs were also deregulated in the plasma of a small group (n = 30) of DM2 patients. In conclusion, this study proposes that miRNAs might be useful as DM1 humoral biomarkers.

  3. Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.

    Directory of Open Access Journals (Sweden)

    Alessandra Perfetti

    Full Text Available Myotonic dystrophy type 2 (DM2 is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR, we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis.

  4. Atrial flutter in myotonic dystrophy type 1: Patient characteristics and clinical outcome.

    Science.gov (United States)

    Wahbi, Karim; Sebag, Frederic A; Lellouche, Nicolas; Lazarus, Arnaud; Bécane, Henri-Marc; Bassez, Guillaume; Stojkovic, Tanya; Fayssoil, Abdallah; Laforêt, Pascal; Béhin, Anthony; Meune, Christophe; Eymard, Bruno; Duboc, Denis

    2016-03-01

    The prevalence and the incidence of atrial flutter in patients with myotonic dystrophy type 1 (DM1) and the most appropriate strategies for its management are unknown. We retrospectively included in the DM1 Heart Registry 929 adult patients with DM1 admitted to our Institutions between January 2000 and September 2013. We selected patients presenting with atrial flutter and analysed data relative to the occurrence of arterial thromboembolism, severe bradyarrhythmias and atrial flutter recurrences. Atrial flutter was present in 79 of the 929 patients included in our Registry, representing a 8.5% prevalence. Patients with atrial flutter were older, had a higher muscular disability rating scale score and had higher prevalence of other cardiac manifestations of DM1. Sixty patients presented with a first episode of atrial flutter, representing a 4.6% incidence. Severe bradyarrhythmias requiring permanent pacing were present in 4 patients (6.7%). Over a 53 ± 28 months mean follow-up duration, 2 patients (3.3%) had ischaemic stroke and 12 (20%) had atrial flutter recurrences. Patients who underwent radiofrequency ablation were more frequently free of atrial flutter recurrence than other patients (95 vs. 61%; HR = 0.17; P = 0.04). Atrial flutter is a common manifestation of DM1, potentially complicated by arterial thromboembolism or severe bradyarrhythmias. Radiofrequency catheter ablation is associated with a lower risk for recurrences.

  5. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

    Directory of Open Access Journals (Sweden)

    Ariadna Bargiela

    2015-07-01

    Full Text Available Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1 disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor or muscleblind, or by RNA interference (RNAi-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

  6. SCN4A mutation as modifying factor of myotonic dystrophy type 2 phenotype.

    Science.gov (United States)

    Bugiardini, E; Rivolta, I; Binda, A; Soriano Caminero, A; Cirillo, F; Cinti, A; Giovannoni, R; Botta, A; Cardani, R; Wicklund, M P; Meola, G

    2015-04-01

    In myotonic dystrophy type 2 (DM2), an association has been reported between early and severe myotonia and recessive chloride channel (CLCN1) mutations. No DM2 cases have been described with sodium channel gene (SCN4A) mutations. The aim is to describe a DM2 patient with severe and early onset myotonia and co-occurrence of a novel missense mutation in SNC4A. A 26-year-old patient complaining of hand cramps and difficulty relaxing her hands after activity was evaluated at our department. Neurophysiology and genetic analysis for DM1, DM2, CLCN1 and SCN4A mutations were performed. Genetic testing was positive for DM2 (2650 CCTG repeat) and for a variant c.215C>T (p.Pro72Leu) in the SCN4A gene. The variation affects the cytoplasmic N terminus domain of Nav1.4, where mutations have never been reported. The biophysical properties of the mutant Nav1.4 channels were evaluated by whole-cell voltage-clamp analysis of heterologously expressed mutant channel in tsA201 cells. Electrophysiological studies of the P72L variant showed a hyperpolarizing shift (-5 mV) of the voltage dependence of activation that may increase cell excitability. This case suggests that SCN4A mutations may enhance the myotonic phenotype of DM2 patients and should be screened for atypical cases with severe myotonia.

  7. Validation of plasma microRNAs as biomarkers for myotonic dystrophy type 1

    Science.gov (United States)

    Perfetti, A.; Greco, S.; Cardani, R.; Fossati, B.; Cuomo, G.; Valaperta, R.; Ambrogi, F.; Cortese, A.; Botta, A.; Mignarri, A.; Santoro, M.; Gaetano, C.; Costa, E.; Dotti, M. T.; Silvestri, G.; Massa, R.; Meola, G.; Martelli, F.

    2016-01-01

    Non-invasive and simple to measure biomarkers are still an unmet need for myotonic dystrophy type 1 (DM1). Indeed, muscle biopsies can be extremely informative, but their invasive nature limits their application. Extracellular microRNAs are emerging humoral biomarkers and preliminary studies identified a group of miRNAs that are deregulated in the plasma or serum of small groups of DM1 patients. Here we adopted very stringent selection and normalization criteria to validate or disprove these miRNAs in 103 DM1 patients and 111 matched controls. We confirmed that 8 miRNAs out of 12 were significantly deregulated in DM1 patients: miR-1, miR-27b, miR-133a, miR-133b, miR-206, miR-140-3p, miR-454 and miR-574. The levels of these miRNAs, alone or in combination, discriminated DM1 from controls significantly, and correlated with both skeletal muscle strength and creatine kinase values. Interestingly, miR-133b levels were significantly higher in DM1 female patients. Finally, the identified miRNAs were also deregulated in the plasma of a small group (n = 30) of DM2 patients. In conclusion, this study proposes that miRNAs might be useful as DM1 humoral biomarkers. PMID:27905532

  8. Small molecule kinase inhibitors alleviate different molecular features of myotonic dystrophy type 1.

    Science.gov (United States)

    Wojciechowska, Marzena; Taylor, Katarzyna; Sobczak, Krzysztof; Napierala, Marek; Krzyzosiak, Wlodzimierz J

    2014-01-01

    Expandable (CTG)n repeats in the 3' UTR of the DMPK gene are a cause of myotonic dystrophy type 1 (DM1), which leads to a toxic RNA gain-of-function disease. Mutant RNAs with expanded CUG repeats are retained in the nucleus and aggregate in discrete inclusions. These foci sequester splicing factors of the MBNL family and trigger upregulation of the CUGBP family of proteins resulting in the mis-splicing of their target transcripts. To date, many efforts to develop novel therapeutic strategies have been focused on disrupting the toxic nuclear foci and correcting aberrant alternative splicing via targeting mutant CUG repeats RNA; however, no effective treatment for DM1 is currently available. Herein, we present results of culturing of human DM1 myoblasts and fibroblasts with two small-molecule ATP-binding site-specific kinase inhibitors, C16 and C51, which resulted in the alleviation of the dominant-negative effects of CUG repeat expansion. Reversal of the DM1 molecular phenotype includes a reduction of the size and number of foci containing expanded CUG repeat transcripts, decreased steady-state levels of CUGBP1 protein, and consequent improvement of the aberrant alternative splicing of several pre-mRNAs misregulated in DM1.

  9. Brain Connectomics’ Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1

    Directory of Open Access Journals (Sweden)

    Laura Serra

    2016-01-01

    Full Text Available The adult form of myotonic dystrophy type 1 (DM1 presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients’ brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool.

  10. Characteristic MRI Findings of upper Limb Muscle Involvement in Myotonic Dystrophy Type 1.

    Directory of Open Access Journals (Sweden)

    Kazuma Sugie

    Full Text Available The objective of our study was to evaluate the relation between muscle MRI findings and upper limb weakness with grip myotonia in patients with myotonic dystrophy type 1 (DM1. Seventeen patients with DM1 were evaluated by manual muscle strength testing and muscle MRI of the upper limbs. Many DM1 patients presenting with decreased grasping power frequently showed high intensity signals in the flexor digitorum profundus (FDP muscles on T1-weighted imaging. Patients presenting with upper limb weakness frequently also showed high intensity signals in the flexor pollicis longus, abductor pollicis longus, and extensor pollicis muscles. Disturbances of the distal muscles of the upper limbs were predominant in all DM1 patients. Some DM1 patients with a prolonged disease duration showed involvement of not only distal muscles but also proximal muscles in the upper limbs. Muscle involvement of the upper limbs on MRI strongly correlated positively with the disease duration or the numbers of CTG repeats. To our knowledge, this is the first study to provide a detailed description of the distribution and severity of affected muscles of the upper limbs on MRI in patients with DM1. We conclude that muscle MRI findings are very useful for identifying affected muscles and predicting the risk of muscle weakness in the upper limbs of DM1 patients.

  11. Swallowing assessment in myotonic dystrophy type 1 using fiberoptic endoscopic evaluation of swallowing (FEES).

    Science.gov (United States)

    Pilz, Walmari; Baijens, Laura W J; Passos, Valéria Lima; Verdonschot, Rob; Wesseling, Frederik; Roodenburg, Nel; Faber, Catharina G; Kremer, Bernd

    2014-12-01

    This study describes the swallowing function of patients with myotonic dystrophy type 1 (DM1) and the effect of bolus consistency on swallowing in this group. The aim of the study is twofold: (a) to identify which (and to what extent) swallowing variables change for DM1 patients relative to healthy control subjects and (b) to examine whether the degree of oropharyngeal dysphagia is associated with disease severity. Forty-five consecutive DM1 patients and ten healthy subjects underwent a swallowing assessment, at Maastricht University medical Center in the Netherlands. The assessment included a standardized fiberoptic endoscopic evaluation of swallowing (FEES) protocol using different bolus consistencies. Clinical severity of the disease was assessed using the muscular impairment rating scale (MIRS). Significant differences were found between patients and controls for all FEES variables. The magnitude of these differences depended on the bolus consistency. The odds of a more pathological swallowing outcome increased significantly with higher MIRS levels. In conclusion, swallowing function is found to be significantly altered in DM1 patients. The results emphasize the importance of conducting a detailed swallowing assessment in all patients, even those with mild muscle weakness.

  12. Rationally designed small molecules that target both the DNA and RNA causing myotonic dystrophy type 1.

    Science.gov (United States)

    Nguyen, Lien; Luu, Long M; Peng, Shaohong; Serrano, Julio F; Chan, H Y Edwin; Zimmerman, Steven C

    2015-11-11

    Single-agent, single-target therapeutic approaches are often limited by a complex disease pathobiology. We report rationally designed, multi-target agents for myotonic dystrophy type 1 (DM1). DM1 originates in an abnormal expansion of CTG repeats (CTG(exp)) in the DMPK gene. The resultant expanded CUG transcript (CUG(exp)) identified as a toxic agent sequesters important proteins, such as muscleblind-like proteins (MBNL), undergoes repeat-associated non-ATG (RAN) translation, and potentially causes microRNA dysregulation. We report rationally designed small molecules that target the DM1 pathobiology in vitro in three distinct ways by acting simultaneously as transcription inhibitors, by inhibiting aberrant protein binding to the toxic RNA, and by acting as RNase mimics to degrade the toxic RNA. In vitro, the agents are shown to (1) bind CTG(exp) and inhibit formation of the CUG(exp) transcript, (2) bind CUG(exp) and inhibit sequestration of MBNL1, and (3) cleave CUG(exp) in an RNase-like manner. The most potent compounds are capable of reducing the levels of CUG(exp) in DM1 model cells, and one reverses two separate CUG(exp)-induced phenotypes in a DM1 Drosophila model.

  13. Altered Ca2+ Homeostasis and Endoplasmic Reticulum Stress in Myotonic Dystrophy Type 1 Muscle Cells

    Directory of Open Access Journals (Sweden)

    Gyorgy Szabadkai

    2013-06-01

    Full Text Available The pathogenesis of Myotonic Dystrophy type 1 (DM1 is linked to unstable CTG repeats in the DMPK gene which induce the mis-splicing to fetal/neonatal isoforms of many transcripts, including those involved in cellular Ca2+ homeostasis. Here we monitored the splicing of three genes encoding for Ca2+ transporters and channels (RyR1, SERCA1 and CACN1S during maturation of primary DM1 muscle cells in parallel with the functionality of the Excitation-Contraction (EC coupling machinery. At 15 days of differentiation, fetal isoforms of SERCA1 and CACN1S mRNA were significantly higher in DM1 myotubes compared to controls. Parallel functional studies showed that the cytosolic Ca2+ response to depolarization in DM1 myotubes did not increase during the progression of differentiation, in contrast to control myotubes. While we observed no differences in the size of intracellular Ca2+ stores, DM1 myotubes showed significantly reduced RyR1 protein levels, uncoupling between the segregated ER/SR Ca2+ store and the voltage-induced Ca2+ release machinery, parallel with induction of endoplasmic reticulum (ER stress markers. In conclusion, our data suggest that perturbed Ca2+ homeostasis, via activation of ER stress, contributes to muscle degeneration in DM1 muscle cells likely representing a premature senescence phenotype.

  14. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.

    Science.gov (United States)

    Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M; Vilchez, Juan J; Llamusi, Beatriz; Artero, Ruben

    2015-07-01

    Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

  15. Overweight Is an Independent Risk Factor for Reduced Lung Volumes in Myotonic Dystrophy Type 1.

    Directory of Open Access Journals (Sweden)

    Charlotte G W Seijger

    Full Text Available In this large observational study population of 105 myotonic dystrophy type 1 (DM1 patients, we investigate whether bodyweight is a contributor of total lung capacity (TLC independent of the impaired inspiratory muscle strength.Body composition was assessed using the combination of body mass index (BMI and fat-free mass index. Pulmonary function tests and respiratory muscle strength measurements were performed on the same day. Patients were stratified into normal (BMI < 25 kg/m(2 and overweight (BMI ≥ 25 kg/m(2 groups. Multiple linear regression was used to find significant contributors for TLC.Overweight was present in 59% of patients, and body composition was abnormal in almost all patients. In overweight patients, TLC was significantly (p = 2.40×10(-3 decreased, compared with normal-weight patients, while inspiratory muscle strength was similar in both groups. The decrease in TLC in overweight patients was mainly due to a decrease in expiratory reserve volume (ERV further illustrated by a highly significant (p = 1.33×10(-10 correlation between BMI and ERV. Multiple linear regression showed that TLC can be predicted using only BMI and the forced inspiratory volume in 1 second, as these were the only significant contributors.This study shows that, in DM1 patients, overweight further reduces lung volumes, as does impaired inspiratory muscle strength. Additionally, body composition is abnormal in almost all DM1 patients.

  16. Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion

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    Stefan Winblad

    2009-04-01

    Full Text Available We investigated the ability of patients with myotonic dystrophy type 1 to recognise basic facial emotions. We also explored the relationship between facial emotion recognition, neuropsychological data, personality, and CTG repeat expansion data in the DM-1 group. In total, 50 patients with DM-1 (28 women and 22 men participated, with 41 healthy controls. Recognition of facial emotional expressions was assessed using photographs of basic emotions. A set of tests measured cognition and personality dimensions, and CTG repeat size was quantified in blood lymphocytes. Patients with DM-1 showed impaired recognition of facial emotions compared with controls. A significant negative correlation was found between total score of emotion recognition in a forced choice task and CTG repeat size. Furthermore, specific cognitive functions (vocabulary, visuospatial construction ability, and speed and personality dimensions (reward dependence and cooperativeness correlated with scores on the forced choice emotion recognition task.These findings revealed a CTG repeat dependent facial emotion recognition deficit in the DM-1 group, which was associated with specific neuropsychological functions. Furthermore, a correlation was found between facial emotional recognition ability and personality dimensions associated with sociability. This adds a new clinically relevant dimension in the cognitive deficits associated with DM-1.

  17. Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers.

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    Juan M Fernandez-Costa

    Full Text Available Myotonic dystrophy type 1 (DM1 is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3' untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need. Looking for a novel biomarker, and given that specific miRNAs have been found to be misregulated in DM1 heart and muscle tissues, we profiled the expression of 175 known serum miRNAs in DM1 samples. The differences detected between patients and controls were less than 2.6 fold for all of them and a selection of six candidate miRNAs, miR-103, miR-107, miR-21, miR-29a, miR-30c, and miR-652 all failed to show consistent differences in serum expression in subsequent validation experiments.

  18. Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers.

    Science.gov (United States)

    Fernandez-Costa, Juan M; Llamusi, Beatriz; Bargiela, Ariadna; Zulaica, Miren; Alvarez-Abril, M Carmen; Perez-Alonso, Manuel; Lopez de Munain, Adolfo; Lopez-Castel, Arturo; Artero, Ruben

    2016-01-01

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3' untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need. Looking for a novel biomarker, and given that specific miRNAs have been found to be misregulated in DM1 heart and muscle tissues, we profiled the expression of 175 known serum miRNAs in DM1 samples. The differences detected between patients and controls were less than 2.6 fold for all of them and a selection of six candidate miRNAs, miR-103, miR-107, miR-21, miR-29a, miR-30c, and miR-652 all failed to show consistent differences in serum expression in subsequent validation experiments.

  19. Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1.

    Science.gov (United States)

    Esposito, Fabio; Cè, Emiliano; Rampichini, Susanna; Limonta, Eloisa; Venturelli, Massimo; Monti, Elena; Bet, Luciano; Fossati, Barbara; Meola, Giovanni

    2016-01-01

    The electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Component duration and measurement reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n = 13) and in healthy controls (n = 13). EMG, mechanomyogram, and force were recorded in DM1 and in age- and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles. Measurement reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.

  20. Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing.

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    Hernández-Hernández, Oscar; Sicot, Géraldine; Dinca, Diana M; Huguet, Aline; Nicole, Annie; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-01-01

    The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.

  1. Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity.

    Science.gov (United States)

    Childs-Disney, Jessica L; Yildirim, Ilyas; Park, HaJeung; Lohman, Jeremy R; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C; Disney, Matthew D

    2014-02-21

    Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)(exp)) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5'CCUG/3'GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 Å. Structural analysis of the three 5'CCUG/3'GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na(+) and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5'CCUG/3'GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops.

  2. Six Serum miRNAs Fail to Validate as Myotonic Dystrophy Type 1 Biomarkers

    Science.gov (United States)

    Fernandez-Costa, Juan M.; Llamusi, Beatriz; Bargiela, Ariadna; Zulaica, Miren; Alvarez-Abril, M. Carmen; Perez-Alonso, Manuel; Lopez de Munain, Adolfo

    2016-01-01

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic disease caused by expansion of a CTG microsatellite in the 3’ untranslated region of the DMPK gene. Despite characteristic muscular, cardiac, and neuropsychological symptoms, CTG trinucleotide repeats are unstable both in the somatic and germinal lines, making the age of onset, clinical presentation, and disease severity very variable. A molecular biomarker to stratify patients and to follow disease progression is, thus, an unmet medical need. Looking for a novel biomarker, and given that specific miRNAs have been found to be misregulated in DM1 heart and muscle tissues, we profiled the expression of 175 known serum miRNAs in DM1 samples. The differences detected between patients and controls were less than 2.6 fold for all of them and a selection of six candidate miRNAs, miR-103, miR-107, miR-21, miR-29a, miR-30c, and miR-652 all failed to show consistent differences in serum expression in subsequent validation experiments. PMID:26919350

  3. Duchenne's/Becker's muscular dystrophy: Analysis of genotype-feno-type correlation in 28 patients

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    Keckarević Milica

    2002-01-01

    Full Text Available Duchenne's and Becker's muscular dystrophy (DMD & BMD is a X linked disease caused by mutations in the dystrophic gene. DMD is the malign form of the disease, which significantly shortens the lifetime of the patient, while BMD has late onset with slow progression. Sixty five percent of DMD and BMD cases are caused by deletion of one or more exons in the dystrophic gene, while duplications cause these diseases in 6 to 7% of the cases. There are two hot spots for deletions and duplications. These are exons in the proximal part of the gene (3rd to 18th and exons of a distal part of the gene (45th to 52nd. The remaining 30% of DMD and BMD cases are caused by point mutations, small deletions or inversions in the dystrophic gene. The correlation between School of Medicine, University of Belgrade, Belgrade the severity of the disease and the position of deletion shows that most of the out of frame deletions cause DMD phenotype, while in frame deletions result in BMD pheno-type. We report on the results of 28 non-related DMD and BMD patients. In 57% of cases deletions were detected and all were found in the distal hot spot of the gene. These results suggest that in most of the cases, out of frame deletions produce DMD phenotype while in frame deletions result in BMD phenotype. This is in compliance with data from literature.

  4. How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1

    Science.gov (United States)

    Serra, Laura; Petrucci, Antonio; Spanò, Barbara; Torso, Mario; Olivito, Giusy; Lispi, Ludovico; Costanzi-Porrini, Sandro; Giulietti, Giovanni; Koch, Giacomo; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2015-01-01

    Summary Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tract-based spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1 mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1. PMID:26214024

  5. Brain Connectomics' Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1

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    Serra, Laura; Mancini, Matteo; Silvestri, Gabriella; Petrucci, Antonio; Masciullo, Marcella; Spanò, Barbara; Torso, Mario; Mastropasqua, Chiara; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Meola, Giovanni; Bozzali, Marco

    2016-01-01

    The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool. PMID:27313901

  6. Structural and functional cardiac changes in myotonic dystrophy type 1: a cardiovascular magnetic resonance study

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    Hermans Mieke CE

    2012-07-01

    Full Text Available Abstract Background Myotonic dystrophy type 1 (MD1 is a neuromuscular disorder with potential involvement of the heart and increased risk of sudden death. Considering the importance of cardiomyopathy as a predictor of prognosis, we aimed to systematically evaluate and describe structural and functional cardiac alterations in patients with MD1. Methods Eighty MD1 patients underwent physical examination, electrocardiography (ECG, echocardiography and cardiovascular magnetic resonance (CMR. Blood samples were taken for determination of NT-proBNP plasma levels and CTG repeat length. Results Functional and structural abnormalities were detected in 35 patients (44%. Left ventricular systolic dysfunction was found in 20 cases, left ventricular dilatation in 7 patients, and left ventricular hypertrophy in 6 patients. Myocardial fibrosis was seen in 10 patients (12.5%. In general, patients had low left ventricular mass indexes. Right ventricular involvement was uncommon and only seen together with left ventricular abnormalities. Functional or structural cardiac involvement was associated with age (p = 0.04, male gender (p Conclusions CMR can be useful to detect early structural and functional myocardial abnormalities in patients with MD1. Myocardial involvement is strongly associated with conduction abnormalities, but a normal ECG does not exclude myocardial alterations. These findings lend support to the hypothesis that MD1 patients have a complex cardiac phenotype, including both myocardial and conduction system alteration.

  7. Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies.

    Science.gov (United States)

    Bachinski, Linda L; Baggerly, Keith A; Neubauer, Valerie L; Nixon, Tamara J; Raheem, Olayinka; Sirito, Mario; Unruh, Anna K; Zhang, Jiexin; Nagarajan, Lalitha; Timchenko, Lubov T; Bassez, Guillaume; Eymard, Bruno; Gamez, Josep; Ashizawa, Tetsuo; Mendell, Jerry R; Udd, Bjarne; Krahe, Ralf

    2014-03-01

    The prevailing pathomechanistic paradigm for myotonic dystrophy (DM) is that aberrant expression of embryonic/fetal mRNA/protein isoforms accounts for most aspects of the pleiotropic phenotype. To identify aberrant isoforms in skeletal muscle of DM1 and DM2 patients, we performed exon-array profiling and RT-PCR validation on the largest DM sample set to date, including Duchenne, Becker and tibial muscular dystrophy (NMD) patients as disease controls, and non-disease controls. Strikingly, most expression and splicing changes in DM patients were shared with NMD controls. Comparison between DM and NMD identified almost no significant differences. We conclude that DM1 and DM2 are essentially identical for dysregulation of gene expression, and DM expression changes represent a subset of broader spectrum dystrophic changes. We found no evidence for qualitative splicing differences between DM1 and DM2. While some DM-specific splicing differences exist, most of the DM splicing differences were also seen in NMD controls. SSBP3 exon 6 missplicing was observed in all diseased muscle and led to reduced protein. We conclude there is no widespread DM-specific spliceopathy in skeletal muscle and suggest that missplicing in DM (and NMD) may not be the driving mechanism for the muscle pathology, since the same pathways show expression changes unrelated to splicing.

  8. Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing.

    Science.gov (United States)

    Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E; Luebbe, Elizabeth A; Moxley, Richard T; Toji, Lorraine

    2013-07-01

    Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing.

  9. Frontostriatal dysexecutive syndrome: a core cognitive feature of myotonic dystrophy type 2.

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    Peric, Stojan; Mandic-Stojmenovic, Gorana; Stefanova, Elka; Savic-Pavicevic, Dusanka; Pesovic, Jovan; Ilic, Vera; Dobricic, Valerija; Basta, Ivana; Lavrnic, Dragana; Rakocevic-Stojanovic, Vidosava

    2015-01-01

    The aim of this study was to assess cognitive status in a large group of patients with myotonic dystrophy type 2 (DM2) compared to type 1 (DM1) subjects matched for gender and age, using a comprehensive battery of neuropsychological tests. Thirty-four genetically confirmed adult DM2 patients were recruited and matched for gender and age with 34 adult-onset DM1 subjects. All patients underwent detailed classic pen and pencil neuropsychological investigation and also computerized automated battery-CANTAB. More than half of DM2 patients had abnormal results on executive tests [Intra/Extradimensional Set Shift (IED), Stockings of Cambridge (SOC)] and verbal episodic memory (Ray Auditory Verbal Learning Test). Regarding DM1, abnormal results in more than 50 % of subjects were achieved in even ten tests, including visuospatial, language, executive, cognitive screening and visual memory tests. Direct comparison between patient groups showed that lower percentage of DM2 patients had abnormal results on following tests: Addenbrooke's Cognitive Examination-Revised, Raven Standard Progressive Matrices, Block Design, copy and recall of Rey-Osterieth Complex Figure, number of categories and perseverative responses on Wisconsin Card Sorting Test and Boston Naming Test (p < 0.01), as well as Trail Making Test-B and Spatial Span (p < 0.05). Our results showed significant dysexecutive syndrome and certain impairment of episodic verbal memory in DM2 patients that are reflective of frontal (especially frontostriatal) and temporal lobe dysfunction. On the other hand, dysexecutive and visuospatial/visuoconstructional deficits predominate in DM1 which correspond to the frontal, parietal (and occipital) lobe dysfunction.

  10. Ullrich Congenital Muscular Dystrophy

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    Goknur Haliloglu

    2011-09-01

    Full Text Available ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenitalmuscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in theWestern world mostly seen with de novo dominant mutations in the collagenVI genes. Milder form of the condition is the Bethlem myopathy. There may beoverlap forms in the clinic resembling the Ehler-Danlos syndrome. There hasbeen some radical efforts for cure especially through the apoptosis cascades.Key words: Ullrich congenital muscular dystrophy, collgen VI genes, Bethlemmyopathy, autophagy.

  11. Canine parvovirus types 2c and 2b circulating in North American dogs in 2006 and 2007.

    Science.gov (United States)

    Kapil, Sanjay; Cooper, Emily; Lamm, Cathy; Murray, Brandy; Rezabek, Grant; Johnston, Larry; Campbell, Gregory; Johnson, Bill

    2007-12-01

    Parvovirus is the most common viral cause of diarrhea in young puppies. Based on the analysis of a partial VP2 sequence of 54 samples, canine parvovirus type 2c (CPV-2c) (n = 26), CPV-2b (n = 25), and CPV-2 (n = 3) were detected in the United States. The American CPV-2b isolates have unique codons (494 and 572) in VP2.

  12. Plasma microRNAs as biomarkers for myotonic dystrophy type 1.

    Science.gov (United States)

    Perfetti, Alessandra; Greco, Simona; Bugiardini, Enrico; Cardani, Rosanna; Gaia, Paola; Gaetano, Carlo; Meola, Giovanni; Martelli, Fabio

    2014-06-01

    Myotonic dystrophy type 1 (DM1) lacks non-invasive and easy to measure biomarkers, still largely relying on semi-quantitative tests for diagnostic and prognostic purposes. Muscle biopsies provide valuable data, but their use is limited by their invasiveness. microRNA (miRNAs) are small non-coding RNAs regulating gene expression that are also present in biological fluids and may serve as diseases biomarkers. Thus, we tested plasma miRNAs in the blood of 36 DM1 patients and 36 controls. First, a wide miRNA panel was profiled in a patient subset, followed by validation using all recruited subjects. We identified a signature of nine deregulated miRNAs in DM1 patients: eight miRNAs were increased (miR-133a, miR-193b, miR-191, miR-140-3p, miR-454, miR-574, miR-885-5p, miR-886-3p) and one (miR-27b) was decreased. Next, the levels of these miRNAs were used to calculate a "DM1-miRNAs score". We found that both miR-133a levels and DM1-miRNAs score discriminated DM1 from controls significantly and Receiver-Operator Characteristic curves displayed an area under the curve of 0.94 and 0.97, respectively. Interestingly, both miR-133a levels and DM1-miRNAs score displayed an inverse correlation with skeletal muscle strength and displayed higher values in more compromised patients. In conclusion, we identified a characteristic plasma miRNA signature of DM1. Although preliminary, this study indicates miRNAs as potential DM1 humoral biomarkers. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Progression of muscle histopathology but not of spliceopathy in myotonic dystrophy type 2.

    Science.gov (United States)

    Cardani, Rosanna; Giagnacovo, Marzia; Rossi, Giulia; Renna, Laura V; Bugiardini, Enrico; Pizzamiglio, Chiara; Botta, Annalisa; Meola, Giovanni

    2014-12-01

    Myotonic dystrophy type 2 (DM2) is an autosomal dominant progressive disease involving skeletal and cardiac muscle and brain. It is caused by a tetranucleotide repeat within the first intron of the CNBP gene that leads to an alteration of the alternative splicing of several genes. To understand the molecular mechanisms that play a role in DM2 progression, the evolution of skeletal muscle histopathology and biomolecular findings in successive biopsies have been studied. Biceps brachii biopsies from 5 DM2 patients who underwent two successive biopsies at different years of age have been used. Muscle histopathology has been assessed on sections immunostained with fast or slow myosin. FISH in combination with MBNL1-immunofluorescence has been performed to evaluate ribonuclear inclusion and MBNL1 foci dimensions in myonuclei. Gene and protein expression and alteration of alternative splicing of several genes have been evaluated over time. All DM2 patients examined show a worsening of muscle histopathology and an increase of foci dimensions over time. The progressive worsening of myotonia in DM2 patients may be due to the decrease of CLCN1 mRNA observed in all patients examined. However, a worsening of alternative splicing alterations has not been evidenced over time. The data obtained in this study confirm that DM2 is a slow progression disease since histological and biomolecular alterations observed in skeletal muscle are minimal even after 10-year interval. The data indicate that muscle morphological alterations evolve more rapidly over time than the molecular changes thus indicating that muscle biopsy is a more sensitive tool than biomolecular markers to assess disease progression at muscle level.

  14. Detection of large expansions in myotonic dystrophy type 1 using triplet primed PCR

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    Susmita eSingh

    2014-04-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is an autosomal dominant neuromuscular disease caused by expansion of a CTG trinucleotide repeat in the DMPK gene. Methodology for genetic testing of DM1 is currently not optimal, in particular for the early-onset patients in pediatric populations where large expanded (CTGn alleles are usually common. Individuals who are homozygous for a normal allele and individuals who are heterozygous for one normal and one large expanded allele are indistinguishable by conventional PCR, as both generate a single product of the normal allele. Thus, reflex Southern blot has often been needed to distinguish these cases. With the aim to decrease the need for reflex Southern blot tests, a novel, single-tube CTG repeat primed PCR technology was designed to distinguish the true homozygous patients from the individuals whose large alleles are missed by conventional PCR. The method utilizes two gene-specific primers that flank the triplet repeat region and a third primer set complementary to the repeated region to detect the large alleles. Compared to traditional PCR, this novel Triplet-repeat Primed PCR can detect the presence of large expanded alleles with demonstrating a ladder pattern. Using this single-step protocol, 45 specimens were tested. The alleles with sizes ≤ 85 repeats were determined by the gene specific primers. 13 abnormal alleles, which missed by the conventional PCR, were successfully detected by the Triplet-repeat Primed PCR. All the abnormal alleles were confirmed and measured by Southern Blot analysis. In summary, optimized TP-PCR can accurately detect the presence of the large expanded alleles. With the ability to distinguish the true homozygous patients from the false negative homozygous individuals, the application of the optimized TP-PCR can significantly reduce the need of Southern Blot tests.

  15. Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

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    Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

    2012-05-18

    RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence.

  16. Epidemiology of myotonic dystrophy type 1 in the population of central Serbia

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    Mladenović Jelena

    2005-01-01

    Full Text Available The objective of this epidemiological survey was to estimate the frequency and distribution of Myotonic dystrophy type 1 (MD1 (Steinert's disease in central Serbia, during the period 1983-2002. The data on the number of diagnosed MD1 patients were obtained using the analysis of hospital records, which were examined in all the relevant neurological institutions in central Serbia in the mentioned period. Incidence rate and prevalence were used for the data analysis. In the study period in central Serbia, 154 patients (78 males and 76 females with MD1 were identified. The average annual incidence rate of MD1 was 1.3 (95% CI-confidence interval 0.1-7.2 per 1,000,000 population, 1.4/1,000,000 (95% CI 0.1-7.2 for males, 1.3/1,000,000 (95% CI 0.1-7.2 for females. The trend of MD1 incidence rates in the observed period in central Serbia had a tendency of the statistically significant decrease, according to the linear model, in both male (y=0.205-0.0066x, p=0.021 and female populations (y = 0.1788-0.0048×, p = 0.032. The prevalence of MD1 on December 31, 2002 in central Serbia was 3.8/100,000 (95% IP 3.2-4.6, 3.7/100,000 (95% IP 3.3-4.8 for males, 3.3/100,000 (95% IP 3.0-4.4 for females.

  17. Bietti's Crystalline Dystrophy

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    ... Dystrophy > Facts About Bietti's Crystalline Dystrophy Facts About Bietti's Crystalline Dystrophy This information was developed by the ... is the best person to answer specific questions. Bietti’s Crystalline Dystrophy Defined What is Bietti’s Crystalline Dystrophy? ...

  18. Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing.

    Science.gov (United States)

    Dhaenens, C M; Tran, H; Frandemiche, M-L; Carpentier, C; Schraen-Maschke, S; Sistiaga, A; Goicoechea, M; Eddarkaoui, S; Van Brussels, E; Obriot, H; Labudeck, A; Gevaert, M H; Fernandez-Gomez, F; Charlet-Berguerand, N; Deramecourt, V; Maurage, C A; Buée, L; Lopez de Munain, A; Sablonnière, B; Caillet-Boudin, M L; Sergeant, N

    2011-07-01

    Tau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type 1. In myotonic dystrophy type 1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the ribonucleic acid level is a major etiological factor responsible for the mis-splicing of several transcripts in myotonic dystrophy type 1. These are probably the consequence of a loss of muscleblind-like 1 (MBNL1) function or gain of CUGBP1 and ETR3-like factor 1 (CELF1) splicing function. Whether these two dysfunctions occur together or separately and whether all mis-splicing events in myotonic dystrophy type 1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of myotonic dystrophy type 1 patients. Two myotonic dystrophy type 1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all myotonic dystrophy type 1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1), CUGBP1 and ETR3-like factor 2 (CELF2), and CUGBP1 and ETR3-like factor 4 (CELF4) or a dominant-negative CUGBP1 and ETR-3 like factor (CELF) factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CUGBP1 and ETR3-like factor 2 (CELF2) whereas it is insensitive to the loss-of-function of muscleblind-like 1 (MBNL1), CUGBP1 and ETR3-like factor 1 (CELF1) gain-of-function, or a dominant-negative of CUGBP1 and ETR-3 like factor (CELF) factor. Moreover, we observed an increased expression of CUGBP1 and ETR3-like factor 2 (CELF2) only in the brain of myotonic dystrophy type 1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a

  19. Ullrich Congenital Muscular Dystrophy

    OpenAIRE

    2011-01-01

    ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenitalmuscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in theWestern world mostly seen with de novo dominant mutations in the collagenVI genes. Milder form of the condition is the Bethlem myopathy. There may beoverlap forms in the clinic resembling the Ehler-Danlos syndrome. There hasbeen some radical efforts for cure espe...

  20. A Case of Transforming Growth Factor-β-Induced Gene-Related Oculorenal Syndrome: Granular Corneal Dystrophy Type II with a Unique Nephropathy

    Science.gov (United States)

    Iwafuchi, Yoichi; Morioka, Tetsuo; Oyama, Yuko; Nozu, Kandai; Iijima, Kazumoto; Narita, Ichiei

    2016-01-01

    Many types of inherited renal diseases have ocular features that occasionally support a diagnosis. The following study describes an unusual example of a 40-year-old woman with granular corneal dystrophy type II complicated by renal involvement. These two conditions may coincidentally coexist; however, there are some reports that demonstrate an association between renal involvement and granular corneal dystrophy type II. Granular corneal dystrophy type II is caused by a mutation in the transforming growth factor-β-induced (TGFBI) gene. The patient was referred to us because of the presence of mild proteinuria without hematuria that was subsequently suggested to be granular corneal dystrophy type II. A kidney biopsy revealed various glomerular and tubular basement membrane changes and widening of the subendothelial space of the glomerular basement membrane by electron microscopy. However, next-generation sequencing revealed that she had no mutation in a gene that is known to be associated with monogenic kidney diseases. Conversely, real-time polymerase chain reaction, using a simple buccal swab, revealed TGFBI heteromutation (R124H). The TGFBI protein plays an important role in cell-collagen signaling interactions, including extracellular matrix proteins which compose the renal basement membrane. This mutation can present not only as corneal dystrophy but also as renal disease. TGFBI-related oculorenal syndrome may have been unrecognized. It is difficult to diagnose this condition without renal electron microscopic studies. To the best of our knowledge, this is the first detailed report of nephropathy associated with a TGFBI mutation.

  1. A low absolute number of expanded transcripts is involved in myotonic dystrophy type 1 manifestation in muscle

    OpenAIRE

    Gudde, Anke E. E. G.; González-Barriga, Anchel; van den Broek, Walther J. A. A.; Wieringa, Bé; Wansink, Derick G

    2016-01-01

    Muscular manifestation of myotonic dystrophy type 1 (DM1), a common inheritable degenerative multisystem disorder, is mainly caused by expression of RNA from a (CTG·CAG) n -expanded DM1 locus. Here, we report on comparative profiling of expression of normal and expanded endogenous or transgenic transcripts in skeletal muscle cells and biopsies from DM1 mouse models and patients in order to help us in understanding the role of this RNA-mediated toxicity. In tissue of HSA LR mice, the most inte...

  2. Limb-girdle muscular dystrophy type 2A resulting from homozygous G2338C transversion mutation in the calpain-3 gene.

    Science.gov (United States)

    Peddareddygari, Leema Reddy; Surgan, Victoria; Grewal, Raji P

    2010-12-01

    Limb-girdle muscular dystrophy represents a clinically and genetically heterogeneous group of myopathies. Limb-girdle muscular dystrophy Type 2A, which is transmitted in an autosomal-recessive pattern, is caused by mutations in the calpain-3 (CAPN3) gene. A number of mutations have been reported in patients from throughout the world but not in the Asian-Indian population. We describe a genotype/phenotype analysis of an Asian-Indian patient with a history, neurologic examination, and investigations consistent with muscular dystrophy. Genetic analysis of this patient showed a homozygous G2338C transversion resulting in an amino acid change from aspartic acid 780 histidine in the CAPN3 gene confirming Limb-girdle muscular dystrophy Type 2A. Subsequent testing of the patient's family revealed that his parents and sister were heterozygous unaffected carriers. The G2338C transversion was detected as a compound heterozygous mutation in one patient in Germany. We report a homozygous case and expand the clinical spectrum of limb-girdle muscular dystrophy Type 2A to include Asian-Indians.

  3. Limb-girdle type muscular dystrophy%肢带型肌营养不良症

    Institute of Scientific and Technical Information of China (English)

    赵重波

    2006-01-01

    @@ 肌营养不良症(muscular dystrophy,MD)是一组与遗传有关的肌纤维变性和坏死疾病,主要临床特征为进行性肌肉无力和萎缩.一般为临床医生所熟知的是Duchenne/Becker型MD、面肩肱型MD、眼咽肌型MD,但在实践过程中常会碰到不符合上述类型的以肩胛带和骨盆带肌不同程度无力或萎缩为主要特点的MD,多笼统称为肢带型肌营养不良症(limb-girdle muscular dystrophy,LGMD).

  4. Orthopaedic Disorders in Myotonic Dystrophy Type 1: descriptive clinical study of 21 patients.

    Science.gov (United States)

    Schilling, Lisa; Forst, Raimund; Forst, Jürgen; Fujak, Albert

    2013-12-01

    Myotonic Dystrophy Type 1 (DM1) is the most common form of hereditary myopathy presenting in adults. This autosomal-dominant systemic disorder is caused by a CTG repeat, demonstrating various symptoms. A mild, classic and congenital form can be distinguished. Often the quality of life is reduced by orthopaedic problems, such as muscle weakness, contractures, foot or spinal deformities, which limit patients' mobility.The aim of our study was to gather information about the orthopaedic impairments in patients with DM1 in order to improve the medical care of patients, affected by this rare disease. A retrospective clinical study was carried out including 21 patients (11 male and 10 female), all diagnosed with DM1 by genetic testing. All patients were seen during our special consultations for neuromuscular diseases, during which patients were interviewed and examined. We also reviewed surgery reports of our hospitalized patients. We observed several orthopaedic impairments: spinal deformities (scoliosis, hyperkyphosis, rigid spine), contractures (of the upper extremities and the lower extremities), foot deformities (equinus deformity, club foot, pes cavus, pes planovalgus, pes cavovarus, claw toes) and fractures.Five patients were affected by pulmonary diseases (obstructive airway diseases, restrictive lung dysfunctions). Twelve patients were affected by cardiac disorders (congenital heart defects, valvular heart defects, conduction disturbances, pulmonary hypertension, cardiomyopathy).Our patients received conservative therapy (physiotherapy, logopaedic therapy, ergotherapy) and we prescribed orthopaedic technical devices (orthopaedic custom-made shoes, insoles, lower and upper leg orthoses, wheelchair, Rehab Buggy). We performed surgery for spinal and foot deformities: the scoliosis of one patient was stabilized and seven patients underwent surgery for correction of foot deformities. An orthopaedic involvement in DM1 patients should not be underestimated. The most

  5. Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients

    Directory of Open Access Journals (Sweden)

    Angelini Corrado

    2010-05-01

    Full Text Available Abstract Background MicroRNAs are highly conserved, noncoding RNAs involved in post-transcriptional gene silencing. They have been shown to participate in a wide range of biological processes, including myogenesis and muscle regeneration. The goal of this study is to test the hypothesis that myo-miRs (myo = muscle + miR = miRNA expression is altered in muscle from patients affected by myotonic dystrophy type 1 (DM1, the most frequently inherited neuromuscular disease in adults. In order to gain better insights about the role of miRNAs in the DM1 pathogenesis, we have also analyzed the muscular expression of miR-103 and miR-107, which have been identified in silico as attractive candidates for binding to the DMPK mRNA. Methods To this aim, we have profiled the expression of miR-133 (miR-133a, miR-133b, miR-1, miR-181 (miR-181a, miR-181b, miR-181c and miR-206, that are specifically induced during myogenesis in cardiac and skeletal muscle tissues. miR-103 and miR-107, highly expressed in brain, heart and muscle have also been included in this study. QRT-PCR experiments have been performed on RNA from vastus lateralis biopsies of DM1 patients (n = 7 and control subjects (n = 4. Results of miRNAs expression have been confirmed by Northern blot, whereas in situ hybridization technique have been performed to localize misexpressed miRNAs on muscle sections from DM1 and control individuals. Results Only miR-206 showed an over-expression in 5 of 7 DM1 patients (threshold = 2, fold change between 1.20 and 13.22, average = 5.37 compared to the control group. This result has been further confirmed by Northern blot analysis (3.37-fold overexpression, R2 = 0.89. In situ hybridization localized miR-206 to nuclear site both in normal and DM1 tissues. Cellular distribution in DM1 tissues includes also the nuclear regions of centralized nuclei, with a strong signal corresponding to nuclear clumps. Conclusions This work provides, for the first time, evidences about

  6. Muscular Dystrophy

    Science.gov (United States)

    ... muscular dystrophy. It's important to be vaccinated for pneumonia and to keep up to date with influenza shots. Dietary changes haven't been shown to slow the progression of muscular dystrophy. But proper nutrition is essential because limited mobility can contribute to ...

  7. Vaccination with canine parvovirus type 2 (CPV-2) protects against challenge with virulent CPV-2b and CPV-2c.

    Science.gov (United States)

    Siedek, Elisabeth M; Schmidt, Holger; Sture, Gordon H; Raue, Rüdiger

    2011-01-01

    Mutations in canine parvovirus (CPV) field isolates have created concerns regarding the ability of vaccines containing CPV-2 to protect against infection with the newly identified antigenic types CPV-2b and CPV-2c. To address this concern, the efficacy of CPV-2 strain NL-35-D currently in use as a commercial vaccine was demonstrated against an oral challenge with CPV-2b and CPV-2c, respectively. Clinically healthy specific pathogen free Beagle dogs were either vaccinated or treated with water for injection first at 8-9 weeks of age and again at 11-12 weeks of age. All dogs were challenged either with CPV-2b or CPV-2c three weeks after the second vaccination. During the two week period following challenge, clinical signs, white blood cell counts, serology by haemagglutination inhibition (HI) and serum neutralisation tests, and virus shedding by haemagglutination test were assessed. All control dogs developed clinical signs of parvovirosis (including pyrexia and leucopenia) and shed virus. Vaccinated dogs seroconverted (HI titres > or =80), remained healthy throughout the study and shed more than 100 times less virus than controls. In conclusion, vaccination with the low passage, high titre CPV-2 strain NL-35-D cross-protects dogs against virulent challenges with CPV-2b or CPV-2c by preventing disease and substantially reducing viral shedding.

  8. Protein turnover and cellular stress in mildly and severely affected muscles from patients with limb girdle muscular dystrophy type 2I

    DEFF Research Database (Denmark)

    Hauerslev, Simon; Sveen, Marie-Louise; Vissing, John;

    2013-01-01

    Patients with Limb girdle muscular dystrophy type 2I (LGMD2I) are characterized by progressive muscle weakness and wasting primarily in the proximal muscles, while distal muscles often are spared. Our aim was to investigate if wasting could be caused by impaired regeneration in the proximal...

  9. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...

  10. Vaccination of dogs with Duramune DAPPi+LC protects against pathogenic canine parvovirus type 2c challenge.

    Science.gov (United States)

    Wilson, S; Stirling, C; Borowski, S; Thomas, A; King, V; Salt, J

    2013-06-22

    In this study, we determined whether vaccination with Duramune DAPPi+LC containing canine parvovirus (CPV) type 2b protects against challenge with virulent CPV antigenic type 2c. Seven healthy dogs, seronegative for CPV2, were enrolled into two treatment groups; five were vaccinated twice, 21 days apart, with minimum titre vaccine, and two were given saline. Dogs were challenged with CPV 2c three weeks later. Clinical observations, body weight and rectal temperature measurements, blood samples for serology and white blood cell counts and faecal samples for virus excretion were collected. Control dogs remained seronegative until challenge; vaccinated dogs seroconverted and were positive for antibodies to CPV2 from day 21. Four days after challenge, clinical signs associated with parvovirus infection (vomiting, paroxysmal shivering, depression, loose stools) were observed in the control dogs. Both animals were withdrawn from the study for welfare reasons one day later. On day 47, leucopenia was observed in controls, with white blood cell counts less than 50 per cent prechallenge values. No specific clinical sign of parvovirus infection were observed in the vaccinated dogs, nor was (detectable) challenge virus shed in faeces suggesting that antibodies generated contributed sterilising immunity. We conclude that vaccination of dogs with Duramune DAPPi+LC protects against challenge with a virulent field strain of CPV 2c.

  11. Myotonic Dystrophy Family Registry

    Science.gov (United States)

    2016-03-28

    Myotonic Dystrophy; Congenital Myotonic Dystrophy; Myotonic Dystrophy 1; Myotonic Dystrophy 2; Dystrophia Myotonica; Dystrophia Myotonica 1; Dystrophia Myotonica 2; Myotonia Dystrophica; Myotonic Dystrophy, Congenital; Myotonic Myopathy, Proximal; PROMM (Proximal Myotonic Myopathy); Proximal Myotonic Myopathy; Steinert Disease; Steinert Myotonic Dystrophy; Steinert's Disease; Myotonia Atrophica

  12. Tibialis anterior muscle needle biopsy and sensitive biomolecular methods: a useful tool in myotonic dystrophy type 1

    Directory of Open Access Journals (Sweden)

    S. Iachettini

    2015-10-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is a neuromuscular disorder caused by a CTG repeat expansion in 3’UTR of DMPK gene. This mutation causes accumulation of toxic RNA in nuclear foci leading to splicing misregulation of specific genes. In view of future clinical trials with antisense oligonucleotides in DM1 patients, it is important to set up sensitive and minimally-invasive tools to monitor the efficacy of treatments on skeletal muscle. A tibialis anterior (TA muscle sample of about 60 mg was obtained from 5 DM1 patients and 5 healthy subjects through a needle biopsy. A fragment of about 40 mg was used for histological examination and a fragment of about 20 mg was used for biomolecular analysis. The TA fragments obtained with the minimally-invasive needle biopsy technique is enough to perform all the histopathological and biomolecular evaluations useful to monitor a clinical trial on DM1 patients.

  13. Tibialis anterior muscle needle biopsy and sensitive biomolecular methods: a useful tool in myotonic dystrophy type 1.

    Science.gov (United States)

    Iachettini, S; Valaperta, R; Marchesi, A; Perfetti, A; Cuomo, G; Fossati, B; Vaienti, L; Costa, E; Meola, G; Cardani, R

    2015-10-26

    Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in 3'UTR of DMPK gene. This mutation causes accumulation of toxic RNA in nuclear foci leading to splicing misregulation of specific genes. In view of future clinical trials with antisense oligonucleotides in DM1 patients, it is important to set up sensitive and minimally-invasive tools to monitor the efficacy of treatments on skeletal muscle. A tibialis anterior (TA) muscle sample of about 60 mg was obtained from 5 DM1 patients and 5 healthy subjects through a needle biopsy. A fragment of about 40 mg was used for histological examination and a fragment of about 20 mg was used for biomolecular analysis. The TA fragments obtained with the minimally-invasive needle biopsy technique is enough to perform all the histopathological and biomolecular evaluations useful to monitor a clinical trial on DM1 patients.

  14. Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: The yield and the pitfalls.

    Science.gov (United States)

    Fanin, Marina; Angelini, Corrado

    2015-08-01

    Limb girdle muscular dystrophy type 2A (LGMD2A) is the most frequent form of LGMD worldwide. Comprehensive clinical assessment and laboratory testing is essential for diagnosis of LGMD2A. Muscle immunoblot analysis of calpain-3 is the most useful tool to direct genetic testing, as detection of calpain-3 deficiency has high diagnostic value. However, calpain-3 immunoblot testing lacks sensitivity in about 30% of cases due to gene mutations that inactivate the enzyme. The best diagnostic strategy should be determined on a case-by-case basis, depending on which tissues are available, and which molecular and/or genetic methods are adopted. In this work we survey the current knowledge, advantages, limitations, and pitfalls of protein testing and mutation detection in LGMD2A and provide an update of genetic epidemiology.

  15. Limb-girdle muscular dystrophy type 2a with mutation in CAPN3: the first report in Taiwan.

    Science.gov (United States)

    Wang, Chien-Hua; Liang, Wen-Chen; Minami, Narihiro; Nishino, Ichizo; Jong, Yuh-Jyh

    2015-02-01

    The autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 (CAPN3) gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. We report a 33-year-old woman with initial presentations of exercise intolerance and running difficulty at age 15 years. At presentation, waddling gait, positive Gowers' sign, and marked muscle atrophy in pelvic and leg muscles were noted. Muscle computed tomography (CT) imaging demonstrated symmetric involvement of the posterior thigh muscles with relative sparing of vastus lateralis, sartorius, and gracilis. Muscle biopsy revealed a dystrophic change and many lobulated fibers on NADH-tetrazolium reductase staining. Genetic analysis of the CAPN3 gene identified a novel homozygous mutation of c2047_2050 del4, p.Lys683fs mutation, confirming the first LGMD2A patient in Taiwan.

  16. CT evaluation of the damaged upper limb muscle in patients with Duchenne type progressive muscular dystrophy (DMD)

    Energy Technology Data Exchange (ETDEWEB)

    Saito, Hiroshi (Anan Central Hospital, Tokushima (Japan)); Matsuke, Yutaka

    1992-04-01

    In order to evaluate the changes of CT numbers and cross sectional areas of the muscles, we determined CT scores of the muscle. In twelve patients with Duchenne type progressive muscular dystrophy (DMD), we assessed the difference of CT scores of the muscle and the correlation between CT score of the muscle and 9-stage classification of upper extremities. CT scores of the subscapularis muscle and infraspinatus muscle were significantly lower than deltoideus muscle at the level of the shoulder, and flexor muscles showed also significantly lower than extensor muscles at the level of the upper extremity. Good correlations between CT score of the muscle and 9-stage classification of upper extremities were observed in the muscles of shoulder and upper arm. (author).

  17. Limb-girdle muscular dystrophy type 2A in Brazilian children

    Directory of Open Access Journals (Sweden)

    Marco Antônio Veloso de Albuquerque

    2015-12-01

    Full Text Available ABSTRACT Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years. The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.

  18. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

    DEFF Research Database (Denmark)

    Semplicini, Claudio; Vissing, John; Dahlqvist, Julia R

    2015-01-01

    OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol...... was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. RESULTS: Thirty...... (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation...

  19. Ullrich Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Goknur Haliloglu

    2011-06-01

    Full Text Available ObjectiveUllrich congenital muscular dystrophy is a rather severe type of congenital muscular dystrophy with early onset features related to motor development.In general it is inherited in autosomal recessive principles, however in the Western world mostly seen with de novo dominant mutations in the collagen VI genes. Milder form of the condition is the Bethlem myopathy. There may be overlap forms in the clinic resembling the Ehler-Danlos syndrome. There has been some radical efforts for cure especially through the apoptosis cascades.

  20. Level of muscle regeneration in limb-girdle muscular dystrophy type 2I relates to genotype and clinical severity

    Directory of Open Access Journals (Sweden)

    Krag Thomas O

    2011-10-01

    Full Text Available Abstract Background The balance between muscle regeneration and ongoing degeneration is a relationship that greatly influences the progression of muscular dystrophy. Numerous factors may influence the muscle regeneration, but more information about the relationship between genotype, clinical severity and the ability to regenerate is needed. Methods Muscle biopsies were obtained from the tibialis anterior muscle, and frozen sections were stained for general histopathological and immunohistological evaluation. Differences between groups were considered statistical significant at P t-test. Results We found that all patients with limb-girdle muscular dystrophy type 2I (LGMD2I had a large number of internally nucleated fibers, a sign of previous regeneration. The level of expression of muscle-specific developmental proteins, such as neonatal myosin heavy chain (nMHC and myogenin, was related to the clinical severity. Additionally, we found that the majority of nMHC-positive fibers did not stain positively for utrophin in patients who were compound heterozygous for the L276I mutation, suggesting that the predominant form of regeneration in these patients is fiber repair rather than formation of new fibers. Double staining showed that many smaller nMHC-positive fibers were positive for antibodies against the glycosylation on α-dystroglycan, suggesting that such glycosylation may be a result of muscle regeneration. Conclusion Severely affected patients with LGMD2I have a high level of muscle degeneration, which leads to a high rate of regeneration, but this is insufficient to change the imbalance between degeneration and regeneration, ultimately leading to progressive muscle wasting. Detailed information regarding the level and rate of muscle regeneration and potential obstructions of the regenerative pathway should be of use for future therapies involving satellite-cell activation.

  1. Canine parvovirus type 2c identified from an outbreak of severe gastroenteritis in a litter in Sweden.

    Science.gov (United States)

    Sutton, David; Vinberg, Carina; Gustafsson, Agneta; Pearce, Jacqueline; Greenwood, Neil

    2013-09-10

    A litter of recently-vaccinated puppies in Sweden experienced signs of severe haemorrhagic gastroenteritis. Canine parvovirus (CPV) was suspected as the cause of this outbreak on the basis of the clinical signs and the presence of parvoviral antigen in the faeces from one of the affected pups - confirmed using a commercial in-clinic faecal antigen ELISA test kit. A concern was raised about whether the vaccine (which contained a live, attenuated strain of CPV) could have caused the disease and so further faecal samples from the affected pups were submitted for laboratory virus isolation and identification.On cell culture, two out of four faecal samples were found to be virus-positive. This was confirmed as being canine parvovirus by immuno-staining with CPV specific monoclonal antibody. The virus was then tested using a series of PCR probes designed to confirm the identity of CPV and to distinguish the unique vaccine strain from field virus. This confirmed that the virus was indeed CPV but that it was not vaccine strain. The virus was then typed by sequencing the 426 amino acid region of the capsid gene which revealed this to be a type 2c virus.Since its emergence in the late 1970s, canine parvovirus 2 (CPV2) has spread worldwide and is recognised as an important canine pathogen in all countries. The original CPV2 rapidly evolved into two antigenic variants, CPV2a and CPV2b, which progressively replaced the original CPV2. More recently a new antigenic variant, CPV2c, has appeared. To date this variant has been identified in many countries worldwide but there have been no reports yet of its presence in any Scandinavian countries. This case report therefore represents the first published evidence of the involvement of CPV2c in a severe outbreak of typical haemorrhagic gastroenteritis in a susceptible litter of pups in Scandinavia.

  2. Delineation of the complement receptor type 2-C3d complex by site-directed mutagenesis and molecular docking.

    Science.gov (United States)

    Shaw, Craig D; Storek, Michael J; Young, Kendra A; Kovacs, James M; Thurman, Joshua M; Holers, V Michael; Hannan, Jonathan P

    2010-12-10

    The interactions between the complement receptor type 2 (CR2) and the C3 complement fragments C3d, C3dg, and iC3b are essential for the initiation of a normal immune response. A crystal-derived structure of the two N-terminal short consensus repeat (SCR1-2) domains of CR2 in complex with C3d has previously been elucidated. However, a number of biochemical and biophysical studies targeting both CR2 and C3d appear to be in conflict with these structural data. Previous mutagenesis and heteronuclear NMR spectroscopy studies directed toward the C3d-binding site on CR2 have indicated that the CR2-C3d cocrystal structure may represent an encounter/intermediate or nonphysiological complex. With regard to the CR2-binding site on C3d, mutagenesis studies by Isenman and coworkers [Isenman, D. E., Leung, E., Mackay, J. D., Bagby, S. & van den Elsen, J. M. H. (2010). Mutational analyses reveal that the staphylococcal immune evasion molecule Sbi and complement receptor 2 (CR2) share overlapping contact residues on C3d: Implications for the controversy regarding the CR2/C3d cocrystal structure. J. Immunol. 184, 1946-1955] have implicated an electronegative "concave" surface on C3d in the binding process. This surface is discrete from the CR2-C3d interface identified in the crystal structure. We generated a total of 18 mutations targeting the two (X-ray crystallographic- and mutagenesis-based) proposed CR2 SCR1-2 binding sites on C3d. Using ELISA analyses, we were able to assess binding of mutant forms of C3d to CR2. Mutations directed toward the concave surface of C3d result in substantially compromised CR2 binding. By contrast, targeting the CR2-C3d interface identified in the cocrystal structure and the surrounding area results in significantly lower levels of disruption in binding. Molecular modeling approaches used to investigate disparities between the biochemical data and the X-ray structure of the CR2-C3d cocrystal result in highest-scoring solutions in which CR2 SCR1-2 is

  3. A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL syndrome type 2C

    Directory of Open Access Journals (Sweden)

    Rinkes Inne

    2007-10-01

    Full Text Available Abstract Background Von Hippel-Lindau (VHL disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership. Case presentation A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser in exon 1 of the VHL gene on chromosome 3 (p25 – p26 was shown in the patient, her father and her daughter confirming the diagnosis of VHL. Conclusion In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

  4. The molecular genetics of the corneal dystrophies--current status.

    Science.gov (United States)

    Klintworth, Gordon K

    2003-05-01

    The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the

  5. Wild-type mouse models to screen antisense oligonucleotides for exon-skipping efficacy in Duchenne muscular dystrophy.

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    Limin Cao

    Full Text Available A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD, a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs.

  6. Role of the intracellular domain of the human type I interferon receptor 2 chain (IFNAR2c) in interferon signaling. Expression of IFNAR2c truncation mutants in U5A cells.

    Science.gov (United States)

    Russell-Harde, D; Wagner, T C; Rani, M R; Vogel, D; Colamonici, O; Ransohoff, R M; Majchrzak, B; Fish, E; Perez, H D; Croze, E

    2000-08-01

    A human cell line (U5A) lacking the type I interferon (IFN) receptor chain 2 (IFNAR2c) was used to determine the role of the IFNAR2c cytoplasmic domain in regulating IFN-dependent STAT activation, interferon-stimulated gene factor 3 (ISGF3) and c-sis-inducible factor (SIF) complex formation, gene expression, and antiproliferative effects. A panel of U5A cells expressing truncation mutants of IFNAR2c on their cell surface were generated for study. Janus kinase (JAK) activation was detected in all mutant cell lines; however, STAT1 and STAT2 activation was observed only in U5A cells expressing full-length IFNAR2c and IFNAR2c truncated at residue 462 (R2.462). IFNAR2c mutants truncated at residues 417 (R2. 417) and 346 (R2.346) or IFNAR2c mutant lacking tyrosine residues in its cytoplasmic domain (R2.Y-F) render the receptor inactive. A similar pattern was observed for IFN-inducible STAT activation, STAT complex formation, and STAT-DNA binding. Consistent with these data, IFN-inducible gene expression was ablated in U5A, R2.Y-F, R2.417, and R2.346 cell lines. The implications are that tyrosine phosphorylation and the 462-417 region of IFNAR2c are independently obligatory for receptor activation. In addition, the distal 53 amino acids of the intracellular domain of IFNAR2c are not required for IFN-receptor mediated STAT activation, ISFG3 or SIF complex formation, induction of gene expression, and inhibition of thymidine incorporation. These data demonstrate for the first time that both tyrosine phosphorylation and a specific domain of IFNAR2c are required in human cells for IFN-dependent coupling of JAK activation to STAT phosphorylation, gene induction, and antiproliferative effects. In addition, human and murine cells appear to require different regions of the cytoplasmic domain of IFNAR2c for regulation of IFN responses.

  7. Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients

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    Ravel-Chapuis, Aymeric; Klein Gunnewiek, Amanda; Bélanger, Guy; Crawford Parks, Tara E.; Côté, Jocelyn; Jasmin, Bernard J.

    2016-01-01

    Myotonic dystrophy (DM1) is caused by an expansion of CUG repeats (CUGexp) in the DMPK mRNA 3′UTR. CUGexp-containing mRNAs become toxic to cells by misregulating RNA-binding proteins. Here we investigated the consequence of this RNA toxicity on the cellular stress response. We report that cell stress efficiently triggers formation of stress granules (SGs) in proliferating, quiescent, and differentiated muscle cells, as shown by the appearance of distinct cytoplasmic TIA-1– and DDX3-containing foci. We show that Staufen1 is also dynamically recruited into these granules. Moreover, we discovered that DM1 myoblasts fail to properly form SGs in response to arsenite. This blockage was not observed in DM1 fibroblasts, demonstrating a cell type–specific defect. DM1 myoblasts display increased expression and sequestration of toxic CUGexp mRNAs compared with fibroblasts. Of importance, down-regulation of Staufen1 in DM1 myoblasts rescues SG formation. Together our data show that Staufen1 participates in the inhibition of SG formation in DM1 myoblasts. These results reveal that DM1 muscle cells fail to properly respond to stress, thereby likely contributing to the complex pathogenesis of DM1. PMID:27030674

  8. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes.

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    Sofia I I Kring

    Full Text Available BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2 and a randomly selected group (n = 831 were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49. Anthropometric, physiological and biochemical measures were available. Logistic regression analyses were used to assess age-adjusted odds ratios. No significant associations were observed of 5HT2A rs6311, 5HT2C rs3813929 and COMT rs4680 with obesity, except that COMT rs4680 GG-genotype was associated with fat-BMI (OR = 1.08, CI = 1.01-1.16. The SNPs were associated with a number of physiological variables; most importantly 5HT2C rs3813929 T-allele was associated with glucose (OR = 4.56, CI = 1.13-18.4 and acute insulin response (OR = 0.65, CI = 0.44-0.94 in S-49. COMT rs4680 GG-genotype was associated with glucose (OR = 1.04, CI = 1.00-1.09. Except for an association between 5HT2A rs6311 and total-cholesterol at both surveys, significant in S-46 (OR = 2.66, CI = 1.11-6.40, no significant associations were observed for the other phenotypes. Significant associations were obtained when combined genotype of 5HT2C rs3813929 and COMT rs4680 were examined in relation to BMI (OR = 1.12, CI = 1.03-1.21, fat-BMI (OR = 1.22, CI = 1.08-1.38, waist (OR = 1.13, CI = 1.04-1.22, and cholesterol (OR = 5.60, CI = 0.99-31.4. Analyses of impaired glucose tolerance (IGT and type 2 diabetes (T2D revealed, a 12.3% increased frequency of 5HT2C rs3813929 T-allele and an 11.6% increased frequency of COMT rs4680 GG-genotype in individuals with IGT or T2D (chi(2, p = 0.05 and p = 0

  9. Micro-RNA expression in muscle and fiber morphometry in myotonic dystrophy type 1.

    Science.gov (United States)

    Fritegotto, Chiara; Ferrati, Chiara; Pegoraro, Valentina; Angelini, Corrado

    2017-04-01

    We aimed to explore the cellular action of micro-RNAs that are non-coding-RNAs modulating gene expression, whose expression is dysregulated in myotonic dystrophy (DM1). Basic procedure was to measure the levels of muscle-specific myo-miRNAs (miR-1, miR-133a/b, miR-206) in muscle of 12 DM1 patients. Muscle fiber morphometry and a new grading of histopathological severity score were used to compare specific myo-miRNA level and fiber atrophy. We found that the levels of miR-1 and miR-133a/b were significantly decreased, while miR-206 was significantly increased as compared to controls. The histopathological score did not significantly correlate with the levels of myo-miRNAs, even if the lowest levels of miRNA-1 and miRNA-133a/b, and the highest levels of miRNA-206 were observed in patients with either severe histopathological scores or long disease duration. The histopathological score was inversely correlated with disease duration. Nowadays that DM1 muscle biopsies are scanty, since patients are usually diagnosed by genetic analysis, our study offers a unique opportunity to present miRNA expression profiles in muscle and correlate them to muscle morphology in this rare multisystem disorder. Our molecular and morphologic data suggest a post-transcriptional regulatory action of myo-miRNA in DM1, highlighting their potential role as biomarkers of muscle plasticity.

  10. Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice.

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    Benjamin Sanchez

    Full Text Available Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx. Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters.Eight wild-type (wt and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg-1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed.As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p 70 Hz, but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01. Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively.Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials.

  11. Ribonuclear inclusions as biomarker of myotonic dystrophy type 2, even in improperly frozen or defrozen skeletal muscle biopsies

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    R Cardani

    2009-08-01

    Full Text Available Myotonic dystrophy type 2 (DM2 is a dominantly inherited disorder caused by a CCTG repeat expansion in intron 1 of ZNF9 gene. The size and the somatic instability of DM2 expansion complicate the molecular diagnosis of DM2. In situ hybridization represents a rapid and sensitive method to obtain a definitive diagnosis in few hours, since it allows the direct visualization of the mutant mRNA foci on skeletal muscle sections. This approach makes the muscle biopsy an important tool for definitive diagnosis of DM2. Consequently, a rapid freezing at ultra cold temperature and a good storage of muscle specimens are essential to avoid morphologic alterations and nucleic acids degradation. However incorrect freezing or thawing may accidentally occur. In this work we report that fluorescence in situ hybridization may be applied on improperly frozen or inappropriately stored muscle biopsies since foci of mutant mRNA are well preserved and can still be detected in muscle sections no more useful for histopathological evaluation.

  12. Reliable and versatile immortal muscle cell models from healthy and myotonic dystrophy type 1 primary human myoblasts.

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    Pantic, Boris; Borgia, Doriana; Giunco, Silvia; Malena, Adriana; Kiyono, Tohru; Salvatori, Sergio; De Rossi, Anita; Giardina, Emiliano; Sangiuolo, Federica; Pegoraro, Elena; Vergani, Lodovica; Botta, Annalisa

    2016-03-01

    Primary human skeletal muscle cells (hSkMCs) are invaluable tools for deciphering the basic molecular mechanisms of muscle-related biological processes and pathological alterations. Nevertheless, their use is quite restricted due to poor availability, short life span and variable purity of the cells during in vitro culture. Here, we evaluate a recently published method of hSkMCs immortalization, relying on ectopic expression of cyclin D1 (CCND1), cyclin-dependent kinase 4 (CDK4) and telomerase (TERT) in myoblasts from healthy donors (n=3) and myotonic dystrophy type 1 (DM1) patients (n=2). The efficacy to maintain the myogenic and non-transformed phenotype, as well as the main pathogenetic hallmarks of DM1, has been assessed. Combined expression of the three genes i) maintained the CD56(NCAM)-positive myoblast population and differentiation potential; ii) preserved the non-transformed phenotype and iii) maintained the CTG repeat length, amount of nuclear foci and aberrant alternative splicing in immortal muscle cells. Moreover, immortal hSkMCs displayed attractive additional features such as structural maturation of sarcomeres, persistence of Pax7-positive cells during differentiation and complete disappearance of nuclear foci following (CAG)7 antisense oligonucleotide (ASO) treatment. Overall, the CCND1, CDK4 and TERT immortalization yields versatile, reliable and extremely useful human muscle cell models to investigate the basic molecular features of human muscle cell biology, to elucidate the molecular pathogenetic mechanisms and to test new therapeutic approaches for DM1 in vitro.

  13. Assessment of Premutation in Myotonic Dystrophy Type 1 Affected Family Members by TP-PCR and Genetic Counseling

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    Ashok Kumar

    2014-01-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is caused by the expansion of an unstable CTG repeat located in the 3′-UTR of (DMPK the DM protein kinase gene. Patients with DM1 have expansions of greater than 50 repeats and up to many thousands. In the present study we aimed to evaluate the utility of TP-PCR in diagnostics as well as the assessment of premutation carriers in proband families. Twenty-seven DM1 cases were enrolled (from twenty-six families and the 13 families of these cases came forward for family screening. The patient group constitute 22 males and 5 females and the average age of onset was 32.8 years (range 17 to 52. All clinically diagnosed DM1 cases and their family members DNA samples were analyzed by TP-PCR. All the cases were found to be positive for the CTG repeat expansion. Among those five families, four had at least an asymptomatic carrier. In the remaining one family other than the proband none was found to be neither affected nor asymptomatic. We reconfirmed the utility of PCR based screening for DM1 as being reliable and rapid molecular test and it should be used as an initial screening test for all patients with DM and their family members for initial screening purpose.

  14. Far field R-wave sensing in Myotonic Dystrophy type 1: right atrial appendage versus Bachmann's bundle region lead placement.

    Science.gov (United States)

    Russo, Vincenzo; Nigro, Gerardo; Antonio Papa, Andrea; Rago, Anna; Di Meo, Federica; Cristiano, Anna; Molino, Antonio; Calabrò, Raffaele; Giovanna Russo, Maria; Politano, Luisa

    2014-10-01

    Aim of the present study was to investigate far field R-wave sensing (FFRS) timing and characteristics in 34 Myotonic Dystrophy type 1 (DM1) patients undergoing dual chamber pacemaker implantation, comparing Bachmann's bundle (BB) stimulation (16 patients) site with the conventional right atrial appendage (RAA) pacing site (18 patients). All measurements were done during sinus rhythm and in supine position, with unipolar (UP) and bipolar (BP) sensing configuration. The presence, amplitude threshold (FFRS trsh) and FFRS timing were determined. There were no differences between both atrial sites in the Pmin and Pmean values of sensed P-wave amplitudes, as well as between UP and BP sensing configurations. The FFRS trsh was lower at the BB region in comparison to the RAA site. The mean BP FFRS trsh was significantly lower than UP configuration in both atrial locations. There were no significant differences in atrial pacing threshold, sensing threshold and atrial lead impedances at the implant time and at FFRS measurements. Bachmann's bundle area is an optimal atrial lead position for signal sensing as well as conventional RAA, but it offers the advantage of reducing the oversensing of R-wave on the atrial lead, thus improving functioning of standard dual chamber pacemakers in DM1 patients.

  15. Cultured myoblasts from patients affected by myotonic dystrophy type 2 exhibit senescence-related features: ultrastructural evidence

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    M. Malatesta

    2011-09-01

    Full Text Available Myotonic dystrophy type 2 (DM2 is an autosomal dominant disorder caused by the expansion of the tetranucleotidic repeat (CCTGn in the first intron of the Zinc Finger Protein-9 gene. In DM2 tissues, the expanded mutant transcripts accumulate in nuclear focal aggregates where splicing factors are sequestered, thus impairing the whole mRNA processing. Interestingly, the ultrastructural alterations in the splicing machinery observed in the myonuclei of DM2 skeletal muscles are reminiscent of the nuclear changes occurring in age-related muscle atrophy. Here, we investigated structural and functional features of satellite cell-derived myoblasts from biceps brachii, in the attempt to investigate cell senescence indices in DM2 patients by ultrastructural cytochemistry. We observed that in satellite cell-derived DM2 myoblasts, cell-senescence alterations and impairment of the pre-mRNA maturation pathways occur earlier than in myoblasts from healthy patients. This suggests that also in vivo the regeneration capability of satellite cells could be reduced in dystrophic muscles.

  16. Brain MRI abnormalities in the adult form of myotonic dystrophy type 1: A longitudinal case series study.

    Science.gov (United States)

    Conforti, Renata; de Cristofaro, Mario; Cristofano, Adriana; Brogna, Barbara; Sardaro, Angela; Tedeschi, Gioacchino; Cirillo, Sossio; Di Costanzo, Alfonso

    2016-02-01

    This study aimed to verify whether brain abnormalities, previously described in patients with myotonic dystrophy type 1 (DM1) by magnetic resonance imaging (MRI), progressed over time and, if so, to characterize their progression. Thirteen DM1 patients, who had at least two MRI examinations, were retrospectively evaluated and included in the study. The mean duration (± standard deviation) of follow-up was 13.4 (±3.8) years, over a range of 7-20 years. White matter lesions (WMLs) were rated by semi-quantitative method, the signal intensity of white matter poster-superior to trigones (WMPST) by reference to standard images and brain atrophy by ventricular/brain ratio (VBR). At the end of MRI follow-up, the scores relative to lobar, temporal and periventricular WMLs, to WMPST signal intensity and to VBR were significantly increased compared to baseline, and MRI changes were more evident in some families than in others. No correlation was found between the MRI changes and age, onset, disease duration, muscular involvement, CTG repetition and follow-up duration. These results demonstrated that white matter involvement and brain atrophy were progressive in DM1 and suggested that progression rate varied from patient to patient, regardless of age, disease duration and genetic defect.

  17. Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels

    Science.gov (United States)

    Lee, Moon Young; Park, Chanjae; Ha, Se Eun; Park, Paul J.; Berent, Robyn M.; Jorgensen, Brian G.; Corrigan, Robert D.; Grainger, Nathan; Blair, Peter J.; Slivano, Orazio J.; Miano, Joseph M.; Ward, Sean M.; Smith, Terence K.; Sanders, Kenton M.

    2017-01-01

    Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca2+ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract. PMID:28152551

  18. Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1.

    Science.gov (United States)

    Algalarrondo, Vincent; Wahbi, Karim; Sebag, Frédéric; Gourdon, Geneviève; Beldjord, Chérif; Azibi, Kamel; Balse, Elise; Coulombe, Alain; Fischmeister, Rodolphe; Eymard, Bruno; Duboc, Denis; Hatem, Stéphane N

    2015-04-01

    Myotonic dystrophy type 1 (DM1) is the most common neuromuscular disorder and is associated with cardiac conduction defects. However, the mechanisms of cardiac arrhythmias in DM1 are unknown. We tested the hypothesis that abnormalities in the cardiac sodium current (INa) are involved, and used a transgenic mouse model reproducing the expression of triplet expansion observed in DM1 (DMSXL mouse). The injection of the class-I antiarrhythmic agent flecainide induced prominent conduction abnormalities and significantly lowered the radial tissular velocities and strain rate in DMSXL mice compared to WT. These abnormalities were more pronounced in 8-month-old mice than in 3-month-old mice. Ventricular action potentials recorded by standard glass microelectrode technique exhibited a lower maximum upstroke velocity [dV/dt](max) in DMSXL. This decreased [dV/dt](max) was associated with a 1.7 fold faster inactivation of INa in DMSXL myocytes measured by the whole-cell patch-clamp technique. Finally in the DMSXL mouse, no mutation in the Scn5a gene was detected and neither cardiac fibrosis nor abnormalities of expression of the sodium channel protein were observed. Therefore, alterations in the sodium current markedly contributed to electrical conduction block in DM1. This result should guide pharmaceutical and clinical research toward better therapy for the cardiac arrhythmias associated with DM1.

  19. Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

    Science.gov (United States)

    Angelbello, Alicia J; González, Àlex L; Rzuczek, Suzanne G; Disney, Matthew D

    2016-12-01

    RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG)(exp)). Several small molecules have been found to disrupt the MBNL1-r(CUG)(exp) complex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells.

  20. Premature senescence in primary muscle cultures of myotonic dystrophy type 2 is not associated with p16 induction

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    L.V. Renna

    2014-10-01

    Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle weakness and atrophy, cardiac dysfunctions, cataracts and insulin-resistance. In both forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus deregulating the activity of some RNAbinding proteins and providing an explanation for the multisystemic phenotype of DM patients. However this pathogenetic mechanism does not explain some histopathological features of DM skeletal muscle like muscle atrophy. It has been observed that DM muscle shares similarities with the ageing muscle, where the progressive muscle weakness and atrophy is accompanied by a lower regenerative capacity possibly due to the failure in satellite cells activation. The aim of our study is to investigate if DM2 satellite cell derived myoblasts exhibit a premature senescence as reported for DM1 and if alterations in their proliferation potential and differentiation capabilities might contribute to some of the histopathological features observed in DM2 muscles. Our results indicate that DM myoblasts have lower proliferative capability than control myoblasts and reach in vitro senescence earlier than controls. Differentely from DM1, the p16 pathway is not responsible for the premature growth arrest observed in DM2 myoblasts which stop dividing with telomeres shorter than controls. During in vitro senescence, a progressive decrease in fusion index is observable in both DM and control myotubes with no significant differences between groups. Moreover, myotubes obtained from senescent myoblasts appear to be smaller than those from young myoblasts. Taken together, our data indicate a possible role of DM2 premature myoblast senescence in skeletal muscle histopathological alterations i.e., dystrophic changes and type 2 fibre atrophy.

  1. Atrial fibrillation burden in Myotonic Dystrophy type 1 patients implanted with dual chamber pacemaker: the efficacy of the overdrive atrial algorithm at 2 year follow-up

    OpenAIRE

    Russo, Vincenzo; NIGRO, GERARDO; Rago, Anna; ANTONIO PAPA, ANDREA; PROIETTI, RICCARDO; Della Cioppa, Nadia; CRISTIANO, ANNA; PALLADINO, ALBERTO; Calabrò, Raffaele; Politano, Luisa

    2013-01-01

    The role that atrial pacing therapy plays on the atrial fibrillation (AF) burden is still unclear. Aim of the study was to evaluate the effect of the atrial preference pacing algorithm on AF burden in patients affected by Myotonic Dystrophy type 1 (DM1) followed for a long follow up period. Sixty DM1 patients were -implanted with a dual chamber pacemaker (PM) for first degree or symptomatic type 1/type 2 second degree atrio-ventricular blocks- were followed for 2-years after implantation, by ...

  2. Report of limb girdle muscular dystrophy type 2a in 6 Iranian patients, one with a novel deletion in CAPN3 gene.

    Science.gov (United States)

    Fadaee, Mahsa; Kariminejad, Ariana; Fattahi, Zohreh; Nafissi, Shahriar; Godarzi, Hamed Reza; Beheshtian, Maryam; Vazehan, Raheleh; Akbari, Mohammad Reza; Kahrizi, Kimia; Najmabadi, Hossein

    2016-01-01

    Calpain3 is a calcium-dependent intracellular protease involved in an autosomal recessive form of muscular dystrophy known as limb-girdle muscular dystrophy type 2A. Many pathogenic mutations have been identified in calpain3, encoded by the CAPN3 gene, which leads to weakness of the pelvic and shoulder girdle muscles. In the present study, whole exome sequencing was performed on six unrelated Iranian families who presented with progressive muscle weakness, with a strong suspicion of Calpainopathies. Genetic analysis of CAPN3 gene revealed five causative variants which had not been reported in the Iranian population before including a novel 6 bp deletion (c.795_800delCATTGA) and four previously reported mutations (c.1939G > T, c.2243G > A, c.2257delGinsAA, and c.2380 + 2T > G). Our findings indicate that exome sequencing can be a very effective and affordable method to diagnose heterogeneous muscular dystrophies, especially in consanguineous populations such as Iran.

  3. Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F

    Science.gov (United States)

    Putker, K.; Tanganyika-de Winter, C. L.; Boertje-van der Meulen, J. W.; van Vliet, L.; Overzier, M.; Plomp, J. J.; Aartsma-Rus, A.; van Putten, M.

    2017-01-01

    Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre

  4. A phylogenetic study of canine parvovirus type 2c in midwestern Brazil Estudo filogenético do parvovírus canino tipo 2c no Centro-Oeste do Brasil

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    Danúbia S. Fontana

    2013-02-01

    Full Text Available Since the late 1970s, canine parvovirus type 2 (CPV-2 has emerged as a causative agent of fatal severe acute hemorrhagic enteritis in dogs. To date, three antigenic types of CPV-2 were described worldwide (CPV-2a/b/c. This study was conducted to determine the variants of CPV-2 circulating in dogs from the Cuiabá Municipality in Midwestern Brazil. Out of 50 fecal samples, collected between 2009 and 2011, 27 tested positive for CPV-2. A 583 bp fragment of the VP2 gene was amplified by PCR, 13 representative samples were analyzed further by DNA sequencing. All strains were characterized as CPV-2c, displayed a low genetic variability although observed several amino acid substitution. These findings indicated that CPV-2c has been circulating in dogs from the Cuiabá Municipality in Midwestern Brazil.Desde o final dos anos de 1970, o parvovírus canino tipo 2 (CPV-2 tem emergido como agente de severa e fatal enterite hemorrágica, principalmente em cães com idade inferior a seis meses. Três variantes antigênicas de CPV-2 foram descritas mundialmente (CPV-2a/b/c. O objetivo do estudo foi determinar a presença do CPV-2 e suas variantes circulantes em cães no Município de Cuiabá, Centro-oeste, Brasil. Das 50 amostras fecais, coletadas entre 2009 e 2011, 27 foram positivas para CPV-2 na PCR, sendo 13 analisadas pelo sequenciamento de um fragmento de 583 pares de base do gene VP2. Todas as cepas foram caracterizadas como CPV-2c e apresentaram baixa variabilidade genética. Estes achados indicaram que o CPV-2c está circulando na população canina do Município de Cuiabá, Região Centro-Oeste do Brasil.

  5. RNA/MBNL1-containing foci in myoblast nuclei from patients affected by myotonic dystrophy type 2: an immunocytochemical study

    Directory of Open Access Journals (Sweden)

    F. Perdoni

    2009-09-01

    Full Text Available Myotonic dystrophy type 2 (DM2 is a dominantly inherited autosomal disease with multi-systemic clinical features and it is caused by expansion of a CCTG tetranucleotide repeat in the first intron of the zinc finger protein 9 (ZNF9 gene in 3q21.The expanded-CCUG-containing transcripts are retained in the cell nucleus and accumulate in the form of focal aggregates which specifically sequester the muscleblind-like 1 (MBNL1 protein, a RNA binding factor involved in the regulation of alternative splicing. The structural organization and composition of the foci are still incompletely known. In this study, the nuclear foci occurring in cultured myoblasts from DM2 patients were characterised at fluorescence and transmission electron microscopy by using a panel of antibodies recognizing transcription and processing factors of pre-mRNAs. MBNL1 proved to co-locate in the nuclear foci with snRNPs and hnRNPs, whereas no co-location was observed with RNA polymerase II, the non-RNP splicing factor SC35, the cleavage factor CStF and the PML protein. At electron microscopy the MBNL1-containing nuclear foci appeared as roundish domains showing a rather homogeneous structure and proved to contain snRNPs and hnRNPs. The sequestration of splicing factors involved in early phases of pre-mRNA processing supports the hypothesis of a general alteration in the maturation of several mRNAs, which could lead to the multiple pathological dysfunctions observed in dystrophic patients.

  6. Myotonic Dystrophy Type 1 RNA Crystal Structures Reveal Heterogeneous 1 × 1 Nucleotide UU Internal Loop Conformations

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    Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W.; Disney, Matthew D. (Scripps)

    2012-03-27

    RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[{und UU}GGGC(C{und U}G){sub 3}GUCC]{sub 2}, refined to 2.20 and 1.52 {angstrom} resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 x 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 {angstrom} structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 x 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 x 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 {angstrom} structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 x 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 x 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.

  7. Autism spectrum conditions in myotonic dystrophy type 1: a study on 57 individuals with congenital and childhood forms.

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    Ekström, Anne-Berit; Hakenäs-Plate, Louise; Samuelsson, Lena; Tulinius, Már; Wentz, Elisabet

    2008-09-05

    Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder, caused by an expansion of a CTG triplet repeat in the DMPK gene. The aims of the present study were to classify a cohort of children with DM1, to describe their neuropsychiatric problems and cognitive level, to estimate the size of the CTG expansion, and to correlate the molecular findings with the neuropsychiatric problems. Fifty-seven children and adolescents (26 females; 31 males) with DM1 (CTG repeats > 40) were included in the study. The following instruments were used: Autism Diagnostic Interview-Revised (ADI-R), 5-15, Griffiths Mental Development Scales, and the Wechsler Scales. Based on age at onset and presenting symptoms, the children were divided into four DM1 groups; severe congenital (n = 19), mild congenital (n = 18), childhood (n = 18), and classical DM1 (n = 2). Forty-nine percent had an autism spectrum disorder (ASD) and autistic disorder was the most common diagnosis present in 35% of the subjects. Eighty-six percent of the individuals with DM1 had mental retardation (MR), most of them moderate or severe MR. ASD was significantly correlated with the DM1 form; the more severe the form of DM1, the higher the frequency of ASD. The frequency of ASD increased with increasing CTG repeat expansions. ASD and/or other neuropsychiatric disorders such as attention deficit hyperactivity disorder, and Tourette's disorder were found in 54% of the total DM1 group. In conclusion, awareness of ASD comorbidity in DM1 is essential. Further studies are warranted to elucidate the molecular etiology causing neurodevelopmental symptoms such as ASD and MR in DM1.

  8. A low absolute number of expanded transcripts is involved in myotonic dystrophy type 1 manifestation in muscle.

    Science.gov (United States)

    Gudde, Anke E E G; González-Barriga, Anchel; van den Broek, Walther J A A; Wieringa, Bé; Wansink, Derick G

    2016-04-15

    Muscular manifestation of myotonic dystrophy type 1 (DM1), a common inheritable degenerative multisystem disorder, is mainly caused by expression of RNA from a (CTG·CAG)n-expanded DM1 locus. Here, we report on comparative profiling of expression of normal and expanded endogenous or transgenic transcripts in skeletal muscle cells and biopsies from DM1 mouse models and patients in order to help us in understanding the role of this RNA-mediated toxicity. In tissue of HSA(LR) mice, the most intensely used 'muscle-only' model in the DM1 field, RNA from the α-actin (CTG)250 transgene was at least 1000-fold more abundant than that from the Dmpk gene, or the DMPK gene in humans. Conversely, the DMPK transgene in another line, DM500/DMSXL mice, was expressed ∼10-fold lower than the endogenous gene. Temporal regulation of expanded RNA expression differed between models. Onset of expression occurred remarkably late in HSA(LR) myoblasts during in vitro myogenesis whereas Dmpk or DMPK (trans)genes were expressed throughout proliferation and differentiation phases. Importantly, quantification of absolute transcript numbers revealed that normal and expanded Dmpk/DMPK transcripts in mouse models and DM1 patients are low-abundance RNA species. Northern blotting, reverse transcriptase-quantitative polymerase chain reaction, RNA-sequencing and fluorescent in situ hybridization analyses showed that they occur at an absolute number between one and a few dozen molecules per cell. Our findings refine the current RNA dominance theory for DM1 pathophysiology, as anomalous factor binding to expanded transcripts and formation of soluble or insoluble ribonucleoprotein aggregates must be nucleated by only few expanded DMPK transcripts and therefore be a small numbers game.

  9. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kring, Sofia I I; Werge, Thomas; Holst, Claus

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these......BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs...

  10. Cancer incidence in type 2 diabetes patients - first results from a feasibility study of the D2C cohort

    Directory of Open Access Journals (Sweden)

    Hense Hans-Werner

    2011-07-01

    Full Text Available Abstract Background A large prospective study in patients with type 2 diabetes (T2D, the German D2C cohort, is presently being enumerated to investigate risk factors of incident cancer in diabetic patients. Study setting A disease management program was offered, on a voluntary basis, to all T2D patients who were members of a statutory health insurance fund in Germany. This first feasibility report uses data from 26.742 T2D patients, who were 40 to 79 years old, resided in the Muenster District, and who were enrolled between June 2003 and July 2008. Cancer cases were identified through the regional Cancer Registry. Methods Invasive cancer cases were identified using probabilistic record linkage procedures and pseudonymised personal identifiers. Censoring date was December 31, 2008. We included only first cancers, leaving 12.650 male and 14.092 female T2D with a total of 88.778 person-years (py. We computed standardised incidence ratios (SIR for external comparisons and we employed Cox regression models and hazard ratios (HR within the cohort. Results We identified 759 first cancers among male T2D patients (18.7 per 1,000 py and 605 among females (12.7 per 1,000 py. The risk of any incident cancer in T2D was raised (SIR = 1.14; 95% confidence interval [1.10 - 1.21], in particular for cancer of the liver (SIR = 1.94 [1.15 - 2.94] and pancreas (SIR = 1.45 [1.07-1.92]. SIRs decreased markedly with time after T2D diagnosis. In Cox models, adjusting for diabetes duration, body mass index and sex, insulin therapy was related to higher cancer risk (HR = 1.25 [1.17 - 1.33]. No effect was seen for metformin. Discussion Our study demonstrates feasibility of record linkage between DMP and cancer registries. These first cohort results confirm previous reports. It is envisaged to enhance this cohort by inclusion of further regions of the state, expansion of the follow-up times, and collection of a more detailed medication history.

  11. CYP2C9*2 allele increases risk for hypoglycemia in POR*1/*1 type 2 diabetic patients treated with sulfonylureas.

    Science.gov (United States)

    Ragia, G; Tavridou, A; Elens, L; Van Schaik, R H N; Manolopoulos, V G

    2014-01-01

    It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug-associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl-urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl-urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly-morphisms may explain individual variability in the effect of sulfonylureas.

  12. Treatment of sleep central apnea with non-invasive mechanical ventilation with 2 levels of positive pressure (bilevel) in a patient with myotonic dystrophy type 1

    Science.gov (United States)

    Akamine, Ricardo Tera; Grossklauss, Luís Fernando; Moreira, Gustavo Antonio; Pradella-Hallinan, Marcia; Chiéia, Marco Antônio; Mesquita, Denis; Bulle Oliveira, Acary Souza; Tufik, Sergio

    2014-01-01

    We are reporting a case of a 29 year-old female with diagnosis of myotonic dystrophy type 1 (Steinert’s disease) with excessive daytime sleepiness, muscle fatigue, snoring, frequent arousals, non-restorative sleep, and witnessed apneas. Pulmonary function tests revealed a mild decrease of forced vital capacity. Nocturnal polysomnography showed an increase of apnea/hypopnea index (85.9 events/h), mainly of central type (236), minimal oxygen saturation of 72%, and end-tidal carbon dioxide values that varied from 45 to 53 mmHg. Bi-level positive airway pressure titration was initiated at an inspiratory pressure (IPAP) of 8 and an expiratory pressure (EPAP) of 4 cm H2O. IPAP was then gradually increased to eliminate respiratory events and improve oxygen saturation. An IPAP of 12cm H20 and an EPAP of 4cm H2O eliminated all respiratory events, and the oxygen saturation remained above 90%. Bi-level positive airway pressure treatment at spontaneous/timed mode showed an improvement in snoring, apneas, and Epworth sleepiness scale decreased from 20 to 10. This case illustrates the beneficial effects of Bi-level positive airway pressure support in central sleep apnea syndrome of a patient with myotonic dystrophy type 1. PMID:26483914

  13. Study on the findings of muscle CT in patients with Fukuyama type congenital muscular dystrophy (FCMD)

    Energy Technology Data Exchange (ETDEWEB)

    Sumida, Sawako; Osawa, Makiko; Okada, Noriko and others

    1988-11-01

    This study was carried out to investigate the process of muscle involvement according to age in patients with FCMD (Brain Dev 1981 ; 3:1 - 29) by CT scans. Fourteen patients with FCMD I (age: 5 months-12 years) and two patients with FCMD III or IV (age: 3, 4 years) were studied. The midcalf, midthigh, L3 and shoulder girdle level were the sites chosen. Two types of change were found in FCMD I. One of them was the attenuation of the density in muscle and the other one was decreased area of muscle as a result of low density which started from periphery of the muscle. The latter was found in m. psoas major after age 9, whilst the former was found in other muscles to some degree. The severity of the changes was related to age. In the case which was examined twice, the changes extended even better motor function had been attained. The changes in midcalf preceded those in midthigh, L3, shoulder girdle. The attenuation of density was found early and severely in m. triceps surae, m. adductor magnus, paravertebral muscles and m. subscapularis, whilst those in m. tibialis anterior and posterior, m. gracilis, m. sartorius, m. quadratus lumborum appeared later and relatively mild. The relationship between the process of extension of low density in muscle and joint contractures were also discussed. The changes in CT scan in FCMD III or IV were milder than those of FCMD I and there was no tendency that the change in midcalf preceded those of other scanned level.

  14. The effect of atrial preference pacing on atrial fibrillation electrophysiological substrate in Myotonic Dystrophy type 1 population.

    Science.gov (United States)

    Russo, Vincenzo; Nigro, Gerardo; DI Meo, Federica; Papa, Andrea Antonio; Cioppa, Nadia Della; Proietti, Riccardo; Russo, Maria Giovanna; Calabrò, Raffaele; Politano, Luisa

    2014-12-01

    P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the possible correlation between atrial preference pacing algorithm, P-wave dispersion and AF burden in DM1 patients with normal cardiac function underwent permanent dual-chamber pacemaker implantation. We enrolled 50 patients with DM1 (age 50.3 ± 7.3; 11 F) underwent dual-chamber pacemaker implantation for various degree of atrioventricula block. The study population was randomized following 1 months stabilization period to APP algorithm features programmed OFF or ON. Patients were assessed every 3 months for the first year, and every 6 months thereafter up to 3 years. At each follow-up visit, we counted: the number of premature atrial beats, the number and the mean duration of AF episodes, AF burden and the percentage of atrial and ventricular pacing. APP ON Group showed lower number of AF episodes (117 ± 25 vs. 143 ± 37; p = 0.03) and AF burden (3059 ± 275 vs. 9010 ± 630 min; p < 0.04) than APP OFF Group. Atrial premature beats count (44903 ± 30689 vs. 13720 ± 7717 beats; p = 0.005) and Pwave dispersion values (42,1 ± 11 ms vs. 29,1 ± 4,2 ms, p = 0,003) were decreased in APP ON Group. We found a significant positive correlation between PD and AF burden (R = 0,8, p = 0.007). Atrial preference pacing algorithm, decreasing the number of atrial premature beats and the P-wave dispersion, reduces the onset and perpetuator factors of AF episodes and decreases the AF burden in DM1 patients underwent dual chamber pacemaker implantation for various degree of atrioventricular blocks

  15. Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.

    Science.gov (United States)

    De Antonio, M; Dogan, C; Hamroun, D; Mati, M; Zerrouki, S; Eymard, B; Katsahian, S; Bassez, G

    2016-10-01

    The broad clinical spectrum of myotonic dystrophy type 1 (DM1) creates particular challenges for both medical care and design of clinical trials. Clinical onset spans a continuum from birth to late adulthood, with symptoms that are highly variable in both severity and nature of the affected organ systems. In the literature, this complex phenotype is divided into three grades (mild, classic, and severe) and four or five main clinical categories (congenital, infantile/juvenile, adult-onset and late-onset forms), according to symptom severity and age of onset, respectively. However, these classifications are still under discussion with no consensus thus far. While some specific clinical features have been primarily reported in some forms of the disease, there are no clear distinctions. As a consequence, no modifications in the management of healthcare or the design of clinical studies have been proposed based on the clinical form of DM1. The present study has used the DM-Scope registry to assess, in a large cohort of DM1 patients, the robustness of a classification divided into five clinical forms. Our main aim was to describe the disease spectrum and investigate features of each clinical form. The five subtypes were compared by distribution of CTG expansion size, and the occurrence and onset of the main symptoms of DM1. Analyses validated the relevance of a five-grade model for DM1 classification. Patients were classified as: congenital (n=93, 4.5%); infantile (n=303, 14.8%); juvenile (n=628, 30.7%); adult (n=694, 34.0%); and late-onset (n=326, 15.9%). Our data show that the assumption of a continuum from congenital to the late-onset form is valid, and also highlights disease features specific to individual clinical forms of DM1 in terms of symptom occurrence and chronology throughout the disease course. These results support the use of the five-grade model for disease classification, and the distinct clinical profiles suggest that age of onset and clinical form may

  16. Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA).

    Science.gov (United States)

    DiPaolo, Giovanni; Jimenez-Moreno, Cecilia; Nikolenko, Nikoletta; Atalaia, Antonio; Monckton, Darren G; Guglieri, Michela; Lochmüller, Hanns

    2017-04-01

    Myotonic dystrophy type 1 (DM1) is not characterised by ataxia per se; however, DM1 and ataxia patients show similar disturbances in movement coordination often experiencing walking and balance difficulties, although caused by different underlying pathologies. This study aims to investigate the use of a scale previously described for the assessment and rating of ataxia (SARA) with the hypothesis that it could have utility in DM1 patients as a measure of disease severity and risk of falling. Data from 54 DM1 patients were pulled from the PHENO-DM1 natural history study for analysis. Mean SARA score in the DM1 population was 5.45 relative to the maximum score of eight. A flooring effect (score 0) was observed in mild cases within the sample. Inter-rater and test-retest reliability was high with intraclass coefficients (ICC) of 0.983 and 1.00, respectively. Internal consistency was acceptable as indicated by a Cronbach's alpha of 0.761. Component analysis revealed two principle components. SARA correlated with: (1) all measures of muscle function tested, including quantitative muscle testing of ankle dorsiflexion (r = -0.584*), the 6 min walk test (r = -0.739*), 10 m walk test (r = 0.741*), and the nine hole peg test (r = 0.602*) and (2) measures of disease severity/burden, such as MIRS (r = 0.718*), MDHI (r = 0.483*), and DM1-Activ (r = -0.749*) (*p < 0.001). The SARA score was predicted by an interaction between modal CTG repeat length and age at sampling (r = 0.678, p = 0.003). A score of eight or above predicted the use of a walking aid with a sensitivity of 100% and a specificity of 85.7%. We suggest that further research is warranted to ascertain whether SARA or components of SARA are useful outcome measures for clinical trials in DM1. As a tool, it can be used for gathering information about disease severity/burden and helping to identify patients in need of a walking aid, and can potentially be applied in both research and healthcare

  17. A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1.

    Science.gov (United States)

    Yu, Zhenming; Goodman, Lindsey D; Shieh, Shin-Yi; Min, Michelle; Teng, Xiuyin; Zhu, Yongqing; Bonini, Nancy M

    2015-02-15

    Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. Interestingly, expression of two isoforms of MBNL1, MBNL135 and MBNL140, leads to cleavage and concurrent upregulation of the levels of the RNA-repeat transcripts, with MBNL140 having more significant effects than MBNL135. This property is shared with a fly CUG-repeat expansion model. Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1.

  18. Ocular abnormality in myotonic dystrophy.

    Science.gov (United States)

    Ginsberg, J; Hamblet, J; Menefee, M

    1978-08-01

    A 61-year-old white woman with terminal myotonic dystrophy exhibited advanced peripheral and central retinopathy. Retinal lesions were characterized by hyperpigmentation, common, though nonspecific, in myotonic dystrophy. They resemble both heredo (tapetoretinal) and idiopathic involutional degenerations but rarely cause severe visual impairment. Neither the type nor degree of retinopathy appears to correlate with other ocular features or with the stage of the underlying disease. Our histologic observations confirm and extend those previously described. Electron microscopy suggests a primary disorder of mitochondria which may also affect smooth muscle and the myocardium.

  19. Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes

    DEFF Research Database (Denmark)

    Kring, Sofia I I; Werge, Thomas; Holst, Claus

    2009-01-01

    BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs......) of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2)) and a randomly selected group (n = 831) were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49...

  20. Delivery of recombinant vaccines against bovine herpesvirus type 1 gD and Babesia bovis MSA-2c to mice using liposomes derived from egg yolk lipids.

    Science.gov (United States)

    Rodriguez, Anabel E; Zamorano, Patricia; Wilkowsky, Silvina; Torrá, Florencia; Ferreri, Lucas; Dominguez, Mariana; Florin-Christensen, Mónica

    2013-06-01

    Liposomes prepared from total egg yolk lipid extracts were used to deliver experimental DNA vaccines to mice consisting of pCI-neo plasmids encoding bovine herpesvirus type 1 (BoHV-1) gD or Babesia bovis MSA-2c. A significantly higher proportion of mice in the B. bovis MSA-2c group, but not those in the BoHV-1 gD group, developed detectable immunoglobulin G responses when vaccinated with liposome encapsulated DNA in comparison with mice vaccinated with naked DNA. In both groups, antibody titres were similar between mice vaccinated with liposome encapsulated DNA and naked DNA.

  1. Cone rod dystrophies

    Directory of Open Access Journals (Sweden)

    Hamel Christian P

    2007-02-01

    Full Text Available Abstract Cone rod dystrophies (CRDs (prevalence 1/40,000 are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP, also called the rod cone dystrophies (RCDs resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7. Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far. The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs, CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs, and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs. It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is

  2. Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3.

    Science.gov (United States)

    Pushechnikov, Alexei; Lee, Melissa M; Childs-Disney, Jessica L; Sobczak, Krzysztof; French, Jonathan M; Thornton, Charles A; Disney, Matthew D

    2009-07-22

    Herein, we describe the design of high affinity ligands that bind expanded rCUG and rCAG repeat RNAs expressed in myotonic dystrophy type 1 (DM1) and spinocerebellar ataxia type 3. These ligands also inhibit, with nanomolar IC(50) values, the formation of RNA-protein complexes that are implicated in both disorders. The expanded rCUG and rCAG repeats form stable RNA hairpins with regularly repeating internal loops in the stem and have deleterious effects on cell function. The ligands that bind the repeats display a derivative of the bisbenzimidazole Hoechst 33258, which was identified by searching known RNA-ligand interactions for ligands that bind the internal loop displayed in these hairpins. A series of 13 modularly assembled ligands with defined valencies and distances between ligand modules was synthesized to target multiple motifs in these RNAs simultaneously. The most avid binder, a pentamer, binds the rCUG repeat hairpin with a K(d) of 13 nM. When compared to a series of related RNAs, the pentamer binds to rCUG repeats with 4.4- to >200-fold specificity. Furthermore, the affinity of binding to rCUG repeats shows incremental gains with increasing valency, while the background binding to genomic DNA is correspondingly reduced. Then, it was determined whether the modularly assembled ligands inhibit the recognition of RNA repeats by Muscleblind-like 1 (MBNL1) protein, the expanded-rCUG binding protein whose sequestration leads to splicing defects in DM1. Among several compounds with nanomolar IC(50) values, the most potent inhibitor is the pentamer, which also inhibits the formation of rCAG repeat-MBNL1 complexes. Comparison of the binding data for the designed synthetic ligands and MBNL1 to repeating RNAs shows that the synthetic ligand is 23-fold higher affinity and more specific to DM1 RNAs than MBNL1. Further studies show that the designed ligands are cell permeable to mouse myoblasts. Thus, cell permeable ligands that bind repetitive RNAs have been designed

  3. Height estimate for special Weingarten surfaces of elliptic type in ${\\mathbb M}^2(c \\times \\mathbb {R}$

    Directory of Open Access Journals (Sweden)

    Filippo Morabito

    2014-01-01

    Full Text Available In this article we provide a vertical height estimate for compact special Weingarten surfaces of elliptic type in ²(×ℝ, i.e. surfaces whose mean curvature ℍ and extrinsic Gauss curvature ₑ satisfy ℍ=(ℍ²-ₑ with 4(’(²<1, for all ∈[0,+∞. The vertical height estimate generalizes a result by Rosenberg and Sa Earp and applies only to surfaces verifying a height estimate condition. When <0, using also a horizontal height estimate, we show a non-existence result for properly embedded Weingarten surfaces of elliptic type in ℍ²(×ℝ with finite topology and one end.

  4. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans

    DEFF Research Database (Denmark)

    Krag, Thomas O; Vissing, John

    2015-01-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I...... mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely...... caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP...

  5. LASIK surgery of granular corneal dystrophy type 2 patients leads to accumulation and differential proteolytic processing of transforming growth factor beta-induced protein (TGFBIp)

    DEFF Research Database (Denmark)

    Poulsen, Ebbe Toftgaard; Nielsen, Nadia Sukusu; Jensen, Morten Mørk;

    2016-01-01

    at position 124 in mature TGFBIp leads to granular corneal dystrophy type 2 (GCD2). Homozygous GCD2 cases develop massive protein accumulation early in life whereas heterozygous GCD2 cases become affected much later and generally with a much less severe outcome. However, if heterozygous GCD2 patients undergo...... laser-assisted in situ keratomileusis (LASIK) surgery protein accumulation is accelerated and they develop massive protein accumulations a few years after surgery. Here, we present the protein profile of aggregate-containing corneal tissue from GCD2 patients with a history of LASIK surgery using LC......-MS/MS. Label-free quantification of corneal extracellular matrix proteins showed accumulation of TGFBIp. This was supported by 2DE and immunoblotting against TGFBIp that revealed the accumulation of full-length TGFBIp. In addition, a high molecular weight TGFBIp complex was more apparent in GCD2 patients after...

  6. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1.

    Science.gov (United States)

    Pandey, Sanjay K; Wheeler, Thurman M; Justice, Samantha L; Kim, Aneeza; Younis, Husam S; Gattis, Danielle; Jauvin, Dominic; Puymirat, Jack; Swayze, Eric E; Freier, Susan M; Bennett, C Frank; Thornton, Charles A; MacLeod, A Robert

    2015-11-01

    Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by an expanded CTG repeat in the 3'-untranslated region of DMPK, the gene encoding dystrophia myotonica protein kinase (DMPK). Antisense oligonucleotides (ASOs) containing 2',4'-constrained ethyl-modified (cEt) residues exhibit a significantly increased RNA binding affinity and in vivo potency relative to those modified with other 2'-chemistries, which we speculated could translate to enhanced activity in extrahepatic tissues, such as muscle. Here, we describe the design and characterization of a cEt gapmer DMPK ASO (ISIS 486178), with potent activity in vitro and in vivo against mouse, monkey, and human DMPK. Systemic delivery of unformulated ISIS 486718 to wild-type mice decreased DMPK mRNA levels by up to 90% in liver and skeletal muscle. Similarly, treatment of either human DMPK transgenic mice or cynomolgus monkeys with ISIS 486178 led to up to 70% inhibition of DMPK in multiple skeletal muscles and ∼50% in cardiac muscle in both species. Importantly, inhibition of DMPK was well tolerated and was not associated with any skeletal muscle or cardiac toxicity. Also interesting was the demonstration that the inhibition of DMPK mRNA levels in muscle was maintained for up to 16 and 13 weeks post-treatment in mice and monkeys, respectively. These results demonstrate that cEt-modified ASOs show potent activity in skeletal muscle, and that this attractive therapeutic approach warrants further clinical investigation to inhibit the gain-of-function toxic RNA underlying the pathogenesis of DM1. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  7. The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome.

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    Tatsuaki Kurosaki

    Full Text Available Myotonic dystrophy type 2 (DM2 is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9 gene. The expansions are extremely unstable and variable, ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3'-end of an AluSx element, flanked by target site duplications (5'-ACTRCCAR-3'or 5'-ACTRCCARTTA-3', followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT-rich repeat motifs in New World monkeys, dinucleotide (TG repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG and tetranucleotide (TCTG and/or CCTG repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s by which Alu-mediated repeats developed into the large, extremely unstable expansions common to these three disorders.

  8. Recent spreading of a divergent canine parvovirus type 2a (CPV-2a) strain in a CPV-2c homogenous population.

    Science.gov (United States)

    Pérez, Ruben; Bianchi, Pablo; Calleros, Lucía; Francia, Lourdes; Hernández, Martín; Maya, Leticia; Panzera, Yanina; Sosa, Katia; Zoller, Stephanie

    2012-03-23

    Canine parvovirus type 2 (CPV-2), which causes acute hemorrhagic enteritis in dogs, is comprised of three antigenic variants (2a, 2b, and 2c) that are distributed worldwide with different frequencies. Variant prevalence was analyzed in 150 CPV-2-positive samples collected from the Uruguayan dog population in 2007-2010. Samples were analyzed with polymerase chain reaction, restriction fragment length polymorphism, and sequencing of the coding region for the largest and most variable loop of the VP2 capsid protein. CPV-2c was the only strain detected from 2007 to 2009. Uruguayan CPV-2c showed high homogeneity in both nucleotide and amino acid sequences, indicating a low level of genetic variability. In 2010, an unexpected epidemiological change occurred in Uruguay as a consequence of the appearance of a novel CPV-2a strain. This variant rapidly spread through the Uruguayan dog population and was detected in 20 of the 52 cases (38%) analyzed in 2010. CPV-2a sequences were identical in all field viruses analyzed, and in addition to the characteristic 426Asn residue, the sequences showed amino acid substitutions (267Tyr, 324Ile, and 440Ala) not observed in the Uruguayan CPV-2c. These data and the first detection in April 2010 suggest that the CPV-2a variant recently emerged in Uruguay and underwent clonal expansion. This observation is the first case in which a CPV-2a variant increased its frequency in a dog population where CPV-2c was prevalent. Our results emphasize the dynamic changes in CPV variants and highlight the importance of ongoing surveillance programs to provide a better understanding of virus epidemiology.

  9. Wasting mechanisms in muscular dystrophy.

    Science.gov (United States)

    Shin, Jonghyun; Tajrishi, Marjan M; Ogura, Yuji; Kumar, Ashok

    2013-10-01

    Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

  10. Genetics Home Reference: myotonic dystrophy

    Science.gov (United States)

    ... Me Understand Genetics Home Health Conditions myotonic dystrophy myotonic dystrophy Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Myotonic dystrophy is part of a group of inherited disorders ...

  11. Collagen VI microfibril formation is abolished by an {alpha}2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.

    Science.gov (United States)

    Tooley, Leona D; Zamurs, Laura K; Beecher, Nicola; Baker, Naomi L; Peat, Rachel A; Adams, Naomi E; Bateman, John F; North, Kathryn N; Baldock, Clair; Lamandé, Shireen R

    2010-10-22

    Collagen VI is an extracellular protein that most often contains the three genetically distinct polypeptide chains, α1(VI), α2(VI), and α3(VI), although three recently identified chains, α4(VI), α5(VI), and α6(VI), may replace α3(VI) in some situations. Each chain has a triple helix flanked by N- and C-terminal globular domains that share homology with the von Willebrand factor type A (VWA) domains. During biosynthesis, the three chains come together to form triple helical monomers, which then assemble into dimers and tetramers. Tetramers are secreted from the cell and align end-to-end to form microfibrils. The precise molecular mechanisms responsible for assembly are unclear. Mutations in the three collagen VI genes can disrupt collagen VI biosynthesis and matrix organization and are the cause of the inherited disorders Bethlem myopathy and Ullrich congenital muscular dystrophy. We have identified a Ullrich congenital muscular dystrophy patient with compound heterozygous mutations in α2(VI). The first mutation causes skipping of exon 24, and the mRNA is degraded by nonsense-mediated decay. The second mutation is a two-amino acid deletion in the C1 VWA domain. Recombinant C1 domains containing the deletion are insoluble and retained intracellularly, indicating that the mutation has detrimental effects on domain folding and structure. Despite this, mutant α2(VI) chains retain the ability to associate into monomers, dimers, and tetramers. However, we show that secreted mutant tetramers containing structurally abnormal C1 VWA domains are unable to associate further into microfibrils, directly demonstrating the critical importance of a correctly folded α2(VI) C1 domain in microfibril formation.

  12. [Dystroglycan linkage and muscular dystrophy].

    Science.gov (United States)

    Shimizu, Teruo

    2002-11-01

    Dystroglycan is a key complex between basal lamina laminin, extracellularly and membrano-cytoskeleton, intracellularly. The damage of this linkage is turned out to cause muscular dystrophies. Dystroglycan knockout is lethal. Dystroglycan-associated intracellular proteins such as dystrophin, dystrobrevin, sarcoglycans, plectin and caveolin-3 are responsible for causing severe (Duchenne type) and moderate forms (Becker, LGMDs). Laminin, dystroglycan-binding extracellular protein, is deficient in the most severe form of congenital muscular dystrophy with normal intelligence and eye. Recently, a remarkable progress is made in most severe forms of congenital muscular dystrophy with anomalies of brain and eye such as Fukuyama type (Japan) and muscle-eye-brain disease (Finland). The gene product for Fukuyama type, fukutin, belongs to a family of glycosylation enzymes in bacteria and yeast. Since alpha-dystroglycan contains 14-15 o-glycans, ser/thr-mannose 2-1 GlcNAc 4-1 Gal 3-2 Sial in the middle third mucin-domain and the sial-o-glycan is essential for laminin-binding, and since alpha-dystroglycan is defective in Fukuyama type sarcolemma with anti both sugar moiety- and peptide-antidodies, defective fukutin causes incomplete o-glycosylation of alpha-dystroglycan. In '02, it is clarified that a glycosylation enzyme, POMGnT1 which modifies GlcNAc onto ser/thr-mannose, is defective in 6 MEB patients. The loss of the enzyme activity is turned out to lose alpha-dystroglycan from sarcolemma of MEB. These data strongly suggests that o-glycosylation defect of alpha-dystroglycan causes the most severe congenital muscular dystrophy such as Fukuyama type, MEB and Walker Warburg syndrome.

  13. A type 2C protein phosphatase FgPtc3 is involved in cell wall integrity, lipid metabolism, and virulence in Fusarium graminearum.

    Directory of Open Access Journals (Sweden)

    Jinhua Jiang

    Full Text Available Type 2C protein phosphatases (PP2Cs play important roles in regulating many biological processes in eukaryotes. Currently, little is known about functions of PP2Cs in filamentous fungi. The causal agent of wheat head blight, Fusarium graminearum, contains seven putative PP2C genes, FgPTC1, -3, -5, -5R, -6, -7 and -7R. In order to investigate roles of these PP2Cs, we constructed deletion mutants for all seven PP2C genes in this study. The FgPTC3 deletion mutant (ΔFgPtc3-8 exhibited reduced aerial hyphae formation and deoxynivalenol (DON production, but increased production of conidia. The mutant showed increased resistance to osmotic stress and cell wall-damaging agents on potato dextrose agar plates. Pathogencity assays showed that ΔFgPtc3-8 is unable to infect flowering wheat head. All of the defects were restored when ΔFgPtc3-8 was complemented with the wild-type FgPTC3 gene. Additionally, the FgPTC3 partially rescued growth defect of a yeast PTC1 deletion mutant under various stress conditions. Ultrastructural and histochemical analyses showed that conidia of ΔFgPtc3-8 contained an unusually high number of large lipid droplets. Furthermore, the mutant accumulated a higher basal level of glycerol than the wild-type progenitor. Quantitative real-time PCR assays showed that basal expression of FgOS2, FgSLT2 and FgMKK1 in the mutant was significantly higher than that in the wild-type strain. Serial analysis of gene expression in ΔFgPtc3-8 revealed that FgPTC3 is associated with various metabolic pathways. In contrast to the FgPTC3 mutant, the deletion mutants of FgPTC1, FgPTC5, FgPTC5R, FgPTC6, FgPTC7 or FgPTC7R did not show aberrant phenotypic features when grown on PDA medium or inoculated on wheat head. These results indicate FgPtc3 is the key PP2C that plays a critical role in a variety of cellular and biological functions, including cell wall integrity, lipid and secondary metabolisms, and virulence in F. graminearum.

  14. Establishing baseline rod electroretinogram values in achromatopsia and cone dystrophy.

    Science.gov (United States)

    Wang, Isaac; Khan, Naheed W; Branham, Kari; Wissinger, B; Kohl, Susanne; Heckenlively, J R

    2012-12-01

    To establish the normal range of values for rod-isolated b-wave amplitudes in achromatopsia and cone dystrophies. We reviewed charts of 112 patients with various types of cone dystrophy, and compared their standardized electroretinographic rod b-wave amplitudes with age-matched normal controls. Twenty-six patients had known mutations in achromatopsia and cone dystrophy genes, while 53 were characterized by their inheritance pattern since they had yet to have their gene identified. Visual acuity information and scotomata were documented. We found that patients with achromatopsia and cone dystrophy had rod b-wave amplitudes that were significantly lower than age-matched controls, but found no evidence of rod amplitude progression nor loss of peripheral visual fields in the study group. We found that cone dystrophy patients of all types had depressed rod-isolated ERGs across the board. If typical diagnostic criteria are used, these patients might be considered to have "abnormal" rod-isolated electroretinographic values, and might be called "cone-rod dystrophy", even though the waveforms are stable for years. Patients with cone-rod dysfunction patterns on ERG can be better understood by also performing kinetic (Goldmann) visual fields, which will help to distinguish cone dystrophies from progressive cone-rod dystrophies by central scotomata size and progression over time in many forms of cone-rod dystrophy.

  15. Isolation and characterization of canine parvovirus type 2c circulating in Uruguay Isolamento e caracterização da cepa tipo 2c do parvovirus canino circulante no Uruguai

    Directory of Open Access Journals (Sweden)

    Andrea Blanc Pintos

    2011-08-01

    Full Text Available This research reports the first CPV-2c isolation in cell culture (canine fibroma cell line A-72 in Uruguay. The isolates were obtained from 13 rectal swabs of Uruguayan dogs with parvovirosis. Samples were submitted to PCR with two sets of primers, restriction fragment length polymorphism (RFLP, partial sequencing of the gene encoding for VP2 capsid protein and phylogenetic characterization. The strain isolated was confirmed as CPV-2c. These results contribute to a better knowledge of CPV strains circulating in Uruguay and promote an evaluation of the efficacy of heterologous vaccines used to protect against the circulating strains.Este trabalho relata o primeiro isolamento do CPV-2c em cultura de células (linhagem celular de fibroma canino A-72, no Uruguai. Os isolados foram obtidos a partir de 13 suabes retais de cães uruguaios com parvovirose. As amostras foram submetidas à reação em cadeia da polimerase (PCR com dois pares de primers, polimorfismo de comprimento de fragmentos de restrição (RFLP, sequenciamento parcial do gene que codifica a proteína capsidial VP2 e caracterização filogenética. A cepa isolada foi confirmada como CPV-2c. Os resultados contribuem para um melhor conhecimento das cepas do CPV circulantes no Uruguai e incitam uma maior investigação sobre a eficácia das vacinas produzidas com cepas heterólogas utilizadas atualmente para proteger contra cepas circulantes.

  16. LAMA2-related myopathy; frequency among congenital and limb-girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Løkken, Nicoline; Born, Alfred Peter; Duno, Morten;

    2015-01-01

    Introduction: Muscular dystrophy caused by LAMA2-gene mutations is an autosomal recessive disease typically presenting as a severe, early-onset congenital muscular dystrophy (CMD). However, milder cases with a limb-girdle type muscular dystrophy (LGMD) have been described. Methods: In this study...

  17. Vaccination of dogs with canine parvovirus type 2b (CPV-2b) induces neutralising antibody responses to CPV-2a and CPV-2c.

    Science.gov (United States)

    Wilson, Stephen; Illambas, Joanna; Siedek, Elisabeth; Stirling, Catrina; Thomas, Anne; Plevová, Edita; Sture, Gordon; Salt, Jeremy

    2014-09-22

    Since the identification of canine parvovirus type 2, three variants have subsequently been observed differing from the historical CPV-2 and each other by 1-2 amino acids only. As a result there has been considerable research into differential diagnostics, with some researchers indicating there is a need for new vaccines containing different strains of CPV-2. In this study we investigated whether vaccination with a CPV-2b containing vaccine would induce cross-reactive antibody responses to the other CPV-2 variants. Two studies where dogs were vaccinated with a multivalent vaccine, subsequently challenged with CPV-2b and sera samples analysed are presented. Six week old pups with defined serological status were vaccinated twice, three weeks apart and challenged either 5 weeks (MDA override study) or one year after vaccination (duration of immunity study). Sera samples were collected before each vaccination and at periods throughout each study. In each study the antibody profiles were very similar; serological responses against CPV-2a, CPV-2b and CPV-2c were higher than those for CPV-2. Nevertheless, responses against CPV-2 were well above levels considered clinically protective. In each study dogs also showed a rapid increase in antibody titres following vaccination, reached a plateau following second vaccination with a slight decline to challenge after which rapid anamnestic responses were seen. Evaluation of the serological responses suggests vaccination with CPV-2b would cross-protect against CPV-2a and CPV-2c, as well as against CPV-2 which is now extinct in the field. In conclusion we have demonstrated that vaccination of minimum aged dogs with a multivalent vaccine containing the CPV-2b variant strain will induce serological responses which are cross-reactive against all currently circulating field strains, CPV-2a and CPV-2c, and the now extinct field strain CPV-2.

  18. Somatic CTG•CAG repeat instability in a mouse model for myotonic dystrophy type 1 is associated with changes in cell nuclearity and DNA ploidy

    Directory of Open Access Journals (Sweden)

    Wieringa Bé

    2007-07-01

    Full Text Available Abstract Background Trinucleotide instability is a hallmark of degenerative neurological diseases like Huntington's disease, some forms of spinocerebellar ataxia and myotonic dystrophy type 1 (DM1. To investigate the effect of cell type and cell state on the behavior of the DM1 CTG•CAG repeat, we studied a knock-in mouse model for DM1 at different time points during ageing and followed how repeat fate in cells from liver and pancreas is associated with polyploidization and changes in nuclearity after the onset of terminal differentiation. Results After separation of liver hepatocytes and pancreatic acinar cells in pools with 2n, 4n or 8n DNA, we analyzed CTG•CAG repeat length variation by resolving PCR products on an automated PAGE system. We observed that somatic CTG•CAG repeat expansion in our DM1 mouse model occurred almost uniquely in the fraction of cells with high cell nuclearity and DNA ploidy and aggravated with aging. Conclusion Our findings suggest that post-replicative and terminal-differentiation events, coupled to changes in cellular DNA content, form a preconditional state that influences the control of DNA repair or recombination events involved in trinucleotide expansion in liver hepatocytes and pancreatic acinar cells.

  19. An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

    Science.gov (United States)

    Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

    2016-09-01

    Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable.

  20. EPR spectroscopy of MolB2C2-a reveals mechanism of transport for a bacterial type II molybdate importer.

    Science.gov (United States)

    Rice, Austin J; Alvarez, Frances J D; Schultz, Kathryn M; Klug, Candice S; Davidson, Amy L; Pinkett, Heather W

    2013-07-19

    In bacteria, ATP-binding cassette (ABC) transporters are vital for the uptake of nutrients and cofactors. Based on differences in structure and activity, ABC importers are divided into two types. Type I transporters have been well studied and employ a tightly regulated alternating access mechanism. Less is known about Type II importers, but much of what we do know has been observed in studies of the vitamin B12 importer BtuC2D2. MolB2C2 (formally known as HI1470/71) is also a Type II importer, but its substrate, molybdate, is ∼10-fold smaller than vitamin B12. To understand mechanistic differences among Type II importers, we focused our studies on MolBC, for which alternative conformations may be required to transport its relatively small substrate. To investigate the mechanism of MolBC, we employed disulfide cross-linking and EPR spectroscopy. From these studies, we found that nucleotide binding is coupled to a conformational shift at the periplasmic gate. Unlike the larger conformational changes in BtuCD-F, this shift in MolBC-A is akin to unlocking a swinging door: allowing just enough space for molybdate to slip into the cell. The lower cytoplasmic gate, identified in BtuCD-F as "gate I," remains open throughout the MolBC-A mechanism, and cytoplasmic gate II closes in the presence of nucleotide. Combining our results, we propose a peristaltic mechanism for MolBC-A, which gives new insight in the transport of small substrates by a Type II importer.

  1. LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity.

    Science.gov (United States)

    Yamashita, Yoshihiro; Matsuura, Tohru; Kurosaki, Tatsuaki; Amakusa, Yoshinobu; Kinoshita, Masanobu; Ibi, Tohru; Sahashi, Ko; Ohno, Kinji

    2014-09-01

    Myotonic dystrophy type 1 (DM1) is caused by transcription of CUG repeat RNA, which causes sequestration of muscleblind-like 1 (MBNL1) and upregulation of CUG triplet repeat RNA-binding protein (CUG-BP1). In DM1, dysregulation of these proteins contributes to many aberrant splicing events, causing various symptoms of the disorder. Here, we demonstrate the occurrence of aberrant splicing of LIM domain binding 3 (LDB3) exon 11 in DM1 skeletal muscle. Exon array surveys, RT-PCR, and western blotting studies demonstrated that exon 11 inclusion was DM1 specific and could be reproduced by transfection of a minigene containing the CTG repeat expansion. Moreover, we found that the LDB3 exon 11-positive isoform had reduced affinity for PKC compared to the exon 11-negative isoform. Since PKC exhibits hyperactivation in DM1 and stabilizes CUG-BP1 by phosphorylation, aberrant splicing of LDB3 may contribute to CUG-BP1 upregulation through changes in its affinity for PKC.

  2. Muscle force, balance and falls in muscular impaired individuals with myotonic dystrophy type 1: a five-year prospective cohort study.

    Science.gov (United States)

    Hammarén, Elisabet; Kjellby-Wendt, Gunilla; Lindberg, Christopher

    2015-02-01

    Individuals with myotonic dystrophy type 1 (DM1) have progressive muscle weakness with gait and balance impairments. We explored prospectively the natural history of muscle force, gait, balance, balance confidence and walking ability in muscular affected individuals with DM1. After five years data from 43 individuals (m/f:18/25) were analysed. All measures of balance showed statistically significant deterioration (p < 0.001) with averaged yearly loss of function by 3-4%. In the group as a whole, loss of muscle force was statistically significant in all lower limb muscles measured after five years: changes relative to baseline force were median -6% to -18%. For males muscle force loss was statistically significant in all leg muscles, but only in hip flexors for women. After five years 100% of the men had fallen during the previous year and 67% three times or more, in contrast only 60% of the women had fallen in the previous year and 36% three times or more. The proportion of individuals seeking medical care the previous year, after falling, was more than doubled after five years, albeit the number of falls had not changed. Awareness of this increased risk of falls is important for caregivers and patients.

  3. Assessing upper extremity capacity as a potential indicator of needs related to household activities for rehabilitation services in people with myotonic dystrophy type 1.

    Science.gov (United States)

    Raymond, Kateri; Auger, Louis-Pierre; Cormier, Marie-France; Vachon, Christine; St-Onge, Sabrina; Mathieu, Jean; Noreau, Luc; Gagnon, Cynthia

    2015-06-01

    This study aimed to assess upper extremity capacity as a potential indicator of needs related to household activities for rehabilitation services in people with myotonic dystrophy type 1 (DM1). A cross-sectional study was set in an outpatient neuromuscular clinic where 200 adults with a confirmed diagnosis of DM1 (121 women; mean age: 47 y) were selected from the registry of a neuromuscular clinic to participate. Housing-related activities were assessed using the "housing" section of the Assessment of Life Habits Questionnaire (LIFE-H). The upper extremity assessment included grip strength (Jamar dynamometer), lateral pinch strength (pinch gauge), gross dexterity (Box and Block Test) and fine dexterity (Purdue Pegboard Test). Correlations with the LIFE-H item "housing" were stronger for grip and lateral strength (r = 0.62; 0.61). When difficulties were present in "housing", the cut-off score associated with lateral pinch strength was 4.8 kg (sensitivity: 75.6%; specificity: 79.2%). Grip strength presented cut-off scores that clinically differed by gender. In conclusion, potential indicator of needs related to household activities for rehabilitation services with valid assessment tools were developed for people with DM1 who experience difficulties in housing-related activities. These criteria will assist health professionals in their attempt to refer DM1 patients to rehabilitation services at the appropriate time.

  4. A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans.

    Science.gov (United States)

    Krag, Thomas O; Vissing, John

    2015-12-01

    Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of α-dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely caused by progressive loss of α-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP in maintaining proper glycosylation of α-dystroglycan. The mild progression in the homozygous FKRP L276I model resembles that in patients with LGMD2I who are homozygous for the L276I mutation. This animal model could, therefore, be relevant for understanding the pathophysiology of and developing a treatment strategy for the human disorder.

  5. Quantitative Assessment of Trunk Muscles Involvement in Patients with Myotonic Dystrophy Type 1 Using a Whole Body Muscle Magnetic Resonance Imaging.

    Science.gov (United States)

    Park, Donghwi; Park, Jin-Sung

    2017-01-01

    The aim of this study was to analyze the pattern of trunk muscles involvement through a muscle MRI, in relation to the clinical data of patients diagnosed with myotonic dystrophy type 1 (DM1). Patients with DM1 who visited the neurology department were enrolled (n = 19). In all patients, the fatty degeneration of the muscle MRI in the lower cervical, upper thoracic, middle thoracic, and lumbosacral spine extensor muscle group and trunk flexor muscle group was evaluated. Clinical data, including CTG repeats, spinal deformity were analyzed to find the correlations with the fatty degeneration of trunk muscles in the muscle MRI. All DM1 patients who presented with very mild to severe functional status showed T1-weghted high intensity signals in the upper-thoracic spine extensor muscle group. The sum MRI score of the spine extensor muscle group showed a significant correlation with the 6-min walking test, and Cobb's angle. DM1 frequently affects the trunk muscles, even in the early stage of disease progression, regardless of disease severity or age of onset. Among the para-vertebral muscles, the selective involvement of spine extensor muscles may explain the cause of spinal deformities, which mirrors the functional status of DM1. © 2017 S. Karger AG, Basel.

  6. The D4Z4 macrosatellite repeat acts as a CTCF and A-type lamins-dependent insulator in facio-scapulo-humeral dystrophy.

    Directory of Open Access Journals (Sweden)

    Alexandre Ottaviani

    2009-02-01

    Full Text Available Both genetic and epigenetic alterations contribute to Facio-Scapulo-Humeral Dystrophy (FSHD, which is linked to the shortening of the array of D4Z4 repeats at the 4q35 locus. The consequence of this rearrangement remains enigmatic, but deletion of this 3.3-kb macrosatellite element might affect the expression of the FSHD-associated gene(s through position effect mechanisms. We investigated this hypothesis by creating a large collection of constructs carrying 1 to >11 D4Z4 repeats integrated into the human genome, either at random sites or proximal to a telomere, mimicking thereby the organization of the 4q35 locus. We show that D4Z4 acts as an insulator that interferes with enhancer-promoter communication and protects transgenes from position effect. This last property depends on both CTCF and A-type Lamins. We further demonstrate that both anti-silencing activity of D4Z4 and CTCF binding are lost upon multimerization of the repeat in cells from FSHD patients compared to control myoblasts from healthy individuals, suggesting that FSHD corresponds to a gain-of-function of CTCF at the residual D4Z4 repeats. We propose that contraction of the D4Z4 array contributes to FSHD physio-pathology by acting as a CTCF-dependent insulator in patients.

  7. Transforming growth factor type-β inhibits Mas receptor expression in fibroblasts but not in myoblasts or differentiated myotubes; Relevance to fibrosis associated to muscular dystrophies.

    Science.gov (United States)

    Cofre, Catalina; Acuña, María José; Contreras, Osvaldo; Morales, María Gabriela; Riquelme, Cecilia; Cabello-Verrugio, Claudio; Brandan, Enrique

    2015-01-01

    Duchenne muscular dystrophy is a genetic disorder characterized by myofiber degeneration, muscle weakness, and increased fibrosis. Transforming growth factor type-β (TGF-β), a central mediator of fibrosis, is upregulated in fibrotic diseases. Angiotensin-(1-7) [Ang-(1-7)] is a peptide with actions that oppose those of angiotensin-II (Ang II). Ang-(1-7) effects are mediated by the Mas receptor. Treatment with Ang-(1-7) produce positive effects in the mdx mouse, normalizing skeletal muscle architecture, decreasing local fibrosis, and fibroblasts, and improving muscle function. Mdx mice deficient for the Mas receptor showed the opposite effects. To identify the cell type(s) responsible for Mas receptor expression, and to characterize whether profibrotic effectors had any effect on its expression, we determined the effect of profibrotic agents on Mas expression. TGF-β, but not connective tissue growth factor or Ang-II, reduced the expression of Mas receptor in fibroblasts isolated from skeletal muscle cells and fibroblasts from two established cell lines. In contrast, no effects were observed in myoblasts and differentiated myotubes. This inhibition was mediated by the Smad-dependent (canonical) and the PI3K and MEK1/2 (noncanonical) TGF-β signaling pathways. When both canonical and noncanonical inhibitors of the TGF-β-dependent pathways were added together, the inhibitory effect of TGF-β on Mas expression was lost. The decrease in Mas receptor induced by TGF-β in fibroblasts reduced the Ang-(1-7) mediated stimulation of phosphorylation of AKT pathway proteins. These results suggest that reduction of Mas receptor in fibroblasts, by TGF-β, could increase the fibrotic phenotype observed in dystrophic skeletal muscle decreasing the beneficial effect of Ang-(1-7). © 2015 International Union of Biochemistry and Molecular Biology.

  8. Learning about Myotonic Dystrophy

    Science.gov (United States)

    ... of Genetic Tests Genomics and Health Disparities Genetic Discrimination Human Subjects Research Informed Consent for Genomics Research ... with myotonic dystrophy may have a characteristic facial appearance of wasting and weakness of the jaw and ...

  9. Muscular Dystrophy Association

    Science.gov (United States)

    ... Families Live Unlimited Read More Deflazacort demonstrates significant muscle strength improvement in DMD Read More NDA Filing ... the Boot to Support Kids and Adults with Muscular Dystrophy, ALS and Related Diseases Read More Visit ...

  10. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

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    Oriana del Rocío Cruz Guzmán

    2012-01-01

    Full Text Available Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset.

  11. ACTIVATION OF THE PHOSPHOLIPASE-C PATHWAY BY ATP IS MEDIATED EXCLUSIVELY THROUGH NUCLEOTIDE TYPE P2-PURINOCEPTORS IN C2C12 MYOTUBES

    NARCIS (Netherlands)

    HENNING, RH; DUIN, M; DENHERTOG, A; NELEMANS, A

    1993-01-01

    1 The presence of a nucleotide receptor and a discrete ATP-sensitive receptor on C2C12 myotubes has been shown by electrophysiological experiments. In this study, the ATP-sensitive receptors of C2C12 myotubes were further characterized by measuring the formation of inositol(1,4,5)trisphosphate

  12. ACTIVATION OF THE PHOSPHOLIPASE-C PATHWAY BY ATP IS MEDIATED EXCLUSIVELY THROUGH NUCLEOTIDE TYPE P2-PURINOCEPTORS IN C2C12 MYOTUBES

    NARCIS (Netherlands)

    HENNING, RH; DUIN, M; DENHERTOG, A; NELEMANS, A

    1993-01-01

    1 The presence of a nucleotide receptor and a discrete ATP-sensitive receptor on C2C12 myotubes has been shown by electrophysiological experiments. In this study, the ATP-sensitive receptors of C2C12 myotubes were further characterized by measuring the formation of inositol(1,4,5)trisphosphate (Ins(

  13. Construction of Tightened-Normal- Tightened Schemes of Type TNT-(n1, n2; c Indexed through Nano Quality Levels

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    R. RADHAKRISHNAN

    2011-07-01

    Full Text Available Motorola (1980 introduced the concept of six sigma as a quality philosophy and a management strategy, which when adopted in a system of organization will reduce wastages and increase the profit to themanagement results in enhancing the satisfaction of the customer. If this concept of Six Sigma is adopted in an organization it can results in 3.4 or lower number of defects per million opportunities in the long run. In recent days many companies in developed and developing countries started working beyond Six Sigma level andthereby the performance level increases with number of defectives reduced to near zero level. In those situations a more stringent quality level than six sigma quality level is regarded to construct the sampling plan. In this paper a procedure for the construction of Tightened-Normal-Tightened Schemes of Type TNT-(n1, n2; c indexed through producer’s Nano quality level (PNQL and consumer’s Nano quality level (CNQL is presented and suitable tables are also provided for the easy selection of the plans.

  14. Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1: A multicentre cohort follow-up study

    Science.gov (United States)

    Robb, Yvonne; Cumming, Sarah; Gregory, Helen; Duncan, Alexis; Rahman, Monika; McKeown, Anne; McWilliam, Catherine; Dean, John; Wilcox, Alison; Farrugia, Maria E.; Cooper, Anneli; McGhie, Josephine; Adam, Berit; Petty, Richard; Longman, Cheryl; Findlay, Iain; Japp, Alan; Monckton, Darren G.; Denvir, Martin A.

    2017-01-01

    Objective High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). Methods 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. Results Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level < 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. Conclusions Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting. PMID:28323905

  15. Is one trial enough for repeated testing? Same-day assessments of walking, mobility and fine hand use in people with myotonic dystrophy type 1.

    Science.gov (United States)

    Kierkegaard, Marie; Petitclerc, Emilie; Hébert, Luc J; Gagnon, Cynthia

    2017-02-01

    Performance-based assessments of physical function are essential in people with myotonic dystrophy type 1 (DM1) to monitor disease progression and evaluate interventions. Commonly used are the six-minute walk test, the 10 m-walk test, the timed up-and-go test, the timed-stands test, grip strength tests and the nine-hole peg test. The number of trials needed on a same-day test occasion and whether the first, best or average of trials should be reported as result is unknown. Thus, the aim was to describe and explore differences between trials in these measures of walking, mobility and fine hand use in 70 adults with DM1. Three trials were performed for each test except for the six-minute walk test where two trials were allowed. There were statistical significant differences over trials in all tests except for the 10 m-walk test and grip strength tests. Pair-wise comparisons showed that the second and third trials were in general better than the first, although effect sizes were small. At which trial the individuals performed their best differed between individuals and tests. People with severe muscular impairment had difficulties to perform repeated trials. Intraclass correlation coefficients were all high in analyses exploring how to report results. The conclusion and clinical implication is that, for a same-day test occasion, one trial is sufficient for the 10 m-walk test and grip strength tests, and that repeated trials should be allowed in the timed up-and-go test, timed-stands test and nine-hole peg tests. We recommend that two trials are performed for these latter tests as such a protocol could accommodate people with various levels of impairments and physical limitations.

  16. [Current studies in myotonic dystrophy].

    Science.gov (United States)

    Zhao, Yimeng; Ishiura, Shoichi

    2014-03-01

    Myotonic dystrophy (DM) is a genetic, progressive, multisystemic disease with muscular disorder as its primary symptom. There are two types of DM (DM1 and DM2) caused by mutations in different genes, and in Japan, DM occurs with an incidence of approximately 1 in 20,000. The pathogenic mechanism underlying the disease is RNA toxicity caused by transcripts of aberrantly elongated CTG or CCTG repeats located in the 3' untranslated region or in the intron. The current treatments for DM is limited to symptomatic care. In this review, we will discuss several new therapeutic strategies based on recent studies of RNA toxicity.

  17. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease.

    Science.gov (United States)

    Minnerop, Martina; Weber, Bernd; Schoene-Bake, Jan-Christoph; Roeske, Sandra; Mirbach, Sandra; Anspach, Christian; Schneider-Gold, Christiane; Betz, Regina C; Helmstaedter, Christoph; Tittgemeyer, Marc; Klockgether, Thomas; Kornblum, Cornelia

    2011-12-01

    Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T(1)/T(2)/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (P(corrected) brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1

  18. Occult Macular Dystrophy

    Directory of Open Access Journals (Sweden)

    Işıl Sayman Muslubaş

    2016-04-01

    Full Text Available Occult macular dystrophy is an inherited macular dystrophy characterized by a progressive decline of bilateral visual acuity with normal fundus appearance, fluorescein angiogram and full-field electroretinogram. This case report presents a 20-year-old female patient with bilateral progressive decline of visual acuity for six years. Her visual acuity was 3-4/10 in both eyes. Anterior segment and fundus examination, fluorescein angiogram and full-field electroretinogram were normal. She could read all Ishihara pseudoisochromatic plates. Fundus autofluorescence imaging was normal. There was a mild central hyporeflectance on fundus infrared reflectance imaging in both eyes. Reduced foveal thickness and alterations of the photoreceptor inner and outer segment junction were observed by optical coherence tomography in both eyes. Central scotoma was also found by microperimetry and reduced central response was revealed by multifocal electroretinogram in both eyes. These findings are consistent with the clinical characteristics of occult macular dystrophy

  19. Open reduction and internal fixation of OTA type C2-C4 fractures of the calcaneus with a triple-plate technique.

    Science.gov (United States)

    Brunner, Alexander; Müller, Jochen; Regazzoni, Pietro; Babst, Reto

    2012-01-01

    to 34°; SD 8.7°) at the final follow-up, and the mean postoperative Gissane's angle was 108.6° (range 80° to 140°; SD 11.8°), which finally decreased to 102.4° (range 72° to 126°; SD 12.7°). No statistically significant differences regarding Böhler's and Gissane's angles were found between different OTA fracture types. In conclusion, the presented surgical technique was found to provide comparable and adequate reduction of OTA type C2-C4 injuries based on statistically insignificant differences in radiographic measures of postoperative fracture reduction. Greater limitation in subtalar motion was observed in OTA type C4 fractures in comparison with less severe fractures (p < .01).

  20. 4-Phenylbutyric acid reduces mutant-TGFBIp levels and ER stress through activation of ERAD pathway in corneal fibroblasts of granular corneal dystrophy type 2.

    Science.gov (United States)

    Choi, Seung-Il; Lee, Eunhee; Jeong, Jang Bin; Akuzum, Begum; Maeng, Yong-Sun; Kim, Tae-Im; Kim, Eung Kweon

    2016-09-02

    Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the transforming growth factor β-induced (TGFBI) gene. In GCD2 corneal fibroblasts, secretion of the accumulated mutant TGFBI-encoded protein (TGFBIp) is delayed via the endoplasmic reticulum (ER)/Golgi-dependent secretory pathway. However, ER stress as the pathogenic mechanism underlying GCD2 has not been fully characterized. The aim of this study was to confirm whether ER stress is linked to GCD2 pathogenesis and whether the chemical chaperone, 4-phenylbutyric acid (4-PBA), could be exploited as a therapy for GCD2. We found that the ER chaperone binding immunoglobulin protein (BiP) and the protein disulfide isomerase (PDI) were elevated in GCD2. Western bolt analysis also showed a significant increase in both the protein levels and the phosphorylation of the key ER stress kinases, inositol-requiring enzyme 1α (IRE1α) and double stranded RNA activated protein kinase (PKR)-like ER kinase, as well as in levels of their downstream targets, X box-binding protein 1 (XBP1) and activating transcription factor 4, respectively, in GCD2 corneal fibroblasts. GCD2 cells were found to be more susceptible to ER stress-induced cell death than were wild-type corneal fibroblasts. Treatment with 4-PBA considerably reduced the levels of BiP, IRE1α, and XBP1 in GCD2 cells; notably, 4-PBA treatment significantly reduced the levels of TGFBIp without change in TGFBI mRNA levels. In addition, TGFBIp levels were significantly reduced under ER stress and this reduction was considerably suppressed by the ubiquitin proteasome inhibitor MG132, indicating TGFBIp degradation via the ER-associated degradation pathway. Treatment with 4-PBA not only protected against the GCD2 cell death induced by ER stress but also significantly suppressed the MG132-mediated increase in TGFBIp levels under ER stress. Together, these results suggest that ER stress might comprise an important factor in GCD2 pathophysiology and

  1. Epidemiological and Molecular Characterization of a Mexican Population Isolate with High Prevalence of Limb-Girdle Muscular Dystrophy Type 2A Due to a Novel Calpain-3 Mutation

    Science.gov (United States)

    Pantoja-Melendez, Carlos A.; Miranda-Duarte, Antonio; Roque-Ramirez, Bladimir; Zenteno, Juan C.

    2017-01-01

    Limb-Girdle Muscular Dystrophy type 2 (LGMD2) is a group of autosomally recessive inherited disorders defined by weakness and wasting of the shoulder and pelvic girdle muscles. In the past, several population isolates with high incidence of LGMD2 arising from founder mutation effects have been identified. The aim of this work is to describe the results of clinical, epidemiologic, and molecular studies performed in a Mexican village segregating numerous cases of LGMD2. A population census was conducted in the village to identify all LGMD affected patients. Molecular analysis included genome wide homozygosity mapping using a 250K SNP Affymetrix microarray followed by PCR amplification and direct nucleotide sequencing of the candidate gene. In addition, DNA from 401 randomly selected unaffected villagers was analyzed to establish the carrier frequency of the LGMD2 causal mutation. A total of 32 LGMD2 patients were identified in the village, rendering a disease prevalence of 4.3 (CI: 2.9–5.9) cases per 1,000 habitants (1 in 232). Genome wide homozygosity mapping revealed that affected individuals shared a 6.6 Mb region of homozygosity at chromosome 15q15. The identified homozygous interval contained CAPN3, the gene responsible for LGMD2 type A (LGMD2A). Direct sequencing of this gene revealed homozygosity for a novel c.348C>A mutation (p.Ala116Asp) in DNA from all 20 affected subjects available for genetic screening, except one which was heterozygous for the mutation. In such patient, a heterozygous c.2362AG>TCATCT deletion/insertion was recognized as the second CAPN3 mutation. Western blot and autocatalytic activity analyses in protein lysates from skeletal muscle biopsy obtained from a p.Ala116Asp homozygous patient suggested that this particular mutation increased the autocatalytic activity of CAPN3. Thirty eigth heterozygotes of the p.Ala116Asp mutation were identified among 401 genotyped unaffected villagers, yielding a population carrier frequency of 1 in 11

  2. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hsu-Pin; Hsu, Shu-Yuan [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Wu, Wen-Ai; Hu, Ji-Wei [Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Ouyang, Pin, E-mail: ouyang@mail.cgu.edu.tw [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Molecular Medicine Research Center, Chang Gung University, Taiwan (China)

    2014-01-03

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.

  3. Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness

    Science.gov (United States)

    Prehn, Christian; Krogias, Christos; Schneider, Ruth; Klein, Jan; Gold, Ralf; Lukas, Carsten

    2015-01-01

    Objectives Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). Methods 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. Results Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected. Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. Conclusion GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes

  4. Limb girdle muscular dystrophies

    DEFF Research Database (Denmark)

    Vissing, John

    2016-01-01

    PURPOSE OF REVIEW: The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these conditions. RECENT FINDINGS: Close to half of all LGMD subtypes have been...

  5. Dominant cystoid macular dystrophy

    NARCIS (Netherlands)

    Saksens, N.T.M.; Huet, R.A.C. van; Lith-Verhoeven, J.J. van; Hollander, A.I. den; Hoyng, C.B.; Boon, C.J.

    2015-01-01

    OBJECTIVE: To describe the clinical characteristics and long-term follow-up in patients with autosomal dominant cystoid macular dystrophy (DCMD). DESIGN: Retrospective case series. PARTICIPANTS: Ninety-seven patients with DCMD. METHODS: Extensive ophthalmic examination, including visual acuity (VA),

  6. Central areolar choroidal dystrophy.

    NARCIS (Netherlands)

    Boon, C.J.F.; Klevering, B.J.; Cremers, F.P.M.; Zonneveld-Vrieling, M.N.; Theelen, T.; Hollander, A.I. den; Hoyng, C.B.

    2009-01-01

    OBJECTIVE: To describe the clinical characteristics, follow-up data and molecular genetic background in a large group of patients with central areolar choroidal dystrophy (CACD). DESIGN: Retrospective case series study. PARTICIPANTS: One hundred three patients with CACD from the Netherlands. METHODS

  7. Genetics Home Reference: Bietti crystalline dystrophy

    Science.gov (United States)

    ... Understand Genetics Home Health Conditions Bietti crystalline dystrophy Bietti crystalline dystrophy Enable Javascript to view the expand/ ... boxes. Download PDF Open All Close All Description Bietti crystalline dystrophy is a disorder in which numerous ...

  8. Ndrg2 is a PGC-1α/ERRα target gene that controls protein synthesis and expression of contractile-type genes in C2C12 myotubes.

    Science.gov (United States)

    Foletta, Victoria C; Brown, Erin L; Cho, Yoshitake; Snow, Rod J; Kralli, Anastasia; Russell, Aaron P

    2013-12-01

    The stress-responsive, tumor suppressor N-myc downstream-regulated gene 2 (Ndrg2) is highly expressed in striated muscle. In response to anabolic and catabolic signals, Ndrg2 is suppressed and induced, respectively, in mouse C2C12 myotubes. However, little is known about the mechanisms regulating Ndrg2 expression in muscle, as well as the biological role for Ndrg2 in differentiated myotubes. Here, we show that Ndrg2 is a target of a peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and estrogen-related receptor alpha (ERRα) transcriptional program and is induced in response to endurance exercise, a physiological stress known also to increase PGC-1α/ERRα activity. Analyses of global gene and protein expression profiles in C2C12 myotubes with reduced levels of NDRG2, suggest that NDRG2 affects muscle growth, contractile properties, MAPK signaling, ion and vesicle transport and oxidative phosphorylation. Indeed, suppression of NDRG2 in myotubes increased protein synthesis and the expression of fast glycolytic myosin heavy chain isoforms, while reducing the expression of embryonic myosin Myh3, other contractile-associated genes and the MAPK p90 RSK1. Conversely, enhanced expression of NDRG2 reduced protein synthesis, and furthermore, partially blocked the increased protein synthesis rates elicited by a constitutively active form of ERRα. In contrast, suppressing or increasing levels of NDRG2 did not affect mRNA expression of genes involved in mitochondrial biogenesis that are regulated by PGC-1α or ERRα. This study shows that in C2C12 myotubes Ndrg2 is a novel PGC-1α/ERRα transcriptional target, which influences protein turnover and the regulation of genes involved in muscle contraction and function.

  9. Synthesis of scroll-type composite microtubes of Mo2C/MoCO by controlled pyrolysis of Mo(CO)6.

    Science.gov (United States)

    Li, Xiao-Lin; Li, Ya-Dong

    2004-01-23

    Composite microtubes of Mo(2)C/MoCO have been synthesized for the first time under well-controlled conditions by thermal decomposition of Mo(CO)(6) at about 600 degrees C. Here, thermal stability and phase transition of the products, as well as the influence of reaction temperature and argon flow rate, have been carefully investigated. All samples were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The reaction model and rolling mechanism were proposed on the basis of the experimental facts.

  10. Severe dystrophy in DiGeorge syndrome

    Institute of Scientific and Technical Information of China (English)

    Barnabás Rózsai; (A)kos Kiss; Gy(o)rgyi Csábi; Márta Czakó; Tamás Decsi

    2009-01-01

    We present the case history of a 3-year-old girl who was examined because of severe dystrophy. In the background, cow's milk allergy was found, but her body weight was unchanged after eliminating milk from her diet. Other types of malabsorption were excluded. Based on nasal regurgitation and facial dysmorphisms, the possibility of DiGeorge syndrome was suspected and was confirmed by fluorescence in situ hybridization. The authors suggest a new feature associated with DiGeorge syndrome.

  11. JAZF1 promotes proliferation of C2C12 cells, but retards their myogenic differentiation through transcriptional repression of MEF2C and MRF4—Implications for the role of Jazf1 variants in oncogenesis and type 2 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Yuasa, Katsutoshi; Aoki, Natsumi; Hijikata, Takao, E-mail: hijikata@musashino-u.ac.jp

    2015-08-15

    Single-nucleotide polymorphisms associated with type 2 diabetes (T2D) have been identified in Jazf1, which is also involved in the oncogenesis of endometrial stromal tumors. To understand how Jazf1 variants confer a risk of tumorigenesis and T2D, we explored the functional roles of JAZF1 and searched for JAZF1 target genes in myogenic C2C12 cells. Consistent with an increase of Jazf1 transcripts during myoblast proliferation and their decrease during myogenic differentiation in regenerating skeletal muscle, JAZF1 overexpression promoted cell proliferation, whereas it retarded myogenic differentiation. Examination of myogenic genes revealed that JAZF1 overexpression transcriptionally repressed MEF2C and MRF4 and their downstream genes. AMP deaminase1 (AMPD1) was identified as a candidate for JAZF1 target by gene array analysis. However, promoter assays of Ampd1 demonstrated that mutation of the putative binding site for the TR4/JAZF1 complex did not alleviate the repressive effects of JAZF1 on promoter activity. Instead, JAZF1-mediated repression of Ampd1 occurred through the MEF2-binding site and E-box within the Ampd1 proximal regulatory elements. Consistently, MEF2C and MRF4 expression enhanced Ampd1 promoter activity. AMPD1 overexpression and JAZF1 downregulation impaired AMPK phosphorylation, while JAZF1 overexpression also reduced it. Collectively, these results suggest that aberrant JAZF1 expression contributes to the oncogenesis and T2D pathogenesis. - Highlights: • JAZF1 promotes cell cycle progression and proliferation of myoblasts. • JAZF1 retards myogenic differentiation and hypertrophy of myotubes. • JAZF1 transcriptionally represses Mef2C and Mrf4 expression. • JAZF1 has an impact on the phosphorylation of AMPK.

  12. Muscle diseases: the muscular dystrophies.

    Science.gov (United States)

    McNally, Elizabeth M; Pytel, Peter

    2007-01-01

    Dystrophic muscle disease can occur at any age. Early- or childhood-onset muscular dystrophies may be associated with profound loss of muscle function, affecting ambulation, posture, and cardiac and respiratory function. Late-onset muscular dystrophies or myopathies may be mild and associated with slight weakness and an inability to increase muscle mass. The phenotype of muscular dystrophy is an endpoint that arises from a diverse set of genetic pathways. Genes associated with muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, and the sarcomere and Z band, as well as nuclear membrane components. Because muscle has such distinctive structural and regenerative properties, many of the genes implicated in these disorders target pathways unique to muscle or more highly expressed in muscle. This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups.

  13. Anoctamin 5 muscular dystrophy in Denmark

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, Morten; Petri, Helle

    2013-01-01

    Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic...... characteristics, and muscle protein expression. All patients in our neuromuscular unit with genetically unclassified, recessive limb girdle muscular dystrophy (LGMD2), Miyoshi-type distal myopathy (MMD) or persistent asymptomatic hyperCK-emia (PACK) were assessed for mutations in the ANO5 gene. Genetically...... confirmed patients were evaluated with muscular and cardiopulmonary examination. Among 40 unclassified patients (28 LGMD2, 5 MMD, 7 PACK), 20 were homozygous or compound heterozygous for ANO5 mutations, (13 LGMD2, 5 MMD, 2 PACK). Prevalence of ANO5 deficiency in Denmark was estimated at 1:100.000 and ANO5...

  14. Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I.

    Science.gov (United States)

    Vannoy, Charles H; Zhou, Haowen; Qiao, Chunping; Xiao, Xiao; Bang, Anne G; Lu, Qi L

    2017-02-01

    Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s). Here, we test whether mAgrin might also improve pathologies associated with FKRP-related dystroglycanopathies, another form of muscular dystrophy characterized by weak interactions between muscle and basement membranes. We demonstrate in vitro that mAgrin enhances laminin binding to primary myoblasts and fibroblasts from an FKRP mutant mouse model and that this enhancement is abrogated when mAgrin is in molar excess relative to laminin. However, in vivo delivery of mAgrin via adeno-associated virus (AAV) into FKRP mutant mice was unable to improve dystrophic phenotypes, both histologically and functionally. These results likely reflect insufficient binding of mAgrin to hypoglycosylated α-DG on muscle fibers and possibly abrogation of binding from molar excess of overexpressed AAV-delivered mAgrin. Further exploration of mAgrin modification is necessary to strengthen its binding to other membrane components, including hypoglycosylated α-DG, for potential therapeutic applications. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  15. Type 2C protein phosphatase Ptc6 participates in activation of the Slt2-mediated cell wall integrity pathway in Saccharomyces cerevisiae.

    Science.gov (United States)

    Sharmin, Dilruba; Sasano, Yu; Sugiyama, Minetaka; Harashima, Satoshi

    2015-04-01

    The phosphorylation status of cellular proteins results from an equilibrium between the activities of protein kinases and protein phosphatases (PPases). Reversible protein phosphorylation is an important aspect of signal transduction that regulate many biological processes in eukaryotic cells. The Saccharomyces cerevisiae genome encodes 40 PPases, including seven members of the protein phosphatase 2C subfamily (PTC1 to PTC7). In contrast to other PPases, the cellular roles of PTCs have not been investigated in detail. Here, we sought to determine the cellular role of PTC6 in S. cerevisiae with disruption of PTC genes. We found that cells with Δptc6 disruption were tolerant to the cell wall-damaging agents Congo red (CR) and calcofluor white (CFW); however, cells with simultaneous disruption of PTC1 and PTC6 were very sensitive to these agents. Thus, simultaneous disruption of PTC1 and PTC6 gave a synergistic response to cell wall damaging agents. The level of phosphorylated Slt2 increased significantly after CR treatment in Δptc1 cells and more so in Δptc1Δptc6 cells; therefore, deletion of PTC6 enhanced Slt2 phosphorylation in the Δptc1 disruptant. The level of transcription of KDX1 upon exposure to CR increased to a greater extent in the Δptc1Δptc6 double disruptant than the Δptc1 single disruptant. The Δptc1Δptc6 double disruptant cells showed normal vacuole formation under standard growth conditions, but fragmented vacuoles were present in the presence of CR or CFW. Our analyses indicate that S. cerevisiae PTC6 participates in the negative regulation of Slt2 phosphorylation and vacuole morphogenesis under cell wall stress conditions.

  16. Association between peroxisome proliferator-activated receptor-γcoactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shao-ling; LU Wen-sheng; YAN Li; WU Mu-chao; XU Ming-tong; CHEN Li-hong; CHENG Hua

    2007-01-01

    Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-Y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1a and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C.Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C.Results Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P<0.01). Even in controls, the 482Ser(A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly(G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between

  17. Constituents of Dragon's Blood. 5. Dracoflavans B1, B2, C1, C2, D1, and D2, new A-type deoxyproanthocyanidins.

    Science.gov (United States)

    Arnone, A; Nasini, G; Vajna de Pava, O; Merlini, L

    1997-10-01

    From Dragon's Blood, a resin produced by plants of the genus Daemonorops (Palmae), six new A-type flavanoid deoxyproanthocyanidins have been isolated. Their structure and stereochemistry, established by chemical degradation and extensive NMR analysis, is consistent with a mechanism of formation common to other constituents of the resin, which involves oxidation of a 6-methylflavan to a quinonemethide, followed by coupling with another flavan moiety.

  18. Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Hauerslev, S; Ørngreen, Mette Cathrine; Hertz, Jens Michael;

    2013-01-01

    The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A.......The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A....

  19. Modifying muscular dystrophy through TGFβ

    OpenAIRE

    Ceco, Ermelinda; McNally, Elizabeth M.

    2013-01-01

    Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing ef...

  20. Morphologic imaging in muscular dystrophies and inflammatory myopathies

    Energy Technology Data Exchange (ETDEWEB)

    Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick [CHU de Lille, Clinique neurologique, Lille (France); Morillon, David; Cotten, Anne [CHRU de Lille, Service de Radiologie Osteoarticulaire, Hopital Roger Salengro, Lille (France); Stojkovic, Tanya [G-H Pitie-Salpetriere, Institut de Myologie, Paris (France)

    2010-12-15

    To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

  1. [Duchenne muscular dystrophy pathophysiology].

    Science.gov (United States)

    Péréon, Y; Mercier, S; Magot, A

    2015-12-01

    Dystrophin is a large cytoskeletal protein located at the plasma membrane in both muscle and non-muscle tissues, which mediates interactions between the cytoskeleton, cell membrane, and extracellular matrix. Dystrophin is a key component of multiprotein complexes (dystrophin- associated glycoprotein complex, or DGC). It is also involved in many intracellular cascades affecting membrane proteins such as calcium channels, or various signalisation pathways. In Duchenne Muscular Dystrophy, both dystrophin and DGC proteins are missing. This induces excessive membrane fragility and permeability, dysregulation of calcium homeostasis, oxidative damage, which in turn favour muscle cell necrosis. The latter is initially followed by regeneration. With age, the regenerative capacity of the muscles appears to be exhausted and muscle fibres are gradually replaced by connective and adipose tissue. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. Adult foveomacular vitelliform dystrophy

    Directory of Open Access Journals (Sweden)

    Valdir Balarin

    2013-06-01

    Full Text Available Adult foveomacular vitelliform dystrophy is a rare pathology. Less than 1% of the reported cases display perifoveal capillary permeability. The three-year follow-up period of the case revealed a rare form, which had not yet been documented. The patient was a 40-year-old female with normal visual acuity, and a minor complaint of metamorphopsia on the left eye. Retinography showed a perifoveal yellowish subretinal area OS.Angiography showed perifoveal leakage OS. Follow up showed that, over 3 years, capillary incompetence disappeared and the yellow area underwent alterations, becoming atrophic OS. Angiography also showed hyperfluorescence (windows defect. Towards the end, it resembled the appearance of late stage of Best's Disease.

  3. Paternal transmission of congenital myotonic dystrophy.

    OpenAIRE

    Bergoffen, J; Kant, J.; Sladky, J; McDonald-McGinn, D; Zackai, E H; Fischbeck, K H

    1994-01-01

    The congenital form of myotonic dystrophy is reported to be almost exclusively, if not exclusively, maternally transmitted. We present a case of congenital myotonic dystrophy which was inherited from a mildly affected father. This family illustrates that the congenital form of myotonic dystrophy can occur without intrauterine or other maternal factors related to the disease. The possibility of paternal transmission of the congenital form of myotonic dystrophy could be considered when counsell...

  4. Limb-girdle muscular dystrophy subtypes First-reported cohort from northeastern China*

    Institute of Scientific and Technical Information of China (English)

    Omar Abdulmonem Mahmood; Xinmei Jiang; Qi Zhang

    2013-01-01

    The relative frequencies of different subtypes of limb-girdle muscular dystrophies vary widely among different populations. We estimated the percentage of limb-girdle muscular dystrophy sub-types in Chinese people based on 68 patients with limb-girdle muscular dystrophy from the Myology Clinic, Neurology Department, First Hospital of Jilin University, China. A diagnosis of calpainopathy was made in 12 cases (17%), and dysferlin deficiency in 10 cases (15%). Two biopsies revealedα-sarcoglycan deficiency (3%), and two others revealed a lack of caveolin-3 (3%). A diagnosis of unclassified limb-girdle muscular dystrophy was made in the remaining patients (62%). The ap-pearances of calpain 3-and dysferlin-deficient biopsies were similar, though rimmed vacuoles were unique to dysferlinopathy, while inflammatory infiltrates were present in both these limb-girdle muscular dystrophy type 2D biopsies. Macrophages were detected in seven dysferlinopathy biop-sies. The results of this study suggest that the distribution of limb-girdle muscular dystrophy sub-types in the Han Chinese population is similar to that reported in the West. The less necrotic, re-generating and inflammatory appearance of limb-girdle muscular dystrophy type 2A, but with more lobulated fibers, supports the idea that calpainopathy is a less active, but more chronic disease than dysferlinopathy. Unusual features indicated an extended limb-girdle muscular dystrophy disease spectrum. The use of acid phosphatase stain should be considered in suspected dysferlinopathies. To the best of our knowledge, this is the first report to define the relative proportions of the various forms of limb-girdle muscular dystrophy in China, based on protein testing.

  5. [A benign variant of the course of Duchenne muscular dystrophy in a child with short stature].

    Science.gov (United States)

    Badalian, L O; Temin, P A; Kamennykh, L N; Zavadenko, N N; Nikanorova, M Iu; Arkhipov, B A; Malygina, N A

    1991-01-01

    The authors describe a case of a benign variety of progressive Duchenne type muscular dystrophy in a 8-year-old short-stature boy. Provide the electromyographic and electroneuromyographic data, measurements of the growth hormone in blood serum and osseous age. Make suggestions about coupled inheritance of progressive Duchenne type muscular dystrophy and short stature . The latter one is likely to be attended by a decrease of anabolic processes, which may determine a more benign course of the myodystrophic process.

  6. A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, AJ; de Visser, M; van Meegen, M; Ginjaar, HB; van Essen, AJ; Jennekens, FGI; Jongen, PJH; Leschot, NJ; Bolhuis, PA

    1998-01-01

    Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family

  7. A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, AJ; de Visser, Marianne; van Meegen, M; Ginjaar, HB; van Essen, AJ; Jennekens, FGI; Jongen, PJH; Leschot, NJ; Bolhuis, PA

    Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family

  8. [Chronologic study of signs of myocardiopathy in progressive muscular dystrophy].

    Science.gov (United States)

    Barona Zamora, P; Narbona García, J; Alvarez Gómez, M J; Fidalgo Andrés, M L; Sáenz de Buruaga, J; Villa Elizaga, I

    1993-02-01

    In order to analyze the evolution of cardiomyopathy in progressive muscular dystrophies, thirty-three patients (17 with Duchenne type, 11 with Becker type and 5 with the autosomal recessive type dystrophy) were studied retrospectively. Cardiac and systemic follow-up every 3-6 months was made in 29 patients. The electrocardiogram was the first test that became altered, followed by the echocardiogram and thoracic radiograph and finally heart failure manifestations. There was a direct correlation between age and the appearance of abnormal cardiac tests. Electrocardiographic alterations, in patients who were less than 12.5 years of age, were significantly more frequent in the group with Duchenne dystrophy that in the no-Duchenne group. In regards to the appearance of the echocardiographic and radiographic abnormalities, there were no significant differences between the two groups. However, we have noticed a trend towards a more frequent and earlier presentation of these abnormalities in the Duchenne's muscular dystrophy than in the no-Duchenne group.

  9. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1.

    Directory of Open Access Journals (Sweden)

    Sandra J Feeney

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.

  10. Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

    Science.gov (United States)

    Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

    2008-01-01

    A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

  11. Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

    Science.gov (United States)

    Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

    2008-01-01

    A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

  12. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy

    DEFF Research Database (Denmark)

    Vissing, John; Barresi, Rita; Witting, Nanna;

    2016-01-01

    Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation...... creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did...... affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered...

  13. Genetics of corneal endothelial dystrophies

    Indian Academy of Sciences (India)

    Chitra Kannabiran

    2009-12-01

    The corneal endothelium maintains the level of hydration in the cornea. Dysfunction of the endothelium results in excess accumulation of water in the corneal stroma, leading to swelling of the stroma and loss of transparency. There are four different corneal endothelial dystrophies that are hereditary, progressive, non-inflammatory disorders involving dysfunction of the corneal endothelium. Each of the endothelial dystrophies is genetically heterogeneous with different modes of transmission and/or different genes involved in each subtype. Genes responsible for disease have been identified for only a subset of corneal endothelial dystrophies. Knowledge of genes involved and their function in the corneal endothelium can aid understanding the pathogenesis of the disorder as well as reveal pathways that are important for normal functioning of the endothelium.

  14. Limb-girdle muscular dystrophy subtypes: First-reported cohort from northeastern China.

    Science.gov (United States)

    Mahmood, Omar Abdulmonem; Jiang, Xinmei; Zhang, Qi

    2013-07-15

    The relative frequencies of different subtypes of limb-girdle muscular dystrophies vary widely among different populations. We estimated the percentage of limb-girdle muscular dystrophy subtypes in Chinese people based on 68 patients with limb-girdle muscular dystrophy from the Myology Clinic, Neurology Department, First Hospital of Jilin University, China. A diagnosis of calpainopathy was made in 12 cases (17%), and dysferlin deficiency in 10 cases (15%). Two biopsies revealed α-sarcoglycan deficiency (3%), and two others revealed a lack of caveolin-3 (3%). A diagnosis of unclassified limb-girdle muscular dystrophy was made in the remaining patients (62%). The appearances of calpain 3- and dysferlin-deficient biopsies were similar, though rimmed vacuoles were unique to dysferlinopathy, while inflammatory infiltrates were present in both these limb-girdle muscular dystrophy type 2D biopsies. Macrophages were detected in seven dysferlinopathy biopsies. The results of this study suggest that the distribution of limb-girdle muscular dystrophy subtypes in the Han Chinese population is similar to that reported in the West. The less necrotic, regenerating and inflammatory appearance of limb-girdle muscular dystrophy type 2A, but with more lobulated fibers, supports the idea that calpainopathy is a less active, but more chronic disease than dysferlinopathy. Unusual features indicated an extended limb-girdle muscular dystrophy disease spectrum. The use of acid phosphatase stain should be considered in suspected dysferlinopathies. To the best of our knowledge, this is the first report to define the relative proportions of the various forms of limb-girdle muscular dystrophy in China, based on protein testing.

  15. Corneal stromal dystrophies: a clinical pathologic study

    Directory of Open Access Journals (Sweden)

    Elvira Barbosa Abreu

    2012-12-01

    Full Text Available INTRODUCTION: Corneal dystrophy is defined as bilateral and symmetric primary corneal disease, without previous associated ocular inflammation. Corneal dystrophies are classified according to the involved corneal layer in superficial, stromal, and posterior dystrophy. Incidence of each dystrophy varies according to the geographic region studied. PURPOSE: To evaluate the prevalence of stromal corneal dystrophies among corneal buttons specimens obtained by penetrating keratoplasty (PK in an ocular pathology laboratory and to correlate the diagnosis with patient age and gender. METHODS: Corneal button cases of penetrating keratoplasty from January-1996 to May-2009 were retrieved from the archives of The Henry C. Witelson Ophthalmic Pathology Laboratory and Registry, Montreal, Canada. The cases with histopathological diagnosis of stromal corneal dystrophies were stained with special stains (Peroxid acid Schiff, Masson trichrome, Congo red analyzed under polarized light, and alcian blue for classification and correlated with epidemiological information (age at time of PK and gender from patients' file. RESULTS: 1,300 corneal buttons cases with clinical diagnose of corneal dystrophy were retrieved. Stromal corneal dystrophy was found in 40 (3.1% cases. Lattice corneal dystrophy was the most prevalent with 26 cases (65%. Nineteen were female (73.07% and the PK was performed at average age of 59.3 years old. Combined corneal dystrophy was found in 8 (20% cases, 5 (62.5% of them were female and the average age of the penetrating keratoplasty was 54.8 years old. Granular corneal dystrophy was represented by 5 (12.5% cases, and 2 (40% of them were female. Penetrating keratoplasty was performed at average age of 39.5 years old in granular corneal dystrophy cases. Macular corneal dystrophy was present in only 1 (2.5% case, in a 36 years old female. CONCLUSION: Systematic histopathological approach and evaluation, including special stains in all stromal

  16. Developing 2 C-compatible investment criteria

    Energy Technology Data Exchange (ETDEWEB)

    Roeser, Frauke [NewClimate - Institute for Climate Policy and Global Sustainability gGmbH, Bonn (Germany); Weischer, Lutz [Germanwatch e.V., Koeln (Germany); Thomae, Jakob [2degrees Investing Initiative, New York, NY (United States); Hoehne, Niklas; Hagemann, Markus; El Alaoui, Alexander; Bals, Christoph; Eckstein, David; Kreft, Soenke; Rosse, Morten

    2015-11-30

    This report studies the development of criteria for assessing the compatibility of financial investments with the international goal to limit global temperature increase to below 2 C above pre-industrial levels. The findings are intended as a starting point and a key input for a longer term process to develop consensus-based 2 C investing criteria. The focus here is placed on investments in projects and physical assets, in particular of development and climate finance organisations. In order to limit global temperature increase to 2 C, global greenhouse gas (GHG) emissions will have to be reduced significantly, eventually to zero, during the course of this century. This requires shifting capital from high to low carbon investments as well as significant capital mobilisation for investments in 2 C-compatible infrastructure. Given the long lifetime of physical assets, and the urgency of decarbonisation over the coming decades, this needs to begin today. Public financial institutions can play a prominent role in contributing to aligning investment flows with the 2 C limit, as well as in closing the current infrastructure investment gap, responding to their explicit or implicit climate mandates and leadership role in the finance sector. The majority of international financial institutions integrate climate considerations into their finance decisions to some degree, and are familiar with different types of criteria, including positive and negative lists, qualitative and quantitative benchmarks, and the use of shadow carbon pricing. However, current approaches do not link to the 2 C limit. 2 C investment criteria are therefore needed to guide investors in this regard. Such criteria may also support other purposes, including an understanding of climate risks and improved reporting and accountability.

  17. Benign concentric annular macular dystrophy

    Directory of Open Access Journals (Sweden)

    Luísa Salles de Moura Mendonça

    2015-06-01

    Full Text Available The purpose of the authors is to show clinical findings of a patient with benign concentric annular macular dystrophy, which is an unusual condition, and part of the "bull’s eye" maculopathy differential diagnosis. An ophthalmologic examination with color perception, fluorescein angiography, and ocular electrophysiology was performed.

  18. Prednisone Therapy for Duchenne Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-02-01

    Full Text Available The effects of prednisone on muscle function and the extent of steroid-related adverse effects were studied in 17 ambulant children with Duchenne muscular dystrophy (DMD at University Hospital, Groningen; Rehabilitation Centre, Utrecht; and Leiden University Medical Centre, the Netherlands.

  19. Glucocorticoids for Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-07-01

    Full Text Available Investigators at the Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, and other centers in the UK, conducted a prospective longitudinal study across 17 neuromuscular centers in the UK of 360 boys aged 3-15 years with Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off prednisolone for a mean duration of 4 years.

  20. Inherited myopathies and muscular dystrophies

    NARCIS (Netherlands)

    Cardamone, Michael; Darras, Basil T.; Ryan, Monique M.

    The inherited myopathies and muscular dystrophies are a diverse group of muscle diseases presenting with common complaints and physical signs: weakness, motor delay, and respiratory and bulbar dysfunction. The myopathies are caused by genetic defects in the contractile apparatus of muscle, and

  1. AMPUTATION AND REFLEX SYMPATHETIC DYSTROPHY

    NARCIS (Netherlands)

    GEERTZEN, JHB; EISMA, WH

    Reflex sympathetic dystrophy is a chronic pain syndrome characterized by chronic burning pain, restricted range of motion, oedema and vasolability. Patients are difficult to treat and the prognosis is very often poor. This report emphasizes that an amputation in case of a reflex sympathetic

  2. Porcine models of muscular dystrophy

    Science.gov (United States)

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

  3. The role of stem cells in muscular dystrophies.

    Science.gov (United States)

    Meregalli, Mirella; Farini, Andrea; Colleoni, Federica; Cassinelli, Letizia; Torrente, Yvan

    2012-06-01

    Muscular dystrophies are heterogeneous neuromuscular disorders of inherited origin, including Duchenne muscular dystrophy (DMD). Cell-based therapies were used to promote muscle regeneration with the hope that the host cells repopulated the muscle and improved muscle function and pathology. Stem cells were preferable for therapeutic applications, due to their capacity of self-renewal and differentiative potential. In the last years, encouraging results were obtained with adult stem cells to treat muscular dystrophies. Adult stem cells were found into various tissues of the body and they were able to maintain, generate, and replace terminally differentiated cells within their own specific tissue because of cell turnover or tissue injury. Moreover, it became clear that these cells could participate into regeneration of more than just their resident organ. Here, we described multiple types of muscle and non muscle-derived myogenic stem cells, their characterization and their possible use to treat muscular dystrophies. We also underlined that most promising possibility for the management and therapy of DMD is a combination of different approaches, such as gene and stem cell therapy.

  4. Neurotrophins, cytokines, oxidative parameters and funcionality in Progressive Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    CLARISSA M. COMIM

    2015-09-01

    Full Text Available We investigated the levels of brain derived-neurotrophic factor (BDNF, cytokines and oxidative parameters in serum and tried to correlate them with the age and functionality of patients with Progressive Muscle Dystrophies (PMD. The patients were separated into six groups (case and controls pared by age and gender, as follows: Duchenne Muscular Dystrophy (DMD; Steinert Myotonic Dystrophy (SMD; and Limb-girdle Muscular Dystrophy type-2A (LGMD2A. DMD patients (±17.9 years old had a decrease of functionality, an increase in the IL-1β and TNF-α levels and a decrease of IL-10 levels and superoxide dismutase activity in serum. SMD patients (±25.8 years old had a decrease of BDNF and IL-10 levels and superoxide dismutase activity and an increase of IL-1β levels in serum. LGMD2A patients (±27.7 years old had an decrease only in serum levels of IL-10. This research showed the first evidence of BDNF involvement in the SMD patients and a possible unbalance between pro-inflammatory and anti-inflammatory cytokine levels, along with decreased superoxide dismutase activity in serum of DMD and SMD patients.

  5. Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies

    Directory of Open Access Journals (Sweden)

    A. Romigi

    2013-01-01

    Full Text Available Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert’s Disease and myotonic dystrophy type 2 (DM2. Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB, periodic limb movements (PLMS, central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype. Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea, REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies.

  6. Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

    OpenAIRE

    Scharner, Juergen; Brown, Charlotte A; Bower, Matthew; Iannaccone, Susan T.; Khatri, Ismail A.; Escolar, Diana; Gordon, Erynn; Felice, Kevin; Crowe, Carol A; Grosmann, Carla; Meriggioli, Matthew N.; Asamoah, Alexander; Gordon, Ora; Gnocchi, Viola F.; Ellis, Juliet A.

    2011-01-01

    Abstract Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal-Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD) and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the USA and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA...

  7. A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.

    Science.gov (United States)

    Morales, Fernando; Vásquez, Melissa; Santamaría, Carolina; Cuenca, Patricia; Corrales, Eyleen; Monckton, Darren G

    2016-04-01

    Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p<0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p=0.003); Rs1677658 (p=0.009); and Rs10168 (p=0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target.

  8. Infection par le virus de l'herpès humain de type 8 (HHV8) et inflammation : implications dans le diabète de type 2 cétonurique.

    OpenAIRE

    Lontchi Yimagou, Eric

    2015-01-01

    Ketosis-Prone Diabetes (KPD) is a diabetes phenotype intermediate between type 1 and type 2 diabetes, frequently encountered in populations of African origin. This form of diabetes arouses some interest because of its clinical course marked in particular by restoring the initial impaired insulin secretion. Sobngwi et al. in 2008 established an association between HHV-8 virus and KPD in African population living in France. Nowhere else has the study been replicated. The objective of this thesi...

  9. Pattern Dystrophy of the Macula in a Case of Steinert Disease

    Directory of Open Access Journals (Sweden)

    Filipe Esteves

    2013-09-01

    Full Text Available Introduction: Myotonic dystrophies are typically associated with ocular complications like ptosis, weakness of the ocular muscle and cataracts, but also with less recognized retinal changes. Case Report: A 41-year-old female with type 1 myotonic dystrophy complained of progressive vision loss. Slit lamp examination revealed the presence of typical bilateral polychromatic cataract with posterior subcapsular component. Dilated fundus examination was remarkable for bilateral macular depigmented changes. Multimodal imaging analysis of the macula suggested the presence of a butterfly-shaped pattern dystrophy. Discussion: In cases of myotonic dystrophies it is of great relevance to analyze the presence of retinal changes that might limit the visual improvement following cataract extraction.

  10. Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

    Science.gov (United States)

    2017-07-11

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Disease; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  11. The analysis of the clinical and tool parameters characterizing a cardiomyopathyat various forms of the progressing muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Poverennova I.E.

    2017-03-01

    Full Text Available Purpose: studying of clinical and tool characteristics of cardiomyopathies at various forms of the progressing muscular dystrophies. Material and methods. There had been 103 patients with hereditary forms of the progressing muscular dystrophies examined, among which 35 persons were with Duchenne muscular dystrophy, 28 with an atrophic myo-tonia, and 40 with a limb girdle dystrophy is conducted. Assessment of clinical and tool features of cardiomyopathies at these types of the hereditary progressing muscular dystrophies had been carried out. Results. In the group of patients with diffusion damage of a myocardium in the form of dystrophic violations had been revealed. Existence of a negative tooth of T in some assignments and lengthenings of an interval of QT is noted. With a dystrophic myotonia violation of a warm rhythm occurred at patients by 87 times more often than in the group of comparison. Violation of a rhythm of heart in group of patients with a limb girdle dystrophy came to light 91 times more often in reference to the group of comparison. Conclusion. Violations in a cardiovascular system at Duchenne muscular dystrophy are preferentially diffusion changes in a myocardium. At a dystrophic myotonia and a limb girdle dystrophy cardial violations concern mainly excitability and the conductivity of heart which are the main reason of developing of this disease at these patients.

  12. lemmingA encodes the Apc11 subunit of the APC/C in Drosophila melanogaster that forms a ternary complex with the E2-C type ubiquitin conjugating enzyme, Vihar and Morula/Apc2

    Directory of Open Access Journals (Sweden)

    Nagy Olga

    2012-03-01

    Full Text Available Abstract Background Ubiquitin-dependent protein degradation is a critical step in key cell cycle events, such as metaphase-anaphase transition and mitotic exit. The anaphase promoting complex/cyclosome (APC/C plays a pivotal role in these transitions by recognizing and marking regulatory proteins for proteasomal degradation. Its overall structure and function has been elucidated mostly in yeasts and mammalian cell lines. The APC/C is, however, a multisubunit assembly with at least 13 subunits and their function and interaction within the complex is still relatively uncharacterized, particularly in metazoan systems. Here, lemming (lmg mutants were used to study the APC/C subunit, Apc11, and its interaction partners in Drosophila melanogaster. Results The lmg gene was initially identified through a pharate adult lethal P element insertion mutation expressing developmental abnormalities and widespread apoptosis in larval imaginal discs and pupal abdominal histoblasts. Larval neuroblasts were observed to arrest mitosis in a metaphase-like state with highly condensed, scattered chromosomes and frequent polyploidy. These neuroblasts contain high levels of both cyclin A and cyclin B. The lmg gene was cloned by virtue of the lmg03424 P element insertion which is located in the 5' untranslated region. The lemming locus is transcribed to give a 2.0 kb mRNA that contains two ORFs, lmgA and lmgB. The lmgA ORF codes for a putative protein with more than 80% sequence homology to the APC11 subunit of the human APC/C. The 85 amino acid protein also contains a RING-finger motif characteristic of known APC11 subunits. The lmgA ORF alone was sufficient to rescue the lethal and mitotic phenotypes of the lmg138 null allele and to complement the temperature sensitive lethal phenotype of the APC11-myc9 budding yeast mutant. The LmgA protein interacts with Mr/Apc2, and they together form a binding site for Vihar, the E2-C type ubiquitin conjugating enzyme. Despite

  13. Benzalkonium Chloride Accelerates the Formation of the Amyloid Fibrils of Corneal Dystrophy-associated Peptides*

    Science.gov (United States)

    Kato, Yusuke; Yagi, Hisashi; Kaji, Yuichi; Oshika, Tetsuro; Goto, Yuji

    2013-01-01

    Corneal dystrophies are genetic disorders resulting in progressive corneal clouding due to the deposition of amyloid fibrils derived from keratoepithelin, also called transforming growth factor β-induced protein (TGFBI). The formation of amyloid fibrils is often accelerated by surfactants such as sodium dodecyl sulfate (SDS). Most eye drops contain benzalkonium chloride (BAC), a cationic surfactant, as a preservative substance. In the present study, we aimed to reveal the role of BAC in the amyloid fibrillation of keratoepithelin-derived peptides in vitro. We used three types of 22-residue synthetic peptides covering Leu110-Glu131 of the keratoepithelin sequence: an R-type peptide with wild-type R124, a C-type peptide with C124 associated with lattice corneal dystrophy type I, and a H-type peptide with H124 associated with granular corneal dystrophy type II. The time courses of spontaneous amyloid fibrillation and seed-dependent fibril elongation were monitored in the presence of various concentrations of BAC or SDS using thioflavin T fluorescence. BAC and SDS accelerated the fibrillation of all synthetic peptides in the absence and presence of seeds. Optimal acceleration occurred near the CMC, which suggests that the unstable and dynamic interactions of keratoepithelin peptides with amphipathic surfactants led to the formation of fibrils. These results suggest that eye drops containing BAC may deteriorate corneal dystrophies and that those without BAC are preferred especially for patients with corneal dystrophies. PMID:23861389

  14. Fungal keratitis in Lattice dystrophy

    Directory of Open Access Journals (Sweden)

    Chatterjee Samrat

    2010-01-01

    Full Text Available We report a case of fungal keratitis occurring in a patient with lattice dystrophy. A 57-year-old farmer presented with a corneal ulcer following probable entry of paddy husk in the right eye, of one month duration. Corneal scraping revealed pigmented fungal filaments while culture grew Alternaria alternata. Treatment with 5% natamycin eye drops and 1% atropine healed the infection in four weeks. We would like to draw attention to the fact that the cornea in lattice dystrophy is prone to frequent erosions and is a compromised epithelial barrier to invasion by microorganisms. Patients must be made aware of this fact and should seek attention at the earliest following any trivial trauma. Management of minor corneal abrasions in them should be directed at healing the epithelium with adequate lubricants and preventing infection with topical antibiotic prophylaxis.

  15. Translational Research for Muscular Dystrophy

    Science.gov (United States)

    2014-05-01

    by successful treatment of patient mutations. In Aim 3, we have completed generation of a DBA/2J congenic mdx strain that appears to better model the...in-frame deletions that are expected to arise by successful treatment of patient mutations. Our transgenic experiments will model the best-case...macrophage infiltration and necrosis), weight loss after weaning, joint contractures , kyphosis, dystrophy of extraocular muscles, abnormal

  16. Bietti crystalline dystrophy and choroidal neovascularisation.

    Science.gov (United States)

    Gupta, B; Parvizi, S; Mohamed, M D

    2011-02-01

    Bietti crystalline dystrophy is a rare autosomal recessive condition characterised by the presence of crystals in the retina and is followed by retinal and choroidal degeneration. We present a novel finding of juxtafoveal choroidal neovascularisation in Bietti crystalline dystrophy and demonstrate a spectral domain optical coherence tomography image of this disorder.

  17. LW2C-220型开关直动密封部位SF6气体超标泄漏质量缺陷分析%Quality Defect Analysis of SF6 Gas Leakage Exceeding Standard on LW2C- 220 Type Switch Translation Sealed Part

    Institute of Scientific and Technical Information of China (English)

    白银川

    2004-01-01

    通过对一组LW2C-220型SF6开关进行检漏试验,发现其直动密封部位SF6气体超标泄漏.文章针对此事故和测试的过程进行了分析说明,并提出了动态检漏的新观念,对今后SF6电器检漏试验工作具有指导意义.

  18. Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy

    Science.gov (United States)

    Burch, Peter M.; Pogoryelova, Oksana; Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Morris, Carl

    2015-01-01

    Abstract Background: Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy. Objective: The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury. Method: Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls. Results: All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog. Conclusions: These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies. PMID:26870665

  19. Keratoconus in Patients with Macular Stromal Dystrophy.

    Science.gov (United States)

    Kosrirukvongs, Panida; Ngowyutagon, Panotsom; Booranapong, Wipawee

    2016-01-01

    To show the association between keratoconus and macular dystrophy. All patients with macular dystrophy and associated clinical findings leading to a diagnosis of keratoconus by corneal topography were retrospectively reviewed during a 10-year period. Uncorrected and best-corrected visual acuity, automated refraction, manifest refraction, corneal thickness, and corneal curvature by corneal topography were evaluated Three patients with macular dystrophy exhibiting decreased vision, multifocal white dense deposits, and haze surrounding the deposits in the corneal stroma were evaluated. All had a steep corneal curvature of >47 diopters and a thin cornea consistent with keratoconus. Penetrating keratoplasty was performed in one patient with severely decreased vision. Macular dystrophy was diagnosed based on an Alcian blue-stained pathological specimen. Keratoconus may develop as a result of changes associated with macular dystrophy. Therefore, patients with severely decreased vision should be evaluated for keratoconus to ensure proper management.

  20. Distrofia miotônica tipo 1 em pacientes com catarata: diagnóstico molecular para triagem e aconselhamento genético Myotonic dystrophy type 1 in cataract patients: Molecular diagnosis for screening and genetic counseling

    Directory of Open Access Journals (Sweden)

    María Verónica Muñoz Rojas

    2005-02-01

    Full Text Available OBJETIVOS: Detectar novos pacientes portadores da mutação e pré-mutação da DM1, entre pacientes com catarata e realizar aconselhamento genético. MÉTODOS: Foi estudado o DNA de 60 pacientes, por meio da análise por reação em cadeia de polimerase. Este estudo foi realizado no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto e os pacientes foram selecionados a partir dos atendimentos realizados no Ambulatório de Catarata do Departamento de Oftalmologia, entre 01/01/1982 a 30/06/1995. Os critérios de seleção foram pacientes com menos de 55 anos, com catarata bilateral, sem fator causal que justificasse a lesão, exceto por diabete melito tipo 2 com ou sem sinais neuromusculares sugestivos de distrofia miotônica. RESULTADOS: Foram encontrados 3 pacientes com a mutação completa, correspondendo a 5% da amostra. Nenhum portador da pré-mutação foi encontrado. A partir dos pacientes diagnosticados, outros familiares afetados foram detectados. CONCLUSÕES: Este estudo enfatiza a importância da triagem de distrofia miotônica tipo 1 (DM1 entre pacientes com catarata, e mostra, também, a importância do aconselhamento genético destes pacientes.PURPOSE: To detect MD1 premutation and full mutation carriers among cataract patients and offer familial genetic counseling. METHODS: We studied the DNA of 60 selected cataract patients through polymerase chain reaction analysis. This study was performed at the "Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto" where selected patients had been examined at the Cataract Outpatient Clinic from 01/01/1982 to 30/06/1995. Selection criteria were age under 55 with no obvious precipitating factor, except diabetes mellitus type 2, with or without neuromuscular signs suggestive of myotonic dystrophy. RESULTS: Three patients were found to have a full mutation corresponding to 5% of the group. Additional affected individuals were found among patients' relatives. No

  1. Muscular dystrophy meets protein biochemistry, the mother of invention.

    Science.gov (United States)

    Funk, Steven D; Miner, Jeffrey H

    2017-03-01

    Muscular dystrophies result from a defect in the linkage between the muscle fiber cytoskeleton and the basement membrane (BM). Congenital muscular dystrophy type MDC1A is caused by mutations in laminin α2 that either reduce its expression or impair its ability to polymerize within the muscle fiber BM. Defects in this BM lead to muscle fiber damage from the force of contraction. In this issue of the JCI, McKee and colleagues use a laminin polymerization-competent, designer chimeric BM protein in vivo to restore function of a polymerization-defective laminin, leading to normalized muscle structure and strength in a mouse model of MDC1A. Delivery of such a protein to patients could ameliorate many aspects of their disease.

  2. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... MD Living With MD en español Qué significa distrofia muscular Over Labor Day, just as you're ... grown-up. This article talks about two types: Duchenne and Becker MD. Generally, only boys get Duchenne ...

  3. Ti2C80 is more likely a titanium carbide endohedral metallofullerene (Ti2C2)@C78.

    Science.gov (United States)

    Tan, Kai; Lu, Xin

    2005-09-21

    We show by means of density functional calculations that the previously synthesized metallofullerene Ti2C80 does not take the form of Ti2@C80, but is a titanium carbide endohedral metallofullerene, Ti2C2@C78, that has a C78(6-)(D3h) cage which follows faithfully the stable closed-shell electronic rule.

  4. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    Science.gov (United States)

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

  5. What Are the Types of Muscular Dystrophy?

    Science.gov (United States)

    ... appear at birth or during infancy Develop chronic shortening of muscles or tendons around joints, which prevents joints from ... People with this form may also Develop chronic shortening of muscles around joints (preventing them from moving freely), in ...

  6. Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Hori, Yusuke S; Kuno, Atsushi; Hosoda, Ryusuke; Tanno, Masaya; Miura, Tetsuji; Shimamoto, Kazuaki; Horio, Yoshiyuki

    2011-09-01

    Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+)-dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of δ-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and δ-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of α-smooth muscle actin (α-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-β1 (TGF-β1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-β1-induced increase in reactive oxygen species, fibronectin production, and expression of α-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.

  7. Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-α2 chain-null congenital muscular dystrophy mice.

    Science.gov (United States)

    Aoki, Yoshitsugu; Nagata, Tetsuya; Yokota, Toshifumi; Nakamura, Akinori; Wood, Matthew J A; Partridge, Terence; Takeda, Shin'ichi

    2013-12-15

    Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches to the treatment of several neuromuscular disorders including Duchenne muscular dystrophy. The main weakness of this approach arises from the low efficiency and sporadic nature of the delivery of charge-neutral PMO into muscle fibers, the mechanism of which is unknown. In this study, to test our hypothesis that muscle fibers take up PMO more efficiently during myotube formation, we induced synchronous muscle regeneration by injection of cardiotoxin into the tibialis anterior muscle of Dmd exon 52-deficient mdx52 and wild-type mice. Interestingly, by in situ hybridization, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibers. In addition, we showed that PMO or 2'-O-methyl phosphorothioate is taken up efficiently into C2C12 myotubes when transfected 24-72 h after the induction of differentiation but is poorly taken up into undifferentiated C2C12 myoblasts suggesting efficient uptake of PMO in the early stages of C2C12 myotube formation. Next, we tested the therapeutic potential of PMO for laminin-α2 chain-null dy(3K)/dy(3K) mice: a model of merosin-deficient congenital muscular dystrophy (MDC1A) with active muscle regeneration. We confirmed the recovery of laminin-α2 chain and slightly prolonged life span following skipping of the mutated exon 4 in dy(3K)/dy(3K) mice. These findings support the idea that PMO entry into fibers is dependent on a developmental stage in myogenesis rather than on dystrophinless muscle membranes and provide a platform for developing PMO-mediated therapies for a variety of muscular disorders, such as MDC1A, that involve active muscle regeneration.

  8. The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes

    DEFF Research Database (Denmark)

    Stage, Tore B; Christensen, Mette M H; Feddersen, Søren

    2013-01-01

    OBJECTIVE: The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse...

  9. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle F Goody

    Full Text Available Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction

  10. Sarcopenia and sarcopenic obesity in patients with muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Luciano eMerlini

    2014-10-01

    Full Text Available Aging sarcopenia and muscular dystrophy are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called sarcopenic obesity characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with muscular dystrophy we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual energy X-ray absorptiometry (DXA, for muscle strength hand held dynamometry, and for physical performance gait speed. The study involved 14 adult patients with different types of muscular dystrophy. We were able to demonstrate that all patient were sarcopenic-obese. We showed in fact that all were sarcopenic based on appendicular lean, fat & bone free, mass index (ALMI. In addition all resulted obese according to the % of body fat determined by DXA in contrast with their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by hand held dynamometry, and physical performances determined by gait speed and respiratory function. Finally we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggest the relevance of a proper evaluation of body composition in muscular dystrophy and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia.

  11. Uncovering the profile of mutations of transforming growth factor beta-induced gene in Chinese corneal dystrophy patients

    Directory of Open Access Journals (Sweden)

    Xiao-Dan Hao

    2016-02-01

    Full Text Available AIM: To uncover the mutations profile of transforming growth factor beta-induced (TGFBI gene in Chinese corneal dystrophy patients and further investigate the characteristics of genotype-phenotype correlations. METHODS: Forty-two subjects (6 unrelated families including 15 patients and 8 unaffected members, and 19 sporadic patients of Chinese origin were subjected to phenotypic and genotypic characterization. The corneal phenotypes of patients were documented by slit lamp photography. Mutation screening of the coding regions of TGFBI was performed by direct sequencing. RESULTS: We detected four corneal dystrophy types. The most frequent phenotypes were granular corneal dystrophy (GCD (including 3 families and 8 sporadic patients and lattice corneal dystrophy (LCD (including 2 families and 9 sporadic patients. The next phenotypes were corneal dystrophy of Bowman layer (CDB (1 family and 1 sporadic patient and epithelial basement membrane dystrophy (EBMD (1 sporadic patient. Six distinct mutations responsible for TGFBI corneal dystrophies were identified in 30 individuals with corneal dystrophies. Those were, p.R124H mutation in 1 family and 2 sporadic patients with GCD, p.R555W mutation in 2 families and 3 sporadic patients with GCD, p.R124C mutation in 2 families and 7 sporadic patients with LCD, p.A620D mutation in 1 sporadic patient with LCD, p.H626R mutation in 1 sporadic patient with LCD, and p.R555Q in 1 family and 1 sporadic patient with CDB. No mutation was detected in the remaining 3 atypical GCD patients and 1 EBMD patient. CONCLUSION: GCD and LCD are the most frequent phenotypes in Chinese population. R555W was the most common mutation for GCD; R124C was the most common mutation for LCD. Our findings extend the mutational spectrum of TFGBI, and this is the extensively delineated TGFBI mutation profile associated with the various corneal dystrophies in the Chinese population.

  12. [Muscular Dystrophies Involving the Retinal Function].

    Science.gov (United States)

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis.

  13. Anesthesia for a Patient with Myotonic Dystrophy

    Directory of Open Access Journals (Sweden)

    Dilek Kalaycı

    2016-09-01

    Full Text Available Myotonic dystrophy is the most common myotonic syndrome causing abnormalities of the skeletal and smooth muscles as well as problems related to the cardiac, gastrointestinal and endocrine systems. In affected people, reduced functional residual capacity, vital capacity, and peak inspiratory pressure are observed within the respiratory system. As would be expected, anesthetic management of these patients is challenging for anesthesiologists. In addition, delayed recovery from anesthesia and cardiac and pulmonary complications may develop in the intraoperative and early postoperative periods due to sensitivity to sedatives, anesthetic agents, and neuromuscular blocking agents. Myotonic dystrophy can be performed with the use of appropriate anesthesia procedures as well as carefully communication between anesthesiologists and surgeons. In conclusion, myotonic dystrophy has variations, which makes it important to preoperatively determine specific surgical and anesthetic management strategies for each patient. In this article, we present a patient with myotonic dystrophy who underwent laparoscopic cholecystectomy surgery for symptomatic cholelithiasis and to discuss the relevant literature.

  14. Duchenne muscular dystrophy - a molecular service

    African Journals Online (AJOL)

    Duchenne muscular dystrophy using molecular technology was instituted at the ..... utilising non-fat dry milk for analysis of proteins and nucleic acids transferred ... acid to high specific activity in vitro by nick translation with DNA polymerase.

  15. Non-Coding RNAs in Muscle Dystrophies

    Directory of Open Access Journals (Sweden)

    Alessandra Ferlini

    2013-09-01

    Full Text Available ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies.

  16. Prevalence of generalized retinal dystrophy in Denmark

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Bregnhøj, Jesper F;

    2014-01-01

    of this study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in the Danish population. METHODS: A population-based cross-sectional study with data from the Danish Retinitis Pigmentosa Registry that comprises all patients in Denmark with generalized retinal....... RESULTS: Of the 5,602,628 Danish citizens on January 1, 2013, 1622 patients were registered as having a generalized retinal dystrophy and were alive and living in Denmark, corresponding to a prevalence of 1:3,454. In 28% of cases the eye condition was part of a syndrome, while the remaining 72% had eye...... disease only. Aside from simplex cases (45%), the most common hereditary pattern was autosomal recessive (23%). CONCLUSION: This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in the Danish population is 1:3454. Many of the dystrophies are the subjects of clinical...

  17. Targeting latent TGFβ release in muscular dystrophy.

    Science.gov (United States)

    Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

    2014-10-22

    Latent transforming growth factor-β (TGFβ) binding proteins (LTBPs) bind to inactive TGFβ in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGFβ release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGFβ signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGFβ release and activity and decrease inflammation and muscle damage in muscular dystrophy.

  18. Ventilatory support in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Wohlgemuth, M.; Kooi, E.L. van der; Kesteren, R.G. van; Maarel, S.M. van der; Padberg, G.W.A.M.

    2004-01-01

    Respiratory insufficiency due to respiratory muscle weakness is a common complication of many neuromuscular diseases. The prevalence of respiratory failure in facioscapulohumeral muscular dystrophy (FSHD) is unknown. The authors identified 10 FSHD patients on nocturnal ventilatory support at home,

  19. Brain MRI Findings in Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-03-01

    Full Text Available Brain magnetic resonance imaging (MRI findings in 13 patients with congenital muscular dystrophy (MDCIC and Fukutin-related protein (FKRP gene mutations were retrospectively reviewed in a study at Hammersmith Hospital, London, UK, and European centers.

  20. Wnt7a treatment ameliorates muscular dystrophy.

    Science.gov (United States)

    von Maltzahn, Julia; Renaud, Jean-Marc; Parise, Gianni; Rudnicki, Michael A

    2012-12-11

    Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder of childhood marked by progressive debilitating muscle weakness and wasting, and ultimately death in the second or third decade of life. Wnt7a signaling through its receptor Fzd7 accelerates and augments regeneration by stimulating satellite stem cell expansion through the planar cell polarity pathway, as well as myofiber hypertrophy through the AKT/mammalian target of rapamycin (mTOR) anabolic pathway. We investigated the therapeutic potential of the secreted factor Wnt7a for focal treatment of dystrophic DMD muscles using the mdx mouse model, and found that Wnt7a treatment efficiently induced satellite cell expansion and myofiber hypertrophy in treated mucles in mdx mice. Importantly, Wnt7a treatment resulted in a significant increase in muscle strength, as determined by generation of specific force. Furthermore, Wnt7a reduced the level of contractile damage, likely by inducing a shift in fiber type toward slow-twitch. Finally, we found that Wnt7a similarly induced myotube hypertrophy and a shift in fiber type toward slow-twitch in human primary myotubes. Taken together, our findings suggest that Wnt7a is a promising candidate for development as an ameliorative treatment for DMD.

  1. The limb-girdle muscular dystrophies.

    Science.gov (United States)

    Wicklund, Matthew P; Kissel, John T

    2014-08-01

    A collection of more than 30 genetic muscle diseases that share certain key features, limb-girdle muscular dystrophies are characterized by progressive weakness and muscle atrophy of the hips, shoulders, and proximal extremity muscles with postnatal onset. This article discusses clinical, laboratory, and histologic features of the 6 most prevalent limb-girdle dystrophies. In this large group of disorders, certain distinctive features often can guide clinicians to a correct diagnosis.

  2. Duchenne muscular dystrophy: the management of scoliosis

    Science.gov (United States)

    Gardner, Adrian C.; Roper, Helen P.; Chikermane, Ashish A.; Tatman, Andrew J.

    2016-01-01

    This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.

  3. [Genetic diagnostic testing in inherited retinal dystrophies].

    Science.gov (United States)

    Kohl, S; Biskup, S

    2013-03-01

    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  4. Cardiac involvement in myotonic dystrophy

    DEFF Research Database (Denmark)

    Lund, Marie; Diaz, Lars Jorge; Ranthe, Mattis Flyvholm

    2014-01-01

    disorders, arrhythmias, and device implantation). In the DM cohort, SIR for any cardiac disease was 3.42 [95% confidence interval (CI) 3.01-3.86]; for a cardiac disease belonging to the selected subgroups 6.91 (95% CI: 5.93-8.01) and for other cardiac disease 2.59 (95% CI: 2.03-3.25). For a cardiac disease......AIMS: To quantify the association between myotonic dystrophy (DM) and cardiac disease in a nationwide cohort. METHODS AND RESULTS: We identified a nationwide cohort of 1146 DM patients (period 1977-2011) using the National Patient Registry (NPR) and a subcohort of 485 patients who had undergone...... genetic testing for DM1. Information on incident cardiac diseases was obtained from the NPR. We estimated standardized incidence ratios (SIRs) of cardiac disease compared with the background population, overall and according to selected diagnostic subgroups (cardiomyopathy, heart failure, conduction...

  5. Porcine models of muscular dystrophy.

    Science.gov (United States)

    Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease.

  6. Cardiac involvement in myotonic dystrophy

    Directory of Open Access Journals (Sweden)

    Koroush Khalighi

    2015-02-01

    Full Text Available Background: Myotonic dystrophy (DM is an inherited progressive muscle disorder caused by defects in muscle proteins. As the incidence of this condition is low, not many are familiar with the multisystem involvement. At times, cardiac disease may even be the predominant manifestation in the form of arrhythmias, conduction defects, and cardiomyopathies. The progression of the disease can lead to sudden, unpredictable death. Thus, it is important to identify this subgroup and treat accordingly. Objective: To identify patients with DM and assess their risk for sudden cardiac death. Methods: Nine patients previously diagnosed with muscular dystrophy were evaluated by cardiologists for various reasons, from a general follow-up to cardiac arrest. All of them had electrocardiograms (EKG and 2-D echocardiograms, and seven of them had further electrophysiological (EP studies. Results: Of the nine patients with DM, eight had EKG evidence of conduction abnormalities ranging from first-degree heart block to complete heart block. Of the seven who had EP studies, five had inducible ventricular tachycardia requiring immediate cardioversion and implantable cardioverter defibrillator (ICD implant. Two of them underwent permanent pacemaker placement due to complete heart block and infra-Hissian block. The remaining two patients opted for a conservative approach with yearly EKG monitoring. Conclusion: Because one-third of the cardiac deaths in patients with DM are sudden, there is a strong need to identify these patients and intervene in those at high risk. Prophylactic pacemaker placement is recommended even in those with minimal conduction system abnormality. However, the common practice is to identify patients at high risk of conduction abnormalities by EP studies and then provide them with prophylactic invasive strategies.

  7. A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus

    Science.gov (United States)

    Barateau, Alice; Vadrot, Nathalie; Vicart, Patrick; Ferreiro, Ana; Mayer, Michèle; Héron, Delphine; Vigouroux, Corinne

    2017-01-01

    A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient’s skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient’s mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype. PMID:28125586

  8. FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy

    Science.gov (United States)

    ... html FDA OKs 1st Drug to Treat Duchenne Muscular Dystrophy Exondys 51 seems to fill unmet need ... the first drug for a rare form of muscular dystrophy. Exondys 51 (eteplirsen) was granted accelerated approval ...

  9. Falls and stumbles in myotonic dystrophy.

    Science.gov (United States)

    Wiles, C M; Busse, M E; Sampson, C M; Rogers, M T; Fenton-May, J; van Deursen, R

    2006-03-01

    To investigate falls and risk factors in patients with myotonic dystrophy type 1 (DM1) compared with healthy volunteers. 13 sequential patients with DM1 from different kindreds were compared with 12 healthy volunteers. All subjects were evaluated using the Rivermead Mobility Index, Performance Oriented Mobility Assessment, and modified Activities Specific Balance Confidence scale. Measures of lower limb muscle strength, gait speed, and 7-day ambulatory activity monitoring were recorded. Subjects returned a weekly card detailing stumbles and falls. 11 of 13 patients (mean age 46.5 years, seven female) had 127 stumbles and 34 falls over the 13 weeks, compared with 10 of 12 healthy subjects (34.4 years, seven female) who had 26 stumbles and three falls. Patients were less active than healthy subjects but had more falls and stumbles per 5000 right steps taken (mean (SD) events, 0.21 (0.29) v 0.02 (0.02), p = 0.007). Patients who fell (n = 6) had on average a lower Rivermead Mobility score, slower self selected gait speed, and higher depression scores than those who did not. DM1 patients stumble or fall about 10 times more often than healthy volunteers. Routine inquiry about falls and stumbles is justified. A study of multidisciplinary intervention to reduce the risk of falls seems warranted.

  10. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour.

    Science.gov (United States)

    Hernández-Hernández, Oscar; Guiraud-Dogan, Céline; Sicot, Géraldine; Huguet, Aline; Luilier, Sabrina; Steidl, Esther; Saenger, Stefanie; Marciniak, Elodie; Obriot, Hélène; Chevarin, Caroline; Nicole, Annie; Revillod, Lucile; Charizanis, Konstantinos; Lee, Kuang-Yung; Suzuki, Yasuhiro; Kimura, Takashi; Matsuura, Tohru; Cisneros, Bulmaro; Swanson, Maurice S; Trovero, Fabrice; Buisson, Bruno; Bizot, Jean-Charles; Hamon, Michel; Humez, Sandrine; Bassez, Guillaume; Metzger, Friedrich; Buée, Luc; Munnich, Arnold; Sergeant, Nicolas; Gourdon, Geneviève; Gomes-Pereira, Mário

    2013-03-01

    Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.

  11. Genetics Home Reference: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

    Science.gov (United States)

    ... alopecia, and nail dystrophy is a type of severe combined immunodeficiency (SCID), which is a group of disorders characterized ... Diseases Educational Resources (7 links) Boston Children's Hospital: Severe Combined Immunodeficiency Disease InfoSearch: T-cell immunodeficiency, congenital alopecia and ...

  12. Living with myotonic dystrophy; what can be learned from couples? A qualitative study

    NARCIS (Netherlands)

    Cup, E.H.C.; Kinebanian, A.; Satink, T.J.; Pieterse, A.J.; Hendricks, H.T.; Oostendorp, R.A.B.; Wilt, G.J. van der; Engelen, B.G.M. van

    2011-01-01

    BACKGROUND: Myotonic dystrophy type 1 (MD1) is one of the most prevalent neuromuscular diseases, yet very little is known about how MD1 affects the lives of couples and how they themselves manage individually and together. To better match health care to their problems, concerns and needs, it is

  13. Design and analysis of effects of triplet repeat oligonucleotides in cell models for myotonic dystrophy

    NARCIS (Netherlands)

    Gonzalez-Barriga, A.; Mulders, S.A.M.; Giessen, J. van der; Hooijer, J.D.; Bijl, S.; Kessel, I.D.G. van; Beers, J. van; Deutekom, J.C. van; Fransen, J.A.M.; Wieringa, B.; Wansink, D.G.

    2013-01-01

    Myotonic dystrophy type 1 (DM1) is caused by DM protein kinase (DMPK) transcripts containing an expanded (CUG)n repeat. Antisense oligonucleotide (AON)-mediated suppression of these mutant RNAs is considered a promising therapeutic strategy for this severe disorder. Earlier, we identified a 2'-O-met

  14. Design and analysis of effects of triplet repeat oligonucleotides in cell models for myotonic dystrophy

    NARCIS (Netherlands)

    Gonzalez-Barriga, A.; Mulders, S.A.M.; Giessen, J. van der; Hooijer, J.D.; Bijl, S.; Kessel, I.D.G. van; Beers, J. van; Deutekom, J.C. van; Fransen, J.A.M.; Wieringa, B.; Wansink, D.G.

    2013-01-01

    Myotonic dystrophy type 1 (DM1) is caused by DM protein kinase (DMPK) transcripts containing an expanded (CUG)n repeat. Antisense oligonucleotide (AON)-mediated suppression of these mutant RNAs is considered a promising therapeutic strategy for this severe disorder. Earlier, we identified a 2'-O-met

  15. Limb-girdle muscular dystrophy type 2G: clinical, pathological and genetic analysis of a case%一例肢带型肌营养不良2G亚型患者的临床、病理及基因分析

    Institute of Scientific and Technical Information of China (English)

    汪伟; 郝莹; 汪仁斌; 金淼; 焦劲松

    2014-01-01

    Objective To investigate TCAP gene mutation and clinical features of a Chinese patient with limb-girdle muscular dystrophy type 2G(LGMD 2G).Methods Clinical data of the patient was analyzed.Exons of the TCAP gene were amplified and sequenced.Results The patient has presented clinically as LGMD and pathologically as vacuolar myopathy.Genetic analysis has identified compound heterozygous mutations of exons 1 and 2 of the TCAP gene(c.100delC,c.166insG).Conclusion LGMD is a group of neuromuscular disorders with substantial phenotypic heterogeneity.Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.%目的 探讨1例肢带型肌营养不良2G亚型(limb-girdle muscular dystrophy type 2G,LGMD 2G)患者的临床、病理特点及基因突变情况.方法 对1例LGMD 2G患者进行临床资料收集及骨骼肌病理检查,PCR扩增患者TCAP基因的全部外显子,通过直接测序检测突变情况,并结合文献进行总结.结果 该患者临床表现符合肢带型肌营养不良,骨骼肌病理可见镶边空泡肌纤维,基因检测发现LGMD 2G致病基因TCAP基因存在复合杂合突变(c.100delC,c.166insG).结论 LGMD 2G的诊断需综合患者临床、病理分析,但最终确诊需结合基因诊断.

  16. Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.

    Science.gov (United States)

    Couthouis, Julien; Raphael, Alya R; Siskind, Carly; Findlay, Andrew R; Buenrostro, Jason D; Greenleaf, William J; Vogel, Hannes; Day, John W; Flanigan, Kevin M; Gitler, Aaron D

    2014-05-01

    Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.

  17. [Congenital muscular dystrophies in children].

    Science.gov (United States)

    Scavone-Mauro, Cristina; Barros, Graciela

    2013-09-06

    From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

  18. Duchenne muscular dystrophy and epilepsy.

    Science.gov (United States)

    Pane, M; Messina, S; Bruno, C; D'Amico, A; Villanova, M; Brancalion, B; Sivo, S; Bianco, F; Striano, P; Battaglia, D; Lettori, D; Vita, G L; Bertini, E; Gualandi, F; Ricotti, V; Ferlini, A; Mercuri, E

    2013-04-01

    Cognitive and behavioral difficulties occur in approximately a third of patients with Duchenne muscular dystrophy. The aim of our study was to assess the prevalence of epilepsy in a cohort of 222 DMD patients. Epileptic seizures were found in 14 of the 222 DMD patients (6.3%). The age of onset ranged from 3 months to 16 years (mean 7.8). Seizures were more often focal epilepsy (n=6), generalized tonic-clonic seizures (n=4) or absences (n=4). They were present in 12 of the 149 boys with normal IQ (8.1%) and in two of the 73 with mental retardation (2.7%). In two cases the parents did not report any past or present history of seizures but only 'staring episodes' interpreted as a sign of 'poor attention'. In both patients EEG showed the typical pattern observed in childhood absence epilepsy. Our results suggest that the prevalence of epilepsy in our study (6.3%) is higher than in the general pediatric population (0.5-1%). The risk of epilepsy does not appear to increase in patients with mental retardation.

  19. Therapeutics in duchenne muscular dystrophy.

    Science.gov (United States)

    Strober, Jonathan B

    2006-04-01

    Duchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3,500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child's quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

  20. Genetics of Bietti Crystalline Dystrophy.

    Science.gov (United States)

    Ng, Danny S C; Lai, Timothy Y Y; Ng, Tsz Kin; Pang, Chi Pui

    2016-01-01

    Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy.

  1. Circulating Biomarkers for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-01-01

    Abstract Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. PMID:27858763

  2. Median nail dystrophy involving the thumb nail

    Directory of Open Access Journals (Sweden)

    Rahulkrishna Kota

    2016-01-01

    Full Text Available Median canaliform dystrophy of Heller is a rare entity characterized by a midline or a paramedian ridge or split and canal formation in nail plate of one or both the thumb nails. It is an acquired condition resulting from a temporary defect in the matrix that interferes with nail formation. Habitual picking of the nail base may be responsible for some cases. Histopathology classically shows parakeratosis, accumulation of melanin within and between the nail bed keratinocytes. Treatment of median nail dystrophy includes injectable triamcinalone acetonide, topical 0.1% tacrolimus, and tazarotene 0.05%, which is many a times challenging for a dermatologist. Psychiatric opinion should be taken when associated with the depressive, obsessive-compulsive, or impulse-control disorder. We report a case of 19-year-old male diagnosed as median nail dystrophy.

  3. Weight reduction in boys with muscular dystrophy.

    Science.gov (United States)

    Edwards, R H; Round, J M; Jackson, M J; Griffiths, R D; Lilburn, M F

    1984-06-01

    Many children with muscular dystrophy are overweight, and although weight control is pursued in some centres it is unusual to encourage severe dietary restriction for fear that it might lead to accelerated loss of muscle. In this study, two overweight boys with muscular dystrophy were monitored by whole-body nitrogen balance, total body potassium, strength and functional measurements during calorie restriction. Both patients were found to have a transient loss of nitrogen on commencing the low calorie intake: thereafter, weight loss was not found to have any deleterious effect on muscle bulk or function in either patient. It is suggested that controlled weight-reduction in obese children with muscular dystrophy is a safe and practical way of losing excess fat, which can improve mobility and self-esteem, and may possibly effect longevity.

  4. Expression of the myodystrophic R453W mutation of lamin A in C2C12 myoblasts causes promoter-specific and global epigenetic defects.

    Science.gov (United States)

    Håkelien, Anne-Mari; Delbarre, Erwan; Gaustad, Kristine G; Buendia, Brigitte; Collas, Philippe

    2008-05-01

    Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) is characterized by muscle wasting and is caused by mutations in the LMNA gene encoding A-type lamins. Overexpression of the EDMD lamin A R453W mutation in C2C12 myoblasts impairs myogenic differentiation. We show here the influence of stable expression of the R453W and of the Dunnigan-type partial lipodystrophy R482W mutation of lamin A in C2C12 cells on transcription and epigenetic regulation of the myogenin (Myog) gene and on global chromatin organization. Expression of R453W-, but not R482W-lamin A, impairs activation of Myog and maintains a repressive chromatin state on the Myog promoter upon induction of differentiation, marked by H3 lysine (K) 9 dimethylation and failure to hypertrimethylate H3K4. Cells expressing WT-LaA also fail to hypertrimethylate H3K4. No defect occurs at the level of Myog promoter DNA methylation in any of the clones. Expression of R453W-lamin A and to a lesser extent R482W-lamin A in undifferentiated C2C12 cells redistributes H3K9me3 from pericentric heterochromatin. R453W-lamin A also elicits a redistribution of H3K27me3 from inactive X (Xi) and partial decondensation of Xi, but maintains Xist expression and coating of Xi, indicating that Xi remains inactivated. Our results argue that gene-specific and genome-wide chromatin rearrangements may constitute a molecular basis for laminopathies.

  5. Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.

    Science.gov (United States)

    Szmidt-Sałkowska, Elżbieta; Gaweł, Małgorzata; Lipowska, Marta

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration.

  6. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran

    Directory of Open Access Journals (Sweden)

    Mohammad BARZEGAR

    2015-01-01

    Full Text Available How to Cite This Article: Barzegar M, Habibi P, Bonyady M, Topchizadeh V, Shiva Sh. Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran. Iran J Child Neurol. 2015 Winter; 9(1: 42-48.AbstractObjectiveDuchene and Becker Muscular Dystrophy (DMD/ BMD are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different populations. This study investigates the deletion rate, type, and distribution of this gene in the Azeri Turk population of North West Iran.Materials &MethodsIn this study, 110 patients with DMD/ BMD were studied for intragenic deletions in 24 exons and promoter regions of dystrophin genes by using multiplex PCR.ResultsDeletions were detected in 63 (57.3% patients, and around 83% localized in the mid-distal hotspot of the gene (on exons 44–52, 21 cases (33.3 % with singleexon deletions, and 42 cases (66.6% with multi-exonic deletions. The most frequent deleted exons were exon 50 (15 % and exon 49 (14%. No deletion was detected in exon 3.ConclusionThis study suggests that the frequency and pattern of dystrophin gene deletions in DMD/ BMD in the Azeri Turk population of North West Iran occur in the same pattern when compared with other ethnic groups.ReferencesEmery AE. Clinical and molecular studies in Duchenne muscular dystrophy. Prog Clin Biol Res 1989; 306:15-28.Moser H. Duchenne muscular dystrophy: pathogenic aspects and genetic prevention. Hum Genet 1984; 66(1:17-40.Emery AE. Population Frequencies of inherited neuromuscular diseases: a world survey Neuromuscul Disord 1991; I (I:19-29.Bushby KM, Thmabyayah M, Gardner M D. Prevalence and incidence of Becker muscular dystrophy. Lancet 1991; 337(8748:1022-1024.Koenig M, Hoffman EP, Bertelosn CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD DNA and

  7. Advances in gene therapy for muscular dystrophies.

    Science.gov (United States)

    Abdul-Razak, Hayder; Malerba, Alberto; Dickson, George

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

  8. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.

    Science.gov (United States)

    Fugier, Charlotte; Klein, Arnaud F; Hammer, Caroline; Vassilopoulos, Stéphane; Ivarsson, Ylva; Toussaint, Anne; Tosch, Valérie; Vignaud, Alban; Ferry, Arnaud; Messaddeq, Nadia; Kokunai, Yosuke; Tsuburaya, Rie; de la Grange, Pierre; Dembele, Doulaye; Francois, Virginie; Precigout, Guillaume; Boulade-Ladame, Charlotte; Hummel, Marie-Christine; Lopez de Munain, Adolfo; Sergeant, Nicolas; Laquerrière, Annie; Thibault, Christelle; Deryckere, François; Auboeuf, Didier; Garcia, Luis; Zimmermann, Pascale; Udd, Bjarne; Schoser, Benedikt; Takahashi, Masanori P; Nishino, Ichizo; Bassez, Guillaume; Laporte, Jocelyn; Furling, Denis; Charlet-Berguerand, Nicolas

    2011-06-01

    Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.

  9. Corneal Higher Order Aberrations in Granular, Lattice and Macular Corneal Dystrophies

    Science.gov (United States)

    Yagi-Yaguchi, Yukari; Yamaguchi, Takefumi; Okuyama, Yumi; Satake, Yoshiyuki; Tsubota, Kazuo; Shimazaki, Jun

    2016-01-01

    Purpose To evaluate the corneal higher-order aberrations (HOAs) in granular, lattice and macular corneal dystrophies. Methods This retrospective study includes consecutive patients who were diagnosed as granular corneal dystrophy type2 (GCD2; 121 eyes), lattice corneal dystrophies type 1, type 3A (LCDI; 20 eyes, LCDIIIA; 32 eyes) and macular corneal dystrophies (MCD; 13 eyes), and 18 healthy control eyes. Corneal HOAs were calculated using anterior segment optical coherence tomography, and the correlations between HOAs and visual acuity were analyzed. Results HOAs of the total cornea within 4 mm diameter were significantly larger in GCD2 (0.17 ± 0.35 μm), in LCDI (0.33 ± 0.27), LCDIIIA (0.61 ± 1.56) and in MCD (0.23 ± 0.18), compared with healthy controls (0.09 ± 0.02μm, all P GCD2 (0.32 ± 0.48), in LCDI (0.60 ± 0.46), LCDIIIA (0.83 ± 2.29) and in MCD (0.44 ± 0.24), compared with healthy controls (0.19 ± 0.06, all P GCD2, there was no significant correlation between logMAR and HOAs (r = 0.113, P = 0.227). In MCD, LCDI and LCDIIIA, logMAR was positively significantly correlated with HOAs (r = 0.620 and P = 0.028, r = 0.587 and P = 0.007, r = 0.614 and P < 0.001, respectively). Conclusions Increased HOAs occur in eyes with corneal dystrophies, especially in eye with LCD and MCD. Larger amount corneal HOAs are associated with poorer visual acuity in patients with LCD and MCD. PMID:27536778

  10. GENETIC POLYMORPHISM OF CYTOCHROMES P450 2C9 AND 2C19 IN SLOVENIAN POPULATION

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    Darja Herman

    2003-06-01

    Full Text Available Background. Cytochrome P450 2C9 (CYP2C9 and 2C19 (CYP2C19 participate in metabolism of many clinically important drugs. Genetic polymorphisms of the CYP2C9 and CYP2C19 genes are described which may affect drug treatment. The aim of this study was to determine the frequencies of polymorphic CYP2C9 and CYP2C19 alleles in Slovenian population in order to estimate the proportion of the population that might experience adverse drug reaction.Methods. The polymorphism of CYP2C9 and CYP2C19 was analysed by a genotyping technique, based on polymerase chain reaction (PCR followed by restriction enzyme analysis. DNA samples from 129 unrelated healthy subjects were obtained from the Blood Transfusion Centre of Slovenia and University Children’s Hospital in Ljubljana.Results. In the analysed group of samples one-third of individuals carried at least one of the defective CYP2C9 alleles while among them 3.2% of individuals had both alleles affected. The frequencies of CYP2C9*2 and CYP2C9*3 were 0.122 and 0.063, respectively. Almost one-third of Slovenian individuals analysed carried at least one of the CYP2C19 polymorphic allele. The frequencies of CYP2C19*2 and CYP2C19*3 were 0.159 and 0.004, respectively.Conclusions. The results of our study indicate that approximately one-third of the patients from Slovenian population may require either adjustments of dose or increased monitoring when initiating treatment with CYP2C9 and CYP2C19 substrates having a narrow therapeutic index. High risk of adverse drug reaction may be expected in 1–3% of eventual patients.

  11. A Drosophila model for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Plas, Mariska Cathelijne van der

    2008-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal

  12. Cardiomyopathy in becker muscular dystrophy:Overview

    Institute of Scientific and Technical Information of China (English)

    Rady Ho; My-Le Nguyen; Paul Mather

    2016-01-01

    Becker muscular dystrophy(BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.

  13. Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2010-09-13

    following are key research accomplishments for the Year 1 funding period: Manuscripts in process • DM Escolar, C Tesi -Rocha, E Henricson, J Florence, J...in steroid treated Duchenne Muscular Dystrophy. In revision for journal submission. • A. Zimmerman, C. Tesi -Rocha, P.R. Clemens, A. Connolly, S.T

  14. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

    NARCIS (Netherlands)

    Gerard, X.; Garanto Iglesias, A.; Rozet, J.M.; Collin, R.W.J.

    2016-01-01

    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several

  15. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD.

  16. Brain Function in Duchenne Muscular Dystrophy

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    J. Gordon Millichap

    2002-02-01

    Full Text Available The role of dystrophin disorders in the CNS function of boys with Duchenne muscular dystrophy (DMD and the dystrophin-deficient mdx mouse, an animal model of DMD, is reviewed at the University of New South Wales, University of Sydney, Australia.

  17. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  18. INTESTINAL PSEUDOOBSTRUCTION IN MYOTONIC-DYSTROPHY

    NARCIS (Netherlands)

    BRUNNER, HG; HAMEL, BCJ; RIEU, P; HOWELER, CJ; PETERS, FTM

    1992-01-01

    We describe four myotonic dystrophy (DM) patients who developed recurrent intestinal pseudo-obstruction. Some episodes were associated with gastroenteritis, while abdominal crowding may have occurred in one case during the third trimester of pregnancy. In most instances, however, no apparent cause c

  19. Clinical features of facioscapulohumeral muscular dystrophy 2.

    NARCIS (Netherlands)

    Greef, J.C. de; Lemmers, R.J.; Camano, P.; Day, J.W.; Sacconi, S.; Dunand, M.; Engelen, B.G.M. van; Kiuru-Enari, S.; Padberg, G.W.A.M.; Rosa, A.L.; Desnuelle, C.; Spuler, S.; Tarnopolsky, M.; Venance, S.L.; Frants, R.R.; Maarel, S.M. van der; Tawil, R.

    2010-01-01

    OBJECTIVE: In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4

  20. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    Science.gov (United States)

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  1. Epilepsy, speech delay, and mental retardation in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Grosso, Salvatore; Mostardini, Rosa; Di Bartolo, Rosanna Maria; Balestri, Paolo; Verrotti, Alberto

    2011-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies which is related to the deletion of tandem repeats on chromosome 4q35. Extramuscular features such as hearing loss, retinopathy, mental retardation, and epilepsy, may be observed in patients carrying large 4q35 deletions resulting in fragment sizes less than 12 kilobases (kb) (normal >35 kb). We report on a family affected by FSHD carrying a small 4q35 deletion and residual fragments length of 17 kb, presenting with epilepsy (three patients), speech delay (two), and mental retardation (one). In all patients semeiology of seizures and interictal EEG anomalies were congruent with a localization-related epilepsy possibly involving the temporal lobe. In conclusion, we provide further evidences that extramuscular findings such as epilepsy, speech delay, and mental retardation may occur in those patients carrying smaller 4q35 deletions, suggesting that a close correlation between 4q35 fragment size and clinical severity in FSHD is therefore not constant. Moreover, a review of the literature and our observations seem to suggest that focal epilepsies, likely related to the temporal lobe in the present family, represent the main type of epilepsy occurring in children with FSHD. Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  2. Stem Cell Differentiation Toward the Myogenic Lineage for Muscle Tissue Regeneration: A Focus on Muscular Dystrophy.

    Science.gov (United States)

    Ostrovidov, Serge; Shi, Xuetao; Sadeghian, Ramin Banan; Salehi, Sahar; Fujie, Toshinori; Bae, Hojae; Ramalingam, Murugan; Khademhosseini, Ali

    2015-12-01

    Skeletal muscle tissue engineering is one of the important ways for regenerating functionally defective muscles. Among the myopathies, the Duchenne muscular dystrophy (DMD) is a progressive disease due to mutations of the dystrophin gene leading to progressive myofiber degeneration with severe symptoms. Although current therapies in muscular dystrophy are still very challenging, important progress has been made in materials science and in cellular technologies with the use of stem cells. It is therefore useful to review these advances and the results obtained in a clinical point of view. This article focuses on the differentiation of stem cells into myoblasts, and their application in muscular dystrophy. After an overview of the different stem cells that can be induced to differentiate into the myogenic lineage, we introduce scaffolding materials used for muscular tissue engineering. We then described some widely used methods to differentiate different types of stem cell into myoblasts. We highlight recent insights obtained in therapies for muscular dystrophy. Finally, we conclude with a discussion on stem cell technology. We discussed in parallel the benefits brought by the evolution of the materials and by the expansion of cell sources which can differentiate into myoblasts. We also discussed on future challenges for clinical applications and how to accelerate the translation from the research to the clinic in the frame of DMD.

  3. Living with muscular dystrophy: health related quality of life consequences for children and adults

    Directory of Open Access Journals (Sweden)

    de Boone Judith

    2007-06-01

    Full Text Available Abstract Background Muscular dystrophies are chronic diseases manifesting with progressive muscle weakness leading to decreasing activities and participation. To understand the impact on daily life, it is important to determine patients' quality of life. Objective To investigate Health Related Quality of Life (HRQoL of children and adults with muscular dystrophy (MD, and to study the influence of type and severity of MD on HRQoL in adult patients. Methods Age-related HRQoL questionnaires were administered to 40 children (8–17 years, and 67 adult patients with muscular dystrophies. Results Significant differences in HRQoL were found in children and adults with MD compared to healthy controls. Patients with Becker muscular dystrophy reported a better HRQoL on the several scales compared to patients with other MDs. Severity was associated with worse fine motor functioning and social functioning in adult patients. Conclusion This is one of the first studies describing HRQoL of patients with MD using validated instruments in different age groups. The results indicate that having MD negatively influences the HRQoL on several domains.

  4. Identification of the CRB1 gene and analysis of its role in autosomal recessive retinal dystrophies

    NARCIS (Netherlands)

    Hollander, Antonia Ingrid den

    2002-01-01

    Inherited retinal dystrophies generally lead to severe visual impairment early in life. Most genes involved in retinal dystrophies are expressed exclusively or predominantly in the retina or the RPE. To identify candidate genes for inherited retinal dystrophies, we isolated

  5. Cataract extraction in eyes with Fuchs' endothelial dystrophy in China

    Institute of Scientific and Technical Information of China (English)

    XIE Li-xin; HUANG Yu-sen; Ann Mei-Chi Chiu; LIN Ping; YAO Zhan; SUN Jie

    2005-01-01

    @@ It is a common belief that Fuchs' endothelial dystrophy predominantly affects Caucasians but rarely Asians. However, in one Japanese study, primary corneal guttae (first stage of Fuchs' dystrophy) were found in four of 107 cataract patients.1 With the growing popularity of phacoemulsification in China in the past decade, the increased incidence of endothelial decompensation may be due to learning curves among surgeons as well as that the prevalence of Fuchs' dystrophy among Chinese is higher than we thought. Low index of suspicion for Fuchs' dystrophy may result in missing of diagnosis and occurrence of endothelial decompensation, particularly when no extra protection is provided for endothelial cells during phacoemulsification. This study was aimed at improving our knowledge about Fuchs' dystrophy among Chinese population and reminding surgeons of extra endothelial protection during cataract surgery for patients with Fuchs' dystrophy.

  6. Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

    Science.gov (United States)

    2017-05-30

    Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

  7. [Ventricular Tachycardia as a First Manifestation of Myotonic Dystrophy].

    Science.gov (United States)

    Mironov, N Yu; Mironova, N A; Sokolov, S F; Mareev, Yu V; Shlevkov, N B; Saidova, M A; Stukalova, O V; Golitsyn, S P

    2015-01-01

    We report a case of bundle-branch reentrant ventricular tachycardia as a first and severe manifestation of myotonic dystrophy. Progressive cardiac conduction disturbances and cardiac arrhythmias are well-known features of myotonic dystrophy, although they are commonly found in late stage of disease in patients with established diagnosis. We review clinical manifestations, diagnostics, management, and prognostic value of cardiac involvement in myotonic dystrophy.

  8. An unusual central retinal dystrophy associated with ichthyosis vulgaris.

    Science.gov (United States)

    Saatci, O A; Ozbek, Z; Köse, S; Durak, I; Kavukçu, S

    2000-06-01

    A number of ichthyosis syndromes may have retinal abnormalities such as the retinitis pigmentosa-like diffuse rod-cone dystrophy in Refsum's syndrome and the maculopathy in Sjögren-Larsson syndrome. We present two sisters who have an unusual, almost identical, bilaterally symmetric central retinal dystrophy associated with ichthyosis vulgaris in the absence of other systemic disorders. We believe that this dystrophy has not been previously described in patients with any of the known varieties of ichthyosis.

  9. Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

    OpenAIRE

    Oriana del Rocío Cruz Guzmán; Ana Laura Chávez García; Maricela Rodríguez-Cruz

    2012-01-01

    Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine di...

  10. Corneal Topography Analysis of Stromal Corneal Dystrophies

    OpenAIRE

    Kocluk, Yusuf; Yalniz-Akkaya, Zuleyha; Burcu, Ayse; Ornek, Firdevs

    2015-01-01

    Objective: The aim was to compare the corneal topography and tomography parameters of macular corneal dystrophy (MCD), granular corneal dystrophy (GCD) and lattice corneal dystrophy (LCD) patients obtained by Scheimpflug imaging system. Methods: The charts, photographs and topography images of patients were reviewed retrospectively. This study included 73 eyes of 73 patients (28 MCD, 20 GCG and 25 LCD patients). Topography images were obtained by Pentacam (Oculus Optikgerate, Wetzlar, Germany...

  11. Distinct genetic regions modify specific muscle groups in muscular dystrophy

    OpenAIRE

    2010-01-01

    Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein γ-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quan...

  12. Molecular mechanisms in muscular dystrophy: a gene expression profiling study.

    OpenAIRE

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di¬vergence are largely unknown as well. In this thesis, gene e...

  13. Trendelenburg-Like Gait, Instability and Altered Step Patterns in a Mouse Model for Limb Girdle Muscular Dystrophy 2i

    OpenAIRE

    Maricelli, Joseph W.; Lu, Qi L.; Lin, David C.; Rodgers, Buel D.

    2016-01-01

    Limb-girdle muscular dystrophy type 2i (LGMD2i) affects thousands of lives with shortened life expectancy mainly due to cardiac and respiratory problems and difficulty with ambulation significantly compromising quality of life. Limited studies have noted impaired gait in patients and animal models of different muscular dystrophies, but not in animal models of LGMD2i. Our goal, therefore, was to quantify gait metrics in the fukutin-related protein P448L mutant (P448L) mouse, a recently develop...

  14. Facioscapulohumeral dystrophy: case report and discussion.

    Science.gov (United States)

    Castellano, Vincenzo; Feinberg, Joseph; Michaels, Jennifer

    2008-09-01

    Facioscapulohumeral dystrophy (FSHD) is often cited as the third most common form of muscular dystrophy. Therefore, it should be considered in patients with complaints of progressive weakness. We present the case of a man with facial, truncal, and leg weakness that initially sought medical attention for lower back pain. Electrodiagnostic testing revealed findings in the trapezius, serratus anterior, biceps, triceps, pectoralis major, tibialis anterior, and gastrocnemius muscles consistent with a myopathic disorder. Subsequent genetic testing identified a FSHD allele size consistent with a FSHD deletion mutation. Therefore, confirming the diagnosis of FSHD. Unfortunately, no effective treatments currently exist for FSHD. However, supportive measures involving physical therapy and the use of orthotics may aid in improving function and mobility.

  15. New Advanced Technology for Muscular Dystrophy

    Science.gov (United States)

    2009-11-01

    References Aristotle. 350 BC. Historia Animalium: Books VII–X. 1991 edition. D.M. Balme, editor. Harvard University Press, Cambridge, MA. 435–437...hematological disease, and have been proposed as a source for cell based therapies of muscular dystrophy. Since the University of Minnesota is a center...Blood and Marrow Transplantation program at the University of Minnesota to assure that we receive appropriate tissues as they become available. Having

  16. Growth hormone evaluation in Duchenne muscular dystrophy.

    Science.gov (United States)

    Merlini, L; Granata, C; Ballestrazzi, A; Cornelio, F; Tassoni, P; Tugnoli, S; Cacciari, E

    1988-10-01

    Growth hormone (GH) release with pharmacological tests and sleep test, somatomedin C and auxological features were studied in 10 patients affected by Duchenne Muscular Dystrophy. GH release in these patients seems to be lower than normal; moreover some of them are of short stature without an evident relationship with GH deficit. The possible significance of the data obtained is discussed, particularly in relation to the clinical course of the disease, and to current therapeutic trials with a GH release inhibitor (mazindol).

  17. Urological manifestations of Duchenne muscular dystrophy.

    Science.gov (United States)

    Askeland, Eric J; Arlen, Angela M; Erickson, Bradley A; Mathews, Katherine D; Cooper, Christopher S

    2013-10-01

    Duchenne muscular dystrophy is a dystrophinopathy affecting males that is associated with multiple organ system complications. To our knowledge urological complications of Duchenne muscular dystrophy have been described only anecdotally to date. We reviewed the medical charts of 135 patients with Duchenne or Duchenne-Becker muscular dystrophy for demographics and disease progression, urological diagnoses, intervention and followup. Of 135 patients 67 (50%) had at least 1 documented urological diagnosis and 38 (28%) had multiple manifestations. Lower urinary tract symptoms were the most common urological diagnosis (32% of patients). Survival analysis revealed a median age at onset of lower urinary tract symptoms of 23 years (95% CI 17.7-23.9). Intervention was required in 12 patients (9%), most commonly due to nephrolithiasis. Urological morbidity increased with Duchenne muscular dystrophy progression when stratified by clinical progression. Lower urinary tract symptoms were more common in nonambulatory patients (40.7% vs 19%, p = 0.007), those with a diagnosis of scoliosis (44% vs 19.7%, p = 0.003) and/or scoliosis spine surgery (60% vs 22%, p <0.001), and those on invasive respiratory support (53% vs 29%, p = 0.046). Likewise, nephrolithiasis was more common in nonambulatory patients (10% vs 0%, p = 0.017), those with scoliosis (12% vs 0%, p = 0.004) and/or scoliosis spine surgery (20% vs 1%, p <0.001), and those on invasive respiratory support (29% vs 3%, p <0.001). Only 28% of patients with a urological manifestation were referred to urology. As these patients transition into adolescence and adulthood, the increased prevalence of urological manifestations warrants increased awareness and referral to urologists. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  18. The superhealing MRL background improves muscular dystrophy

    OpenAIRE

    2012-01-01

    Abstract Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg), a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dyst...

  19. Bietti’ Crystalline Retinal Dystrophy: A Case Report

    Directory of Open Access Journals (Sweden)

    Muhammed Şahin

    2016-03-01

    Full Text Available Bietti’ crystalline retinal dystrophy (BCD is a rare, auto­somal, recessively inherited disorder, characterized by the deposition of yellow crystals in the corneal limbus and retina. In this paper we aimed to present a pediatric case with BCD, with clinical, electrophysiological and spectral domain optical coherence tomography (SD-OCT findings and discuss BCD with the light of the literature. J Clin Exp Invest 2016; 7 (1: 94-97

  20. A case of myotonic dystrophy with electrolyte imbalance.

    Science.gov (United States)

    Ko, Weon-Jin; Kim, Kwang-Yeol; Kim, So-Mi; Hong, Seung-Jae; Lee, Sang-Hoon; Song, Ran; Yang, Hyung-In; Lee, Yeon-Ah

    2013-07-01

    Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.

  1. Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy

    Directory of Open Access Journals (Sweden)

    Agnieszka Madej-Pilarczyk

    2016-03-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMD, a rare inherited disease, is characterized clinically by humero-peroneal muscle atrophy and weakness, multijoint contractures, spine rigidity and cardiac insufficiency with conduction defects. There are at least six types of EDMD known so far, of which five have been associated with mutations in genes encoding nuclear proteins. The majority of the EDMD cases described so far are of the emerinopathy (EDMD1 kind, with a recessive X-linked mode of inheritance, or else laminopathy (EDMD2, with an autosomal dominant mode of inheritance. In the work described here, the authors have sought to describe the history by which EDMD came to be distinguished as a separate entity, as well as the clinical and genetic characteristics of the disease, the pathophysiology of lamin-related muscular diseases and, finally, therapeutic issues, prevention and ethical aspects.

  2. Laminins in peripheral nerve development and muscular dystrophy.

    Science.gov (United States)

    Yu, Wei-Ming; Yu, Huaxu; Chen, Zu-Lin

    2007-06-01

    Laminins are extracellular matrix (ECM) proteins that play an important role in cellular function and tissue morphogenesis. In the peripheral nervous system (PNS), laminins are expressed in Schwann cells and participate in their development. Mutations in laminin subunits expressed in the PNS and in skeleton muscle may cause peripheral neuropathies and muscular dystrophy in both humans and mice. Recent studies using gene knockout technology, such as cell-type specific gene targeting techniques, revealed that laminins and their receptors mediate Schwann cell and axon interactions. Schwann cells with disrupted laminin expression exhibit impaired proliferation and differentiation and also undergo apoptosis. In this review, we focus on the potential molecular mechanisms by which laminins participate in the development of Schwann cells.

  3. CONGENITAL MYOTONIC DYSTROPHY – CASE REPORT

    Directory of Open Access Journals (Sweden)

    David Neubauer

    2001-07-01

    Full Text Available Background. Myotonic dystrophy is inherited as an autosomal dominant trait. It is characterized by myotonia, myopathy of voluntary and involuntary muscles, frontal baldness in men, cardiac conduction abnormalities, catharacts, intellectual deterioration and endocrinopathy. Men with this disorder have often gonadal atrophy and infertility. On the other hand women are generally fertile. During pregnancy their myopathy worsens, often causing severe obstetrical complications. Their children may develop congenital form of the disease with signs of myopathy in utero and have great difficulties in maintaining life functions after birth, together with other characteristical signs of this form: bilateral facial weakness, severe hypotonia, feeding difficulties, talipes equinovarus and mental retardation. The authors present a female newborn with such congenital form of myotonic dystrophy.Conclusions. The authors have emphasized the importance of medical history, regular updating of all the cases of neuromuscular diseases in the region and clinical characteristics for the recognition of congenital form of myotonic dystrophy because of possible prenatal diagnostics and better antenatal and postantal care.

  4. [Management of myocardial damage in muscular dystrophy].

    Science.gov (United States)

    Tamura, Takuhisa

    2011-11-01

    Heart failure (HF) is a fatal complication in many muscular dystrophy cases and has become the most common cause of death in Duchenne muscular dystrophy (DMD) since 2001. HF deaths in DMD occur in young patients and increase, along with respiratory failure, in older patients. Managing HF, therefore, is the most important component of DMD treatment. Management of HF is necessary in DMD patients of all ages because myocardial damage progresses regardless of age and disability. Electrocardiography, echocardiography, myocardial single-photon emission computed tomography (SPECT), and natriuretic peptides are used for the diagnosis of myocardial damage and chronic HF. Tissue Doppler echocardiography is in particularly useful for early detection of minute myocardial damage and dysfunction in DMD. The first-line drugs for chronic HF are angiotensin-converting enzyme inhibitors, and the prognosis of DMD patients has been improved using these drugs and beta-blockers. Diuretics are added in the presence of pulmonary congestion. Digoxin is most effective at a blood level of 0.5-0.8 ng/mL because of its pharmacokinetics in DMD. Surgical treatment may be necessary in cases of intractable HF. Cardiac resynchronization therapy (biventricular pacing), a treatment with an artificial pacemaker, is indicated for cases that meet specific criteria, including HF with ventricular dyssynchrony. Applications of partial left ventriculectomy (Batista procedure) and left ventricular assist devices in muscular dystrophy are likely in the near future.

  5. Structural and functional insights into CYP2C8.3:A genetic polymorph of cytochrome P450 2C8

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver, and carries out the oxidative metabolism of at least 5% of clinical drugs. Polymorphisms in CYP2C8 have been closely implicated in individualized medication. CYP2C8.3, a common polymorph of CYP2C8 with dual amino acid substitutions R139K and K399R, is found primarily in Caucasians. In this study, CYP2C8.3 and its wild type (WT) CYP2C8 were expressed in E. coli, and their purified proteins were characterized by UV-visible spectroscopy, mass spectrometry, and circular dichroism. Their thermal stability, substrate binding ability, and metabolic activity against paclitaxel were investigated. The electron transfer kinetics during paclitaxel metabolism by WT CYP2C8 or CYP2C8.3 was studied by stopped-flow kinetics. The results revealed that mutations in CYP2C8.3 did not greatly influence the heme active site or protein thermal stability and paclitaxel binding ability, but the metabolic activity against paclitaxel was significantly depressed to just 11% of that of WT CYP2C8. Electron transfer from CYP reductase to CYP2C8.3 was found to be significantly slower than that to WT CYP2C8 during catalysis, and this might be the main reason for the depressed metabolic activity. Since the polymorph CYP2C8.3 is defective in catalyzing substrates of CYP2C8 in vitro, it might be expected to have important clinical and pathophysiological consequences in homozygous individuals, and this study provides valuable information in this aspect.

  6. Coenzyme Q10 Deficiency and Type 2C Muscle Fibers

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-12-01

    Full Text Available Investigators at Washington University School of Medicine, St Louis, MO, evaluated retrospectively clinical, laboratory, and muscle histochemistry and oxidative enzyme characteristics in 49 children with suspected mitochondrial disorders.

  7. LM-2C Series Launch Vehicles

    Institute of Scientific and Technical Information of China (English)

    XueFuxing

    2004-01-01

    On December 30, 2003, a LM-2C/SM launch vehicle was launched from Xichang Satellite Launch Center (XSLC), successfully sending TC-1 satellite into orbit. The satellite is the first one of the two scientific satellites known as Double Star. The operation orbit of the satellite is the highest compared with China's other satellites ever launched.

  8. Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance.

    Science.gov (United States)

    Paolella, Giulia; Pisano, Pasquale; Albano, Raffaele; Cannaviello, Lucio; Mauro, Carolina; Esposito, Gabriella; Vajro, Pietro

    2012-10-31

    We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with "cryptogenic" hypertransaminasemia.

  9. Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance

    Directory of Open Access Journals (Sweden)

    Paolella Giulia

    2012-10-01

    Full Text Available Abstract We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with “cryptogenic” hypertransaminasemia.

  10. In vitro mapping of Myotonic Dystrophy (DM) gene promoter

    Energy Technology Data Exchange (ETDEWEB)

    Storbeck, C.J.; Sabourin, L. [Univ. of Ottawa (Canada); Baird, S. [Children`s Hospital of Eastern Ontario, Ottawa (Canada)] [and others

    1994-09-01

    The Myotonic Dystrophy Kinase (DMK) gene has been cloned and shared homology to serine/threonine protein kinases. Overexpression of this gene in stably transfected mouse myoblasts has been shown to inhibit fusion into myotubes while myoblasts stably transfected with an antisense construct show increased fusion potential. These experiments, along with data showing that the DM gene is highly expressed in muscle have highlighted the possibility of DMK being involved in myogenesis. The promoter region of the DM gene lacks a consensus TATA box and CAAT box, but harbours numerous transcription binding sites. Clones containing extended 5{prime} upstream sequences (UPS) of DMK only weakly drive the reporter gene chloramphenicol acetyl transferase (CAT) when transfected into C2C12 mouse myoblasts. However, four E-boxes are present in the first intron of the DM gene and transient assays show increased expression of the CAT gene when the first intron is present downstream of these 5{prime} UPS in an orientation dependent manner. Comparison between mouse and human sequence reveals that the regions in the first intron where the E-boxes are located are highly conserved. The mapping of the promoter and the importance of the first intron in the control of DMK expression will be presented.

  11. Myocardial Contractile Dysfunction Is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and Is Prevented after Claudin-5 Virotherapy

    Science.gov (United States)

    Milani-Nejad, Nima; Schultz, Eric J.; Slabaugh, Jessica L.; Janssen, Paul M. L.; Rafael-Fortney, Jill A.

    2016-01-01

    Mutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd−/−) of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy withclaudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd−/− mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care. PMID:27999547

  12. Myocardial Contractile Dysfunction is Present Without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and is Prevented after Claudin-5 Virotherapy

    Directory of Open Access Journals (Sweden)

    Nima Milani-Nejad

    2016-12-01

    Full Text Available AbstractMutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd-/- of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy with claudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd-/- mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care.

  13. Gelatinous drop-like corneal dystrophy: a review.

    Science.gov (United States)

    Kaza, Hrishikesh; Barik, Manas R; Reddy, Mamatha M; Mittal, Ruchi; Das, Sujata

    2017-01-01

    Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterised by subepithelial and stromal amyloid deposits. It is relatively common in Japan. It usually presents in the first two decades of life with subepithelial nodular lesions that later coalesce to form mulberry-like opacities. Although various surgical modalities have been attempted, recurrence remains a major challenge.

  14. Molecular mechanisms in muscular dystrophy : a gene expression profiling study.

    NARCIS (Netherlands)

    Turk, Rolf

    2006-01-01

    The muscular dystrophies are a group of neuromuscular disorders characterized by progres¬sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are

  15. Far infrared transmittance of Sc2@C84 and Er2@C82

    NARCIS (Netherlands)

    Grannan, S.M.; Birmingham, J.T.; Richards, P.L.; Bethune, D.S.; Vries, M.S. de; Loosdrecht, P.H.M. van; Dorn, H.C.; Burbank, P.; Bailey, J.; Stevenson, S.

    1997-01-01

    We have measured the far infrared transmittance of Sc2@C84 and Er2@C82 at 1.5 K between 30 and 200 cm-1. Both materials are observed to have a large primary absorption feature centered at 95 cm-1 with a width of approximately 50 cm-1, as well as a number of secondary absorption features which are di

  16. Resistance training in patients with limb-girdle and becker muscular dystrophies

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Andersen, Søren P; Ingelsrud, Lina H;

    2013-01-01

    In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD).......In this study we investigated the effect of strength training in patients with limb-girdle muscular dystrophy (LGMD) and Becker muscular dystrophy (BMD)....

  17. Pathogenic mutations of TGFBI and CHST6 genes in Chinese patients with Avellino, lattice, and macular corneal dystrophies

    Institute of Scientific and Technical Information of China (English)

    Ya-nan HUO; Yu-feng YAO; Ping YU

    2011-01-01

    Objective:To investigate gene mutations associated with three different types of corneal dystrophies (CDs),and to establish a phenotype-genotype correlation.Methods:Two patients with Avellino corneal dystrophy (ACD),four patients with lattice corneal dystrophy type Ⅰ (LCD Ⅰ) from one family,and three patients with macular corneal dystrophy type Ⅰ (MCD Ⅰ) were subjected to both clinical and genetic examinations.Slit lamp examination was performed for all the subjects to assess their corneal phenotypes.Genomic DNA was extracted from peripheral blood leukocytes.The coding regions of the human transforming growth factor β-induced (TGFB/)gene and carbohydrate sulfotransferase 6 (CHST6) gene were amplified by polymerase chain reaction (PCR) and subjected to direct sequencing.DNA samples from 50 healthy volunteers were used as controls.Results:Clinical examination showed three different phenotypes of CDs.Genetic examination identified that two ACD subjects were associated with homozygous R124H mutation of TGFB/,and four LCD Ⅰ subjects were all associated with R124C heterozygous mutation.One MCD Ⅰ subject was associated with a novel S51X homozygous mutation in CHST6,while the other two MCD Ⅰ subjects harbored a previously reported W232X homozygous mutation.Conclusions:Our study highlights the prevalence of codon 124 mutations in the TGFB/gene among the Chinese ACD and LCD Ⅰ patients.Moreover,we found a novel mutation among MCD Ⅰ patients.

  18. Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

    Science.gov (United States)

    Shimizu, Reiko; Ogata, Katsuhisa; Tamaura, Akemi; Kimura, En; Ohata, Maki; Takeshita, Eri; Nakamura, Harumasa; Takeda, Shin'ichi; Komaki, Hirofumi

    2016-07-11

    Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases. To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation. Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time. Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to

  19. Surface reconstruction of W2C(0001)

    Science.gov (United States)

    Aizawa, Takashi; Hishita, Shunichi; Tanaka, Takaho; Otani, Shigeki

    2011-08-01

    A single crystal surface of ditungsten carbide, W2C(0001) was investigated using low-energy (LEED) and high-energy electron diffraction, Auger electron spectroscopy, x-ray photoelectron spectroscopy (XPS), and high-resolution electron energy loss spectroscopy (HREELS). A new reconstruction, \\sqrt {13} \\times \\sqrt {13} {R}+/- 13.9^{\\circ } , was found as a clean surface structure after annealing the W2C at > 1900 K. The surface carbon content is shown as larger than that in the bulk. Our preliminary results showed that the same structure is realized also on WC(0001). The same surface periodicity is described for an Mo2C(0001) LEED pattern in the literature. This reconstruction phase is presumably common on the (0001) surface of hexagonal group-6 transition-metal carbides. In the off-specular HREELS, an atomic vibration of 44.8 meV (361 cm - 1) appeared within the gap energy region of the bulk phonon bands, which was assigned to a surface carbon vibration perpendicular to the surface. One possible explanation of the low vibrational frequency is very low adsorption height of the surface carbon atoms.

  20. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages.

    Science.gov (United States)

    Siciliano, Gabriele; Simoncini, Costanza; Giannotti, Stefano; Zampa, Virna; Angelini, Corrado; Ricci, Giulia

    2015-05-01

    Different genetic mutations underlying distinct pathogenic mechanisms have been identified as cause of muscle fibers degeneration and strength loss in limb girdle muscular dystrophies (LGMD). As a consequence, exercise tolerance is affected in patients with LGMD, either as a direct consequence of the loss of muscle fibers or secondary to the sedentary lifestyle due to the motor impairment. It has been debated for many years whether or not muscle exercise is beneficial or harmful for patients with myopathic disorders. In fact, muscular exercise would be considered in helping to hinder the loss of muscle tissue and strength. On the other hand, muscle structural defects in LGMD can result in instability of the sarcolemma, making it more likely to induce muscle damage as a consequence of intense muscle contraction, such as that performed during eccentric training. Several reports have suggested that supervised aerobic exercise training is safe and may be considered effective in improving oxidative capacity and muscle function in patients with LGMD, such as LGMD2I, LGMD2L, LGMD2A. More or less comfortable investigation methods applied to assess muscle function and structure can be useful to detect the beneficial effects of supervised training in LGMD. However, it is important to note that the available trials assessing muscle exercise in patients with LGMD have often involved a small number of patients, with a wide clinical heterogeneity and a different experimental design. Based on these considerations, resistance training can be considered part of the rehabilitation program for patients with a limb-girdle type of muscular dystrophy, but it should be strictly supervised to assess its effects and prevent possible development of muscle damage.

  1. First Identification of a Triple Corneal Dystrophy Association: Keratoconus, Epithelial Basement Membrane Corneal Dystrophy and Fuchs' Endothelial Corneal Dystrophy

    Directory of Open Access Journals (Sweden)

    Cosimo Mazzotta

    2014-09-01

    Full Text Available Purpose: To report the observation of a triple corneal dystrophy association consisting of keratoconus (KC, epithelial basement membrane corneal dystrophy (EBMCD and Fuchs' endothelial corneal dystrophy (FECD. Methods: A 55-year-old male patient was referred to our cornea service for blurred vision and recurrent foreign body sensation. He reported bilateral recurrent corneal erosions with diurnal visual fluctuations. He underwent corneal biomicroscopy, Scheimpflug tomography, in vivo HRT confocal laser scanning microscopy and genetic testing for TGFBI and ZEB1 mutations using direct DNA sequencing. Results: Biomicroscopic examination revealed the presence of subepithelial central and paracentral corneal opacities. The endothelium showed a bilateral flecked appearance, and the posterior corneal curvature suggested a possible concomitant ectatic disorder. Corneal tomography confirmed the presence of a stage II KC in both eyes. In vivo confocal laser scanning microscopy revealed a concomitant bilateral EBMCD with hyperreflective deposits in basal epithelial cells, subbasal Bowman's layer microfolds and ridges with truncated subbasal nerves as pseudodendritic elements. Stromal analysis revealed honeycomb edematous areas, and the endothelium showed a strawberry surface configuration typical of FECD. The genetic analysis resulted negative for TGFBI mutations and positive for a heterozygous mutation in exon 7 of the gene ZEB1. Conclusion: This is the first case reported in the literature in which KC, EBMCD and FECD are present in the same patient and associated with ZEB1 gene mutation. The triple association was previously established by means of morphological analysis of the cornea using corneal Scheimpflug tomography and in vivo HRT II confocal laser scanning microscopy.

  2. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, M

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of definit

  3. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, Marianne

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of

  4. Muscular dystrophy in dogs: does the crossing of breeds influence disease phenotype?

    Science.gov (United States)

    Miyazato, L G; Moraes, J R E; Beretta, D C; Kornegay, J N

    2011-05-01

    Golden Retriever (GR) muscular dystrophy is an inherited degenerative muscle disease that provides an excellent model for Duchenne muscular dystrophy in humans. This study defined the histopathologic lesions, including the distribution of type I and II muscle fibers (FTI and FTII), in 12 dystrophic and 3 nondystrophic dogs between 7 and 15 months of age. The authors were interested in studying the influence on disease phenotype from crossing the base GR breed with Yellow Labrador Retrievers. The dystrophic dogs were divided according to breed: GRs and Golden Labrador Retrievers (GLRs). On hematoxylin and eosin staining, histopathologic lesions were more severe in GRs than GLRs. Six of eight GR muscles (75%) had a severe lesion grade (grade 3). In contrast, seven GLR muscles (87.5%) had mild lesions (grade 2), and only one had severe lesions (grade 3). Changes in fiber-type distribution were more pronounced in GRs versus GLRs. FTI:FTII ratio inversion was observed in three dystrophic GRs but only one GLR. The mean diameter of FTI and FTII was smaller in GRs and GLRs than in nondystrophic dogs (P muscular dystrophy phenotype.

  5. Enhanced tolerance to low temperature in tobacco by over-expression of a new maize protein phosphatase 2C, ZmPP2C2.

    Science.gov (United States)

    Hu, Xiaoli; Liu, Lixia; Xiao, Beilei; Li, Dapeng; Xing, Xin; Kong, Xiangpei; Li, Dequan

    2010-10-15

    Low temperature is one of the most common environmental stresses affecting plant growth and agricultural production. Serine/threonine protein phosphatases 2C (PP2Cs) have been suggested to play an important role in stress signaling. To identify potential new member of the PP2C proteins in maize and investigate its functions for stress responses, the ZmPP2C2 gene, encoding a new PP2C protein from maize roots, was cloned by RT-PCR and RACE-PCR. Its constitutive expression in roots, stems and leaves of maize seedlings was detected by RNA gel blot, and its regulation in response to cold stress was also examined. To further evaluate its function in the cold stress response, we over-expressed the ZmPP2C2 gene in tobacco under the control of the Cauliflower Mosaic Virus (CaMV) 35S promoter, and assessed a series of physiological changes in wild type and transgenic plants under low temperatures. Compared with wild type tobacco under cold stress, plants that over-expressed ZmPP2C2 displayed higher germination speed and rate, higher antioxidant enzyme (SOD, POD, CAT) activities, with lower cold-induced electrolyte leakage and malondialdehyde (MDA) contents. These results show that over-expression of ZmPP2C2 in tobacco enhanced tolerance to cold stress, suggesting that this new gene, ZmPP2C2, may act as a positive regulator of cold resistance in plants.

  6. Impact of RNA editing on functions of the serotonin 2C receptor in vivo

    Directory of Open Access Journals (Sweden)

    Uade B Olaghere Da Silva

    2010-03-01

    Full Text Available Transcripts encoding 5-HT2C receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT2C-VGV, exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT2C-VGV receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT2C-VGV receptor (VGV/Y, we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT2C-VGV receptors. However, enhanced behavioral sensitivity to a 5-HT2C receptor agonist was also seen in mice expressing 5-HT2C-VGV receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT2C-VGV receptors had greater sensitivity to a 5-HT2C inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT2C receptor binding sites in the brains of mice solely expressing -5HT2C-VGV receptors. We conclude that 5-HT2C-VGV receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5HT2C receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT2C receptor binding sites in brain. We further caution that the pattern of 5-HT2C receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

  7. Noncoding RNAs: Emerging Players in Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Germana Falcone

    2014-01-01

    Full Text Available The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets.

  8. A molecular protocol for diagnosing myotonic dystrophy.

    Science.gov (United States)

    Guida, M; Marger, R S; Papp, A C; Snyder, P J; Sedra, M S; Kissel, J T; Mendell, J R; Prior, T W

    1995-01-01

    Myotonic dystrophy (DM) is an autosomal dominant genetic disease caused by an unstable CTG repeat sequence in the 3' untranslated region of the myotonin protein kinase gene. The CTG repeat is present 5-30 times in the normal population, whereas DM patients have CTG expansions of 50 to several thousand repeats. The age of onset of the disorder and the severity of the phenotype is roughly correlated with the size of the CTG expansion. We developed a molecular protocol for the diagnosis of DM based on an initial polymerase chain reaction screen to detect normal-sized alleles and small expansions, followed by an improved Southern protocol to detect larger expansions.

  9. File list: Oth.ALL.05.TFAP2C.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.ALL.05.TFAP2C.AllCell hg19 TFs and others TFAP2C All cell types SRX673727,SRX67...3728,SRX150450,SRX190406,SRX018833,SRX128099,SRX128102,SRX028632,SRX128100,SRX028633,SRX128101 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.ALL.05.TFAP2C.AllCell.bed ...

  10. Experimental Electronic Structure of Be_2C

    Science.gov (United States)

    Tsuei, K.-D.; Tzeng, C.-T.; Lo, W.-S.; Yuh, J.-Y.; Chu, R.-Y.

    1998-03-01

    The insulating Be_2C thin films have been successfully prepared on a Be surface. LEED pattern shows that the films have (100) orientation along the surface normal. We have used angle-resolved photoemission to map out the occupied bulk band dispersion along Γ-X direction. The band gap edges at X point are 6.5 and 11.7 eV below the valence band maximum which is located at Γ point. These values are in good agreement with theoretical calculations. [1,2] In addition two surface states are observed. One is 0.5 eV above VBM. The other is located at 9.5 eV below VBM in the middle of the band gap at X point. The unoccupied bulk electronic structure is measured using C 1s near edge x-ray absorption spectroscopy. The spectrum is similar in shape to an energy loss spectrum [3] and p-PDOS from the calculation, [2] while the relative peak positions are different. [1] J.L. Corkill and M.L. Cohen, Phy. Rev. B 48, 17138 (1993). [2] C.H. Lee, W.R. Lambrecht, and B. Segall, Phys. Rev. B 51, 10392 (1995). [3] M.M. Disko, J.C.H. Spence, O.F. Sankey, and D. Saldin, Phys. Rev. B 33, 5642 (1986).

  11. TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy.

    Science.gov (United States)

    Yadava, Ramesh S; Foff, Erin P; Yu, Qing; Gladman, Jordan T; Kim, Yun K; Bhatt, Kirti S; Thornton, Charles A; Zheng, Timothy S; Mahadevan, Mani S

    2015-04-01

    Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-κB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1.

  12. Progress and prospects of gene therapy clinical trials for the muscular dystrophies.

    Science.gov (United States)

    Bengtsson, Niclas E; Seto, Jane T; Hall, John K; Chamberlain, Jeffrey S; Odom, Guy L

    2016-04-15

    Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC). The most common and severe form among children is Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, with an average life expectancy around 25 years of age. Another group of MD's referred to as the limb-girdle muscular dystrophies (LGMDs) can affect boys or girls, with different types caused by mutations in different genes. Mutation of the α-sarcoglycan gene, also a DGC component, causes LGMD2D and represents the most common form of LGMD. Early preclinical and clinical trial findings support the feasibility of gene therapy via recombinant adeno-associated viral vectors as a viable treatment approach for many MDs. In this mini-review, we present an overview of recent progress in clinical gene therapy trials of the MD's and touch upon promising preclinical advances.

  13. Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Dandan Tan

    Full Text Available This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA-related muscular dystrophy (MD. The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293 cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD. Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

  14. The Myotonic Dystrophy Health Index: Italian validation of a disease-specific outcome measure.

    Science.gov (United States)

    Sansone, Valeria A; Lizio, Andrea; Greco, Lucia; Gragnano, Gaia; Zanolini, Alice; Gualandris, Marco; Iatomasi, Marino; Heatwole, Chad

    2017-07-10

    The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, self-reported outcome measure that assesses total disease burden and 17 areas of Myotonic Dystrophy type 1 (DM1) specific health. This study translated the MDHI into Italian and validated the instrument using a cohort of Italian DM1 patients. Italian DM1 patients were interviewed regarding the form and content of the instrument. Thirty-eight DM1 patients were subsequently recruited to test the reliability and concurrent validity of the instrument by serially completing the MDHI and a battery of clinical tests. Lastly, we determined the internal consistency of the Italian MDHI and each of its subscales. The internal consistency was excellent in the total Italian MDHI score and acceptable in all of its subscales; the test-retest reliability was high (intraclass correlation coefficient = 0.95); Italian MDHI total scores and subscales were associated with neuromuscular function, cognitive and social health, respiratory function, and quality of life. Overall, the Italian MDHI is valid and well suited to measure the multi-dimensional aspects of disease burden in Myotonic Dystrophy clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Preliminary diffusion tensor imaging studies in limb-girdle muscular dystrophies

    Science.gov (United States)

    Hidalgo-Tobon, S.; Hernandez-Salazar, G.; Vargas-Cañas, S.; Marrufo-Melendez, O.; Solis-Najera, S.; Taboada-Barajas, J.; Rodriguez, A. O.; Delgado-Hernandez, R.

    2012-10-01

    Limb-girdle muscular dystrophies (LGMD) are a group of autosomal dominantly or recessively inherited muscular dystrophies that also present with primary proximal (limb-girdle) muscle weakness. This type of dystrophy involves the shoulder and pelvic girdles, distinct phenotypic or clinical characteristics are recognized. Imaging experiments were conducted on a 1.5T GE scanner (General Electric Medical Systems. Milwaukee. USA), using a combination of two eight-channel coil array. Diffusion Tensor Imaging (DTI) data were acquired using a SE-EPI sequence, diffusion weighted gradients were applied along 30 non-collinear directions with a b-value=550 s/mm2. The connective tissue content does not appear to have a significant effect on the directionality of the diffusion, as assessed by fractional anisotropy. The fibers of the Sartorius muscle and gracilis showed decreased number of tracts, secondary to fatty infiltration and replacement of connective tissue and muscle mass loss characteristic of the underlying pathology. Our results demonstrated the utility of non-invasive MRI techniques to characterize the muscle pathology, through quantitative and qualitative methods such as the FA values and tractrography.

  16. From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies

    Directory of Open Access Journals (Sweden)

    Barresi Rita

    2011-06-01

    Full Text Available Abstract Muscular dystrophies are a large heterogeneous group of inherited diseases that cause progressive muscle weakness and permanent muscle damage. Very few muscular dystrophies show sufficient specific clinical features to allow a definite diagnosis. Because of the currently limited capacity to screen for numerous genes simultaneously, muscle biopsy is a time and cost-effective test for many of these disorders. Protein analysis interpreted in correlation with the clinical phenotype is a useful way of directing genetic testing in many types of muscular dystrophies. Immunohistochemistry and western blot are complementary techniques used to gather quantitative and qualitative information on the expression of proteins involved in this group of diseases. Immunoanalysis has a major diagnostic application mostly in recessive conditions where the absence of labelling for a particular protein is likely to indicate a defect in that gene. However, abnormalities in protein expression can vary from absence to very subtle reduction. It is good practice to test muscle biopsies with antibodies for several proteins simultaneously and to interpret the results in context. Indeed, there is a degree of direct or functional association between many of these proteins that is reflected by the presence of specific secondary abnormalities that are of value, especially when the diagnosis is not straightforward.

  17. SLC4A11 Three-Dimensional Homology Model Rationalizes Corneal Dystrophy-Causing Mutations.

    Science.gov (United States)

    Badior, Katherine E; Alka, Kumari; Casey, Joseph R

    2017-03-01

    We studied the structural effects of point mutations of a membrane protein that cause genetic disease. SLC4A11 is a membrane transport protein (OH(-) /H(+) /NH3 /H2 O) of basolateral corneal endothelium, whose mutations cause some cases of congenital hereditary endothelial dystrophy and Fuchs endothelial corneal dystrophy. We created a three-dimensional homology model of SLC4A11 membrane domain, using Band 3 (SLC4A1) crystal structure as template. The homology model was assessed in silico and by analysis of mutants designed on the basis of the model. Catalytic pathway mutants p.Glu675Gln, p.His724Arg, and p.His724Ala impaired SLC4A11 transport. p.Ala720Leu, in a region of extended structure of the proposed translocation pore, failed to mature to the cell surface. p.Gly509Lys, located in an open region at the core domain/gate domain interface, had wild-type level of transport function. The molecular phenotype of 37 corneal dystrophy-causing point mutants was rationalized, based on their location in the homology model. Four map to the substrate translocation pathway, 25 to regions of close transmembrane helix packing, three to the dimeric interface, and five lie in extramembraneous loops. The model provides a view of the spectrum of effects of disease mutations on membrane protein structure and provides a tool to analyze pathogenicity of additional newly discovered SLC4A11 mutants. © 2016 WILEY PERIODICALS, INC.

  18. MR imaging of fukuyama congenital muscular dystrophy; a case report

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Jeong Hyun; Kim, Yoo Kyung; Koo, Hae Soo; Park, Ki Deuk [Ewha Womans Univ. College of Medicine, Seoul (Korea, Republic of)

    2000-11-01

    Fukuyama congenital muscular dystrophy is a genetic disease and common in Japan. The typical clinical features are hypotonia with an early infantile onset and severe developmental delay. The diagnosis is based on pathologic evidence of muscular dystrophy revealed by biopsy or an increased serum creatine kinase levels. Involvement of the brain is characterized by abnormal cerebral cortical dysplasia, cerebellar dysplasia, and white matter changes. We encountered a case of Fukuyama congenital muscular dystrophy in which brain MRI findings were typical, and present this case together with a review of the literature.

  19. The superhealing MRL background improves muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Heydemann Ahlke

    2012-12-01

    Full Text Available Abstract Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg, a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis. Methods MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains. Results Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis. Conclusions These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease.

  20. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Gerevini, Simonetta; Caliendo, Giandomenico; Falini, Andrea [IRCCS San Raffaele Scientific Institute, Neuroradiology Unit, Head and Neck Department, Milan (Italy); Scarlato, Marina; Previtali, Stefano Carlo [IRCCS San Raffaele Scientific Institute, Department of Neurology, INSPE and Division of Neuroscience, Milan (Italy); Maggi, Lorenzo; Pasanisi, Barbara; Morandi, Lucia [Fondazione IRCCS Istituto Neurologico ' ' Carlo Besta' ' , Neuromuscular Diseases and Neuroimmunology Unit, Milan (Italy); Cava, Mariangela [IRCCS San Raffaele Scientific Institute, Department of Radiology and Center for Experimental Imaging, Milan (Italy)

    2016-03-15

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. (orig.)

  1. Congenital muscular dystrophy with inflammation: Diagnostic considerations

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    Kaumudi Konkay

    2016-01-01

    Full Text Available Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α 2 deficiency on immunohistochemistry (IHC. Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E, enzyme and immunohistochemistry (IHC with laminin α 2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α 2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α 2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α 2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones.

  2. Sleep disordered breathing in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Della Marca, Giacomo; Frusciante, Roberto; Dittoni, Serena; Vollono, Catello; Buccarella, Cristina; Iannaccone, Elisabetta; Rossi, Monica; Scarano, Emanuele; Pirronti, Tommaso; Cianfoni, Alessandro; Mazza, Salvatore; Tonali, Pietro A; Ricci, Enzo

    2009-10-15

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7+/-12.3 years (range: 26-72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD.

  3. Molecular Mimicry Regulates ABA Signaling by SnRK2 Kinases and PP2C Phosphatases

    Energy Technology Data Exchange (ETDEWEB)

    Soon, Fen-Fen; Ng, Ley-Moy; Zhou, X. Edward; West, Graham M.; Kovach, Amanda; Tan, M.H. Eileen; Suino-Powell, Kelly M.; He, Yuanzheng; Xu, Yong; Chalmers, Michael J.; Brunzelle, Joseph S.; Zhang, Huiming; Yang, Huaiyu; Jiang, Hualiang; Li, Jun; Yong, Eu-Leong; Cutler, Sean; Zhu, Jian-Kang; Griffin, Patrick R.; Melcher, Karsten; Xu, H. Eric (Van Andel); (Scripps); (NWU); (Purdue); (UCR); (Chinese Aca. Sci.); (NU Singapore)

    2014-10-02

    Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.

  4. Valley sign in Becker muscular dystrophy and outliers of Duchenne and Becker muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Pradhan Sunil

    2004-04-01

    Full Text Available Valley sign has been described in patients with Duchenne muscular dystrophy (DMD. As there are genetic and clinical similarities between DMD and Becker muscular dystrophy (BMD, this clinical sign is evaluated in this study in BMD and DMD/BMD outliers. To evaluate the sign, 28 patients with Becker muscular dystrophy (BMD, 8 DMD/BMD outliers and 44 age-matched male controls with other neuromuscular diseases were studied. The sign was examined after asking patients to abduct their arms to about 90ºwith hands directed upwards; the muscle bulk over the back of the shoulders was observed. The sign was considered positive if the infraspinatus and deltoid muscles were enlarged and between these two muscles, the muscles forming the posterior axillary fold were wasted as if there were a valley between the two mounts. Twenty-five BMD patients and 7 DMD/BMD outliers had positive valley sign. However, it was less remarkable in comparison to DMD. It was absent in all the 44 controls. It was concluded that the presence of valley sign may help in differentiating BMD from other progressive neuromuscular disorders of that age group.

  5. Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

    Science.gov (United States)

    Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

    2015-03-12

    We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome.

  6. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Research Institute National Institute of Neurological Disorders and Stroke Educational Resources (13 links) Centers for Disease Control and Prevention Centre for Genetics Education Cleveland Clinic: Muscular Dystrophy Disease InfoSearch: Becker ...

  7. Strength training and albuterol in facioscapulohumeral muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, EL; Vogels, OJM; van Asseldonk, RJGP; Lindeman, E; Hendriks, JCM; Wohlgemuth, M; van der Maarel, SM; Padberg, GW

    2004-01-01

    Background: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  8. Cardiac assessment of patients with late stage Duchenne muscular dystrophy

    NARCIS (Netherlands)

    van Bockel, E. A. P.; Lind, J. S.; Zijlstra, J. G.; Wijkstra, P. J.; Meijer, P. M.; van den Berg, M. P.; Slart, R. H. J. A.; Aarts, L. P. H. J.; Tulleken, J. E.

    2009-01-01

    Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, b

  9. Acetazolamide for cystoid macular oedema in Bietti crystalline retinal dystrophy.

    Science.gov (United States)

    Broadhead, Geoffrey K; Chang, Andrew A

    2014-04-01

    Bietti crystalline retinal dystrophy is a rare, inherited disorder whose hallmark is the presence of retinal crystal deposits associated with later chorioretinal degeneration. This condition may rarely be complicated by the development of cystoid macular oedema leading to rapid visual decline. Currently, treatment options for this complication of Bietti dystrophy are limited and the visual prognosis is poor. Here, we present a case of cystoid macular oedema associated with Bietti dystrophy that was successfully diagnosed using multimodal imaging techniques including optical coherence tomography and fluorescein angiography. These modalities confirmed the diagnosis of macular oedema and excluded other possible causes of oedema such as choroidal neovascularisation. In this patient, cystoid macular oedema was resolved with oral acetazolamide therapy, a treatment that has not been previously reported in this context. Acetazolamide treatment resulted in oedema resolution and improvement in visual function, and can be considered a therapeutic option for other patients with Bietti dystrophy who develop cystoid macular oedema.

  10. Iridium Ziegler-type hydrogenation catalysts made from [(1,5-COD)Ir(mu-O2C8H15)](2) and AlEt3: spectroscopic and kinetic evidence for the Ir(n) species present and for nanoparticles as the fastest catalyst.

    Science.gov (United States)

    Alley, William M; Hamdemir, Isil K; Wang, Qi; Frenkel, Anatoly I; Li, Long; Yang, Judith C; Menard, Laurent D; Nuzzo, Ralph G; Ozkar, Saim; Johnson, Kimberly A; Finke, Richard G

    2010-09-06

    Ziegler-type hydrogenation catalysts, those made from a group 8-10 transition metal precatalyst and an AlR(3) cocatalyst, are often used for large scale industrial polymer hydrogenation; note that Ziegler-type hydrogenation catalysts are not the same as Ziegler-Natta polymerization catalysts. A review of prior studies of Ziegler-type hydrogenation catalysts (Alley et al. J. Mol. Catal. A: Chem. 2010, 315, 1-27) reveals that a approximately 50 year old problem is identifying the metal species present before, during, and after Ziegler-type hydrogenation catalysis, and which species are the kinetically best, fastest catalysts--that is, which species are the true hydrogenation catalysts. Also of significant interest is whether what we have termed "Ziegler nanoclusters" are present and what their relative catalytic activity is. Reported herein is the characterization of an Ir Ziegler-type hydrogenation catalyst, a valuable model (vide infra) for the Co-based industrial Ziegler-type hydrogenation catalyst, made from the crystallographically characterized [(1,5-COD)Ir(mu-O(2)C(8)H(15))](2) precatalyst plus AlEt(3). Characterization of this Ir model system is accomplished before and after catalysis using a battery of physical methods including Z-contrast scanning transmission electron microscopy (STEM), high resolution (HR)TEM, and X-ray absorption fine structure (XAFS) spectroscopy. Kinetic studies plus Hg(0) poisoning experiments are then employed to probe which species are the fastest catalysts. The main findings herein are that (i) a combination of the catalyst precursors [(1,5-COD)Ir(mu-O(2)C(8)H(15))](2) and AlEt(3) gives catalytically active solutions containing a broad distribution of Ir(n) species ranging from monometallic Ir complexes to nanometer scale, noncrystalline Ir(n) nanoclusters (up to Ir(approximately 100) by Z-contrast STEM) with the estimated mean Ir species being 0.5-0.7 nm, Ir(approximately 4-15) clusters considering the similar, but not identical

  11. The Mef2 Transcription Network Is Disrupted in Myotonic Dystrophy Heart Tissue, Dramatically Altering miRNA and mRNA Expression

    Directory of Open Access Journals (Sweden)

    Auinash Kalsotra

    2014-01-01

    Full Text Available Cardiac dysfunction is the second leading cause of death in myotonic dystrophy type 1 (DM1, primarily because of arrhythmias and cardiac conduction defects. A screen of more than 500 microRNAs (miRNAs in a DM1 mouse model identified 54 miRNAs that were differentially expressed in heart. More than 80% exhibited downregulation toward the embryonic expression pattern and showed a DM1-specific response. A total of 20 of 22 miRNAs tested were also significantly downregulated in human DM1 heart tissue. We demonstrate that many of these miRNAs are direct MEF2 transcriptional targets, including miRNAs for which depletion is associated with arrhythmias or fibrosis. MEF2 protein is significantly reduced in both DM1 and mouse model heart samples, and exogenous MEF2C restores normal levels of MEF2 target miRNAs and mRNAs in a DM1 cardiac cell culture model. We conclude that loss of MEF2 in DM1 heart causes pathogenic features through aberrant expression of both miRNA and mRNA targets.

  12. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.

    Science.gov (United States)

    Paim, Julia F; Cotta, Ana; Vargas, Antonio P; Navarro, Monica M; Valicek, Jaquelin; Carvalho, Elmano; da-Cunha, Antonio L; Plentz, Estevão; Braz, Shelida V; Takata, Reinaldo I; Almeida, Camila F; Vainzof, Mariz

    2013-06-01

    Limb girdle muscular dystrophy type 2 G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46 years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8 years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41 years old, and now, at 54 years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy.

  13. Eccentric contractions lead to myofibrillar dysfunction in muscular dystrophy.

    Science.gov (United States)

    Blaauw, Bert; Agatea, Lisa; Toniolo, Luana; Canato, Marta; Quarta, Marco; Dyar, Kenneth A; Danieli-Betto, Daniela; Betto, Romeo; Schiaffino, Stefano; Reggiani, Carlo

    2010-01-01

    It is commonly accepted that skeletal muscles from dystrophin-deficient mdx mice are more susceptible than those from wild-type mice to damage from eccentric contractions. However, the downstream mechanisms involved in this enhanced force drop remain controversial. We studied the reduction of contractile force induced by eccentric contractions elicited in vivo in the gastrocnemius muscle of wild-type mice and three distinct models of muscle dystrophy: mdx, alpha-sarcoglycan (Sgca)-null, and collagen 6A1 (Col6a1)-null mice. In mdx and Sgca-null mice, force decreased 35% compared with 14% in wild-type mice. Drop of force in Col6a1-null mice was comparable to that in wild-type mice. To identify the determinants of the force drop, we measured force generation in permeabilized fibers dissected from gastrocnemius muscle that had been exposed in vivo to eccentric contractions and from the contralateral unstimulated muscle. A force loss in skinned fibers after in vivo eccentric contractions was detectable in fibers from mdx and Sgca-null, but not wild-type and Col6a1-null, mice. The enhanced force reduction in mdx and Sgca-null mice was observed only when eccentric contractions were elicited in vivo, since eccentric contractions elicited in vitro had identical effects in wild-type and dystrophic skinned fibers. These results suggest that 1) the enhanced force loss is due to a myofibrillar impairment that is present in all fibers, and not to individual fiber degeneration, and 2) the mechanism causing the enhanced force reduction is active in vivo and is lost after fiber permeabilization.

  14. Current and emerging treatment strategies for Duchenne muscular dystrophy

    OpenAIRE

    Mah JK

    2016-01-01

    Jean K Mah Department of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Abstract: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the...

  15. The new frontier in muscular dystrophy research: booster genes

    DEFF Research Database (Denmark)

    Engvall, Eva; Wewer, Ulla M

    2003-01-01

    More than 30 different forms of muscular dystrophy (MD) have been molecularly characterized and can be diagnosed, but progress toward treatment has been slow. Gene replacement therapy has met with great difficulty because of the large size of the defective genes and because of difficulties...... of the boosters are better understood, drugs may be developed to provide the boost to muscle. Some of the experiences in models of muscular dystrophy may inspire new approaches in other genetic degenerative diseases as well....

  16. Efficacy of piroxicam for postoperative pain after lower third molar surgery associated with CYP2C8*3 and CYP2C9

    Directory of Open Access Journals (Sweden)

    Calvo AM

    2017-07-01

    Full Text Available Adriana Maria Calvo, Paulo Zupelari-Gonçalves, Thiago José Dionísio, Daniel Thomas Brozoski, Flávio Augusto Faria, Carlos Ferreira Santos Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs are metabolized by the cytochrome P450 enzymes (CYPs, predominantly CYP2C8 and CYP2C9. The aim of this study was to evaluate the possible association of polymorphisms in the CYP2C8*3 and CYP2C9 genes with the clinical efficacy of oral piroxicam (20 mg daily for 4 days after lower third molar surgeries with regard to postoperative pain, swelling, trismus, adverse reactions, need for rescue medication and the volunteer’s overall satisfaction. Materials and methods: For this purpose, 102 volunteers were genotyped for CYP2C8*3 and CYP2C9 polymorphisms. Briefly, genomic DNA was isolated from saliva collected from volunteers subjected to invasive lower third molar surgeries, and the preoperative, intraoperative and postoperative parameters were collected and analyzed. Results: An equal amount of piroxicam sufficiently managed postoperative pain and inflammatory symptoms, with visual analog pain scores typically <40 mm for all genotypes investigated. Furthermore, only two out of 102 volunteers heterozygous for CYP2C8*3 and CYP2C9*3 reported adverse side effects. Conclusion: In general, slow metabolizers of piroxicam, who were volunteers with mutant alleles, were indifferent from normal metabolizers with the wild-type alleles and therefore did not require specialized piroxicam doses to manage postoperative pain and inflammation. Keywords: piroxicam, lower third molar surgery, P450, CYP2C8, CYP2C9, pharmacogenetics 

  17. Design and Discovery of Functionally Selective Serotonin 2C (5-HT2C) Receptor Agonists.

    Science.gov (United States)

    Cheng, Jianjun; McCorvy, John D; Giguere, Patrick M; Zhu, Hu; Kenakin, Terry; Roth, Bryan L; Kozikowski, Alan P

    2016-11-10

    On the basis of the structural similarity of our previous 5-HT2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT2A, 5-HT2B, and 5-HT2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-7e produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties.

  18. Cardiac function in muscular dystrophy associates with abdominal muscle pathology

    Science.gov (United States)

    Gardner, Brandon B.; Swaggart, Kayleigh A.; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M.

    2015-01-01

    Background The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Methods Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. Findings The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients. PMID:26029630

  19. Infantile neuroaxonal dystrophy caused by uniparental disomy.

    Science.gov (United States)

    Solomons, Joyce; Ridgway, Oliver; Hardy, Carol; Kurian, Manju A; Kurian, Manju; Jayawant, Sandeep; Hughes, Sarah; Pretorius, Pieter; Németh, Andrea H

    2014-04-01

    Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the phospholipase A2 group 6 (Pla2G6) gene. Affected individuals usually present between the ages of 6 months and 2 years with rapid cognitive and motor regression and axial hypotonia. Gait disturbance, limb spasticity, cerebellar signs, and optic atrophy are other common features associated with INAD. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. In this case report, we describe the first individual (female) with INAD due to a combination of uniparental heterodisomy and isodisomy; we discuss the possible underlying mechanism and highlight the importance of parental carrier testing in accurately predicting the recurrence risk in these families. We also confirm the recent report of hypertrophy of the clava (also known as the 'gracile tubercle') as a useful MRI sign in INAD.

  20. Natural history of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Qing KE

    2015-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is X-linked recessive hereditary disease. DMD gene mutations result in dystrophin deficiency, which causes not only muscle movement disorders but also scoliosis, cognitive dysfunction, urinary tract diseases, respiratory diseases and heart diseases. Most patients die in early adult for respiratory and circulatory failure. Early multidisciplinary therapies will significantly delay disease progression and improve patients' quality of life. However, DMD diagnosis and treatment exist significantly time delay now. In this study, we review the natural history of DMD, including motor, cognitive, respiratory and heart function, for improving DMD early recognition, diagnosis and treatment, so as to benefit DMD patients. DOI: 10.3969/j.issn.1672-6731.2015.05.004

  1. Cardiac involvement in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Finsterer, Josef; Stöllberger, Claudia; Meng, Gerhard

    2005-01-01

    Cardiac involvement (CI) in form of myocardial thickening in a patient with genetically confirmed facioscapulohumeral muscular dystrophy (FSHMD) has not been reported. The patient is a 50-year-old male with a tandem repeat size of 17 and 14 kb in the D4Z4 locus on chromosome 4q35. The clinical cardiologic investigation was normal. Blood pressure was 150/90 mm Hg. Funduscopy, 24-hour ambulatory ECG, and 24-hour blood pressure monitoring were normal. ECG showed incomplete right bundle branch block, ST elevation in V2-V4, tall T waves in V3-V5, and hypertrophy signs. Echocardiography revealed left ventricular myocardial thickening of the posterior wall (11.7 mm) and the septum (15.5 mm). In conclusion, CI in genetically confirmed FSHMD may manifest not only as ECG abnormalities but also as left ventricular myocardial thickening. Copyright 2005 S. Karger AG, Basel.

  2. Oculopharyngeal muscular dystrophy: a polyalanine myopathy.

    Science.gov (United States)

    Brais, Bernard

    2009-01-01

    It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

  3. Recent advances in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Perkins KJ

    2012-10-01

    Full Text Available Kelly J Perkins,1,2 Kay E Davies21Sir William Dunn School of Pathology, 2MRC Functional Genomics Unit, University of Oxford, Oxford, UKAbstract: Duchenne muscular dystrophy (DMD, an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and

  4. Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy

    DEFF Research Database (Denmark)

    Andersen, Søren P; Sveen, Marie-Louise; Hansen, Regitze S

    2013-01-01

    We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies.......We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies....

  5. 假性肥大型肌营养不良儿童血清脑利钠肽水平与心脏功能的相关性%Correlation Between Serum B-Type Natriuretic Peptide Levels and Cardiac Function in Duchenne'S Muscular Dystrophy Patients

    Institute of Scientific and Technical Information of China (English)

    田淑芬

    2011-01-01

    目的:研究假肥大型肌营养不良(DMD)患者血清脑利钠肽(BNP)与左心室功能的相关性.方法:采用电化学发光免疫方法以及心脏超声检查分别测量50名DMD儿童和25名正常儿童的血清BNP水平和左心室功能相关指标.分析DMD儿童血清BNP与不同心脏功能分级的相关性.结果:DMD儿童血清BNP水平与左心室功能与正常对照组有显著性差异(P<0.01).不同心脏功能分级的DMD儿童血清BNP水平和左心室功能显著不同(P<0.05或P<0.01).DMD儿童LVMI、LVEDD、LVPWT与血清BNP水平正相关,LVEF、IVST、FS、E/A与血清BNP水平负相关(r绝对值:0.53-0.75,P<0.05).结论:DMD儿童血清BNP水平与左心室功能显著相关,可作为诊断DMD儿童心脏功能的指标.%Objective: To research the correlation between serum B-type natriuretic peptide (BNP) levels and function of left ventricle in Duchenne's muscular dystrophy (DMD) children.Methods: The serum BNP levels and function of left ventricle in 50 DMD children and 25 control children were detected respectively by electro-chemistry immunity assay and echocardiography, and the correlation between serum BNP levels and function of left ventricle in DMD children was analyzed.Results: The serum BNP levels and function of left ventricle were significantly different in statistics between DMD children and control children (P<0.01).The serum BNP levels and function of left ventricle were significantly different in DMD children with different NYHA grades (P< 0.05 or P<0.01).Left ventricular indices measured by echocardiograpy such as LVMI, LVEDD and LVPWT were positively correlated to serum BNP levels, but LVEF, IVST, FS, and E/A were negatively correlated to serum BNP levels in DMD children (|r|=0.53-0.75, P<0.05).Conclusion: Serum BNP levels correlate to the function of left ventricle, and could be used as the indicators to detect the cardiac function in DMD children.

  6. The clinical and pathological character analysis of limb-girdle muscular dystrophy type 2B misdiagnosed to polymyositis%易误诊为多发性肌炎的肌营养不良临床及病理分析

    Institute of Scientific and Technical Information of China (English)

    郭华; 袁栋才

    2008-01-01

    目的 明确肢带型肌营养不良2B(LGMD2B)与多发性肌炎(PM)的鉴别诊断.方法 分析LGMD2B临床表现、骨骼肌病理学特点及与PM的关系.结果 LGMD2B 临床表现为四肢近端肌无力,血清肌酸激酶显著增高,肌电图呈肌源性损害,与PM相似.组织化学染色:呈不同程度肌纤维变性、坏死、再生和炎性细胞浸润,与PM相似.免疫组织化学染色:抗-Dysferlin单克隆抗体染色,5例LGMD2B患者Dysferlin蛋白在肌膜上完全缺失,PM均表达正常.结论 LGMD2B临床表现、骨骼肌病理学特点与PM相似,抗-Dysferlin单克隆抗体免疫组织化学染色是鉴别二者的关键.%Objective To clarify the differential diagnosis between limb-girdle muscular dystrophy type 2B (LGMD2B) and polymyositis (PM). Methods Analyzed the character of clinical, histochemical and immunohistochemical pathologic with biopsied skeletal muscle in 5 patients with LGMD2B and the relationship with PM. Results Both LGMD2B and PM showed the muscle weakness in proximal limbs and elevated creatinkinase level and electromyogram showed myogenic damage. Histochemical stains: it was similar to PM, that was the muscle fibers degenerating, regenerating and necrotic and the infiltrating inflammatory cells in different extent in 5 patients. Immunohistoehemical stains: anfi-Dysferlin monoelonal antibody showed that Dysferlin was deficient on sarcolemma in LGMD2B, but it was normal in PM. Conclusions It is resemble on the clinical and histoehemieal pathologic characters in both LGMD2B and PM. It is key to antidiastole LGMD2B and PM by the immunohistochemieal stain of anti-Dysferlin monoelonal antibody.

  7. Myotonic Dystrophy-1 Complicated by Factor-V (Leiden Mutation

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2015-01-01

    Full Text Available Objectives. Presence of a factor-V Leiden mutation in a patient with myotonic dystrophy type 1 (DM1 has been reported only once. Here we report the second DM1 patient carrying a factor-V mutation who died from long-term complications of this mutation. Case Report. A 66-year-old DM1 patient with multi-organ-disorder syndrome developed a first deep venous thrombosis (DVT and consecutive pulmonary embolism (PE at age 50 y. Acetyl-salicylic acid was given. One year later he experienced a second DVT; that is why phenprocoumon was started. Despite anticoagulation, he experienced a third DVT bilaterally and a second PE bilaterally at 61 y; that is why a vena cava filter was additionally deployed. Despite therapeutic anticoagulation, he experienced a vena cava filter thrombosis at age 62 y. Genetic workup revealed a heterozygous factor-V mutation in addition to a CTG-repeat expansion of 500. As a consequence of PE he developed chronic obstructive pulmonary disease and experienced recurrent pulmonary infections, which were lastly responsible for decease at age 66 y despite intensive care measures. Conclusion. The heterozygous Leiden mutation may severely affect DM1 patients to such a degree that they die from its complications. If DM1 patients present with unusual manifestations, search for causes other than a CTG-repeat expansion is indicated.

  8. ASSESSMENT OF GRIP FORCE CONTROL IN PATIENTS WITH MUSCULAR DYSTROPHY

    Directory of Open Access Journals (Sweden)

    Gregorij Kurillo

    2004-12-01

    Full Text Available Background. The majority of hand functionality tests are based on qualitative assessment which largely depends on the experience of the therapist. Computer-assisted methods can provide more objective and accurate measurements of the grip force and other parameters related to grasping.Methods. We analysed the grip force control in 12 patients with muscular dystrophy using the tracking system developed. The system consists of a grip-measuring device with endobjects assessing the force applied in different grips. The device was used as input to a tracking task where the patient applied the grip force according to the visual feedback from the computer screen. Each patient performed two tasks which consisted of tracking a ramp and sinus target.Results. We analysed the maximal grip force as assessed in the ramp task and the tracking accuracy of the sinus task. The results are compared among five different grips (cylindrical, lateral, palmar, pinch and spherical grip, applied with dominant and non-dominant hand. The results show no significant difference in tracking accuracy between the dominant and non-dominant hand.Conclusions. The results obtained in tracking the ramp target showed that the method could be used for the assessment of the muscle fatigue, providing quantitative information on muscle capacity. The results of the sinus-tracking task showed that the method can evaluate the grip force control in different types of grips, providing information on hand dexterity, muscle activation patterns or tremor.

  9. Anesthetic and surgical complications in 219 cases of myotonic dystrophy.

    Science.gov (United States)

    Mathieu, J; Allard, P; Gobeil, G; Girard, M; De Braekeleer, M; Bégin, P

    1997-12-01

    The objective of this study was to assess the frequency, type, and severity of perioperative complications after a first surgery under general anesthesia in patients with myotonic dystrophy (DM) and to measure the association with suspected risk factors. Numerous cases of perioperative complications in DM patients have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 DM patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, we found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery (odds ratio (OR), 24.4; 95% CI, 4.0 to 149.3) and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness (OR, 14.1; 95% CI, 1.5 to 134.4). The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic DM patients, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.

  10. Analysis list: Tfap2c [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Tfap2c Breast,Pluripotent stem cell + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Tfap2...c.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Tfap2c.5.tsv http://dbarchiv...e.biosciencedbc.jp/kyushu-u/mm9/target/Tfap2c.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Tfap2...c.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Tfap2c.Pluripo

  11. Endothelial mosaic in Fuchs' dystrophy. A qualitative evaluation with the specular microscope.

    Science.gov (United States)

    Laing, R A; Leibowitz, H M; Oak, S S; Chang, R; Berrospi, A R; Theodore, J

    1981-01-01

    The progressive morphological changes of cornea guttata in Fuchs' endothelial dystrophy have been characterized by clinical specular photomicroscopy. Five specific stages in the development of excrescences can be discerned using this in vivo technique. Several stages can be observed in the same cornea at a given time, although in most cases the majority of guttate changes seemed to have progressed to the same stage of development. All five stages of cornea guttata discerned in this study can occur in a cornea clinically free of edema. Two types of cornea guttata can be identified in vivo. One has a smooth, regular posterior surface, whereas the posterior contour of the second is irregular.

  12. Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T)

    DEFF Research Database (Denmark)

    Østergaard, Sofie Thurø; Stojkovic, T; Dahlqvist, J R

    2016-01-01

    OBJECTIVE: In this study, muscle involvement assessed by MRI and levels of GMPPB and glycosylation of α-dystroglycan expression in muscle were examined in patients with limb-girdle muscular dystrophy (LGMD) type 2T. METHODS: Six new patients with genetically verified mutations in GMPPB were studied....... T1-weighted magnetic resonance images were obtained in 4 participants. Muscle strength and potential involvement of extramuscular organs were examined. Glycosylation of α-dystroglycan in muscle was studied, and GMPPB and α-dystroglycan expression was analyzed by Western blotting. Prevalence of LGMD2...

  13. Comparative analysis of phenotypes features in two common genetic variants of limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    I. V. Sharkova

    2015-01-01

    Full Text Available The algorithm of differential diagnosis of the two most common genetic variants the limb-girdle muscular dystrophy (LGMD2A and DMD, developed on the basis of a comprehensive survey of 85 patients with a diagnosis specification using techniques of DNA analysis. It is shown that the accurate diagnosis of LGMD genetic types should be based on the results of the clinical and genealogical, biochemical and molecular genetic analysis. The proposed algorithm will significantly reduces the economic and time costs with expensive DNA testing.

  14. Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice.

    OpenAIRE

    Panaite, P.A.; Kielar, M.; Kraftsik, R.; Gourdon, G; Kuntzer, T; Barakat-Walter, I.

    2011-01-01

    Myotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology. Here, we investigated the presence or absence of peripheral neuropathy in transgenic mice (DMSXL) that carry more than 1,300 CTG repeats and display a severe form of DM1. Electrophysiologic...

  15. A Case Report on 30-Week Premature Twin Babies with Congenital Myotonic Dystrophy Conceived by In Vitro Fertilization

    OpenAIRE

    Son, Su Bin; Chun, Jung Mi; Kim, Kyung Ah; Ko, Sun Young; Lee,Yeon Kyung; Shin, Son Moon

    2012-01-01

    Congenital myotonic dystrophy type 1 (DM1) presents severe generalized weakness, hypotonia, and respiratory compromise after delivery with high mortality and poor prognosis. We presented a congenital DM1 of premature twins in the 30th week of gestation. These twins were conceived by in vitro fertilization (IVF). Both babies presented apnea and hypotonia and had characteristic facial appearance. They were diagnosed DM1 by genetic method. They were complicated by chylothorax and expired at 100 ...

  16. Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy

    OpenAIRE

    Petrica-Adrian Panaite; Thierry Kuntzer; Geneviève Gourdon; Johannes Alexander Lobrinus; Ibtissam Barakat-Walter

    2013-01-01

    SUMMARY Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory p...

  17. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland paediatric population over the last 30 years.

    OpenAIRE

    Millar, Sarinda; Carson, Dennis

    2012-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyendocrinopathy syndrome type 1, is a rare autosomal recessive disorder with a variable and evolving phenotypic course. It is caused by mutations in the autoimmune regulator (AIRE) gene. APECED syndrome is diagnosed clinically by the presence of 2 from 3 major criteria; chronic mucocutaneous candidasis, primary hypoparathyroidism and primary adrenocortical insufficiency. Many of the patients d...

  18. EMBOLISMO GRASO EN UN NIÑO CON DISTROFIA MUSCULAR DE DUCHENNE Y FRACTURA BILATERAL DE FÉMUR. UNA RARA ASOCIACIÓN. Fat embolism syndrome in a child with muscular dystrophy of Duchenne type bilateral femur fracture. A rare association.

    Directory of Open Access Journals (Sweden)

    Enrique Vergara Amador

    2007-03-01

    Full Text Available Las fracturas de fémur en pacientes que sufren de distrofia muscular de Duchenne (DMD son frecuentes, con una incidencia entre 15-44 por ciento. El embolismo graso se presenta en fracturas de huesos largos generalmente asociado a trauma de alta energía o a lesiones extensas de tejidos blandos. El diagnóstico de embolismo graso no es tan frecuente en niños posiblemente porque cursa con presentaciones subclínicas. No existen reportes de embolismo graso asociado a distrofia muscular de Duchenne. Informamos el caso de un niño con distrofia muscular Duchenne que sufrió fractura bilateral de fémur y embolismo graso.It is high the frequency of femur fracture in children with Duchenne Muscular Dystrophy (DMD, with an incidence between 15 and 44%. The fatty embolism is presented in fractures of long bones generally associated to trauma of high energy or to extensive lesions of soft tissues. The diagnosis is not frequent in children probably because they can be presentations subclínicas. We could not find reports of fatty embolism associated to Duchenne muscular dystrophy. We present the case of a boy with Duchenne muscular dystrophy that suffered bilateral fracture of femur and fatty embolism.

  19. Submillimeter spectroscopy of H$_2$C$^{17}$O and a revisit of the rotational spectra of H$_2$C$^{18}$O and H$_2$C$^{16}$O

    CERN Document Server

    Müller, Holger S P

    2016-01-01

    The rotational spectrum of the formaldehyde isotopologue H2C(17)O was investigated between 0.56 and 1.50 THz using a sample of natural isotopic composition. In addition, transition frequencies were determined for H2C(18)O and H2C(16)O between 1.37 and 1.50 THz. The data were combined with critically evaluated literature data to derive improved sets of spectroscopic parameters which include (17)O or H nuclear hyperfine structure parameters.

  20. CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

    Directory of Open Access Journals (Sweden)

    Carlos Alexandre Twardowschy

    2011-04-01

    Full Text Available OBJECTIVE: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. METHOD: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. RESULTS: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years and duration of epilepsy was 26.5±11.9 years (range 3-48 years. The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years. Frequencies of CYP2C9*1 (84%, CYP2C9*2 (9% and CYP2C9*3 (7% were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34. CONCLUSION: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results.

  1. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.

    Science.gov (United States)

    Vissing, John; Barresi, Rita; Witting, Nanna; Van Ghelue, Marijke; Gammelgaard, Lise; Bindoff, Laurence A; Straub, Volker; Lochmüller, Hanns; Hudson, Judith; Wahl, Christoph M; Arnardottir, Snjolaug; Dahlbom, Kathe; Jonsrud, Christoffer; Duno, Morten

    2016-08-01

    Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings

  2. Prokaryotic expression of Streptococcus pneumoniae phpP gene and evaluation of PP2C type phosphatase activity of the expressed recombinant protein%肺炎链球菌phpP基因重组表达及其产物PP2C型磷酸酶活性的研究

    Institute of Scientific and Technical Information of China (English)

    孙颜红; 张少妮; 楼永良; 严杰; 孙爱华

    2014-01-01

    transcription after the treat-ment with sublethal dosages of penicillin and cefotaxime were determined by real-time fluorescent quantitative RT-PCR.The functional domain in the sequence of the phpP gene and its type was analyzed by bioinformatic softwares.The activity of rPhpP in hydrolyzing the substrate of PP2C phosphotase was measured with Serine/Threonine Phosphotase Assay Kit.The enzyme kinetic parameters of rPhpP were calculated.Results The se-quence of the cloned phpP gene was identical with that reported in GenBank.The rPhpP in soluble form was ex-pressed in the constructed prokaryotic expression system.An increased expression of phpP gene at mRNA level was induced by sublethal dosage of penicillin or cefotaxime.The domain of PP2Cc type phosphatase was detec-ted in the sequence of phpP gene.The purified rPhpP protein could hydrolyze phosphopeptides [ RRA ( pT) VA], a substrate of PP2C type phosphatase, in a dose-dependent manner with Km and Kcat values of 277.35μmol/L and 0.71 S-1 ,respectively.Conclusion The protein encoded by phpP gene of S.pneumoniae was a PP2C type phosphatase.The expression of phpP gene could be enhanced by sublethal dosage of penicillin or ce-fotaxime.

  3. GUCY2C: at the intersection of obesity and cancer

    OpenAIRE

    Kim, Gilbert W.; Lin, Jieru E.; Waldman, Scott A.

    2013-01-01

    Guanylyl cyclase C (GUCY2C) has canonical centrality in defense of key intestinal homeostatic mechanisms, encompassing fluid and electrolyte balance, epithelial dynamics, antitumorigenesis, and intestinal barrier function. Recent discoveries expand the homeostatic role of GUCY2C to reveal a novel gut-brain endocrine axis regulating appetite, anchored by hypothalamic GUCY2C which is responsive to intestine-derived uroguanylin. Thus, GUCY2C may represent a new target for anti-obesity pharmacoth...

  4. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

    Directory of Open Access Journals (Sweden)

    Yan Gong

    2016-11-01

    Full Text Available Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPARα agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs. While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.

  5. Assessment of disease activity in muscular dystrophies by noninvasive imaging.

    Science.gov (United States)

    Maguire, Katie K; Lim, Leland; Speedy, Sedona; Rando, Thomas A

    2013-05-01

    Muscular dystrophies are a class of disorders that cause progressive muscle wasting. A major hurdle for discovering treatments for the muscular dystrophies is a lack of reliable assays to monitor disease progression in animal models. We have developed a novel mouse model to assess disease activity noninvasively in mice with muscular dystrophies. These mice express an inducible luciferase reporter gene in muscle stem cells. In dystrophic mice, muscle stem cells activate and proliferate in response to muscle degeneration, resulting in an increase in the level of luciferase expression, which can be monitored by noninvasive, bioluminescence imaging. We applied this noninvasive imaging to assess disease activity in a mouse model of the human disease limb girdle muscular dystrophy 2B (LGMD2B), caused by a mutation in the dysferlin gene. We monitored the natural history and disease progression in these dysferlin-deficient mice up to 18 months of age and were able to detect disease activity prior to the appearance of any overt disease manifestation by histopathological analyses. Disease activity was reflected by changes in luciferase activity over time, and disease burden was reflected by cumulative luciferase activity, which paralleled disease progression as determined by histopathological analysis. The ability to monitor disease activity noninvasively in mouse models of muscular dystrophy will be invaluable for the assessment of disease progression and the effectiveness of therapeutic interventions.

  6. Vortex lattice transitions in YNi2B2C

    Indian Academy of Sciences (India)

    S J Levett; C D Dewhurst; D McK Paul

    2002-05-01

    We have performed extensive small-angle neutron scattering (SANS) diffraction studies of the vortex lattice in single crystal YNi2B2C for $B||c$. High-resolution SANS, combined with a field-oscillation vortex lattice preparation technique, allows us to separate Bragg scattered intensities from two orthogonal domains and accurately determine the unit cell angle, . The data suggest that upon increasing field there is a finite transition width where both low- and high-field distorted hexagonal vortex lattice phases, mutually rotated by 45°, coexist. The smooth variation of diffracted intensity from each phase through the transition corresponds to a redistribution of populations between the two types of domains.

  7. 输送机刮板刀架精密铸造尺寸精度和形位公差的控制%Dimensional Accuracy and Geometric Tolerance Control of Investment Casting C2, C2K Typed Blade Frame of Scraper for Conveyor

    Institute of Scientific and Technical Information of China (English)

    范修谦; 唐永蓉

    2011-01-01

    C2、C2K输送机刮板刀架设备要求主要安装尺寸精度为铸造CT2~3级.通过试制后调整模具尺寸、模具关键部位尺寸设计成0度起模斜度,用侧芯板和顶出机构起模、设计制造了硬蜡芯减少蜡件形状误差、使用专用修蜡刀修蜡,制订了合理的蜡模组树工艺、采用比较高的浇注温度确保刃口尺寸、铸件热处理后矫形后用专用检具和C形卡板控制刀架形位尺寸公差等措施,使铸件关键形位尺寸达到了CT2~3级精度要求.%The tolerance of the main installed dimension of C2, C2K typed blade fram of scraper for conveyor is required to be CT2~3 class. Through adjusting mould dimension, making the draft angle of some key location in the mould to 0, using side-core-board and push-out mechanism to take out the wax pattern, designing hard-wax core to reduce shaping error of the wax pattern as well as using special knife to repair the wax pattern, and setting rational wax pattern assembling tree , pouring with a higher temperature, CT2~3 class accuracy can be realized in the key location in the heat treated investment castings after controlling geometric tolerance with dedicated gauges and C shaped plate.

  8. The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro.

    Science.gov (United States)

    Pan, Pei-Pei; Weng, Qing-Hua; Zhou, Chen-Jian; Wei, Yan-Li; Wang, Li; Dai, Da-Peng; Cai, Jian-Ping; Hu, Guo-Xin

    2016-02-01

    We aimed at investigating the role of CYP2C9 in carvedilol O-desmethylation and identifying the effect of 35 CYP2C9 allelic variants we found in Chinese Han population on the in vitro metabolism of carvedilol. Recombinant CYP2C9 and CYP2D6 microsomes of the wild type were used to test and verify the enzymes involved in carvedilol O-desmethylation. Recombinant CYP2C9 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity toward carvedilol. 2-100 μM carvedilol was incubated for 30 min at 37 °C. The products were detected using high-performance liquid chromatography. CYP2C9 plays a certain role in carvedilol metabolism. Compared with wild-type CYP2C9*1, the intrinsic clearance (V max/K m) values of all variants toward carvedilol O-desmethylation were significantly altered. The variants exhibited significantly decreased values (from 30 to 99.8 %) due to increased K m and/or decreased V max values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings complement the database where CYP2C9 polymorphism interacts with biotransformation of exogenous substances like drugs and toxins.

  9. We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders.

    Science.gov (United States)

    Cheng, Jianjun; Kozikowski, Alan P

    2015-12-01

    The serotonin 2C (5-HT2C ) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5-HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5-HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2-phenylcyclopropylmethylamine-based 5-HT2C agonists make them preferred candidates for further studies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Serum Creatinine Level: A Supplemental Index to Distinguish Duchenne Muscular Dystrophy from Becker Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Huili Zhang

    2015-01-01

    Full Text Available Background. To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn level reflects disease severity. Methods. Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy. Results. Serum Crn level had a strong inverse correlation with Vignos score by simple correlation (r=-0.793 and partial correlation analysis after adjustment for age, height, and weight (r=-0.791; both P<0.01. Serum Crn level was significantly higher in patients with in-frame than out-of-frame mutations (Z=-4.716, P<0.01 and in Becker muscular dystrophy (BMD patients than Duchenne muscular dystrophy (DMD patients at ages 4, 5, 7, and 9 yr (all P<0.0125. After adjusting for age, height, and weight, BMD patients still had a significantly higher serum Crn level than DMD patients (β=7.140, t=6.277, P<0.01. Conclusions. Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.

  11. The effects of myotonic dystrophy and Duchenne muscular dystrophy on the orofacial muscles and dentofacial morphology.

    Science.gov (United States)

    Kiliaridis, S; Katsaros, C

    1998-12-01

    This article takes a closer view of two of the less rare myopathies, myotonic dystrophy (MyD) and Duchenne muscular dystrophy (DMD). A high prevalence of malocclusions was found among the patients affected by these diseases. The development of the malocclusions in MyD patients seems to be strongly related to the vertical aberration of their craniofacial growth due to the involvement of the masticator, muscles in association with the possibly less affected suprahyoid musculature. Thus, a new situation is established around the teeth transversely. The lowered tongue is not in a position to counterbalance the forces developed during the lowering of the mandible by the stretched facial musculature. This may affect the teeth transversely, decreasing the width of the palate and causing posterior crossbite. The lowered position of the mandible, in combination with the decreased biting forces, may permit an overeruption of the posterior teeth, with increased palatal vault height and development of anterior open bite. The development of the malocclusions in DMD patients also seems to be strongly related to the involvement of the orofacial muscles by the disease. However, the posterior crossbite is not developed owing to the narrow maxillary arch, as is the case in MyD patients. On the contrary, the posterior crossbite in DMD is due to the transversal expansion of the mandibular arch, possibly because of the decreased tonus of the masseter muscle near the molars, in combination with the enlarged hypotonic tongue and the predominance of the less affected orbicularis oris muscle.

  12. Optimizing Bone Health in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Jason L. Buckner

    2015-01-01

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA, as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA.

  13. Electrical impedance myography in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Statland, Jeffrey M; Heatwole, Chad; Eichinger, Katy; Dilek, Nuran; Martens, William B; Tawil, Rabi

    2016-10-01

    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. © 2016 Wiley Periodicals, Inc.

  14. Molecular diagnosis of Duchenne muscular dystrophy.

    Science.gov (United States)

    Nallamilli, Babi Ramesh Reddy; Ankala, Arunkanth; Hegde, Madhuri

    2014-10-01

    Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The mutation spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for sequence variants. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). This unit initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed protocols of current molecular diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing, and NGS-based sequencing assay.

  15. In vivo confocal microscopy in recurrent granular dystrophy in corneal graft after penetrating keratoplasty.

    Science.gov (United States)

    Traversi, Claudio; Martone, Gianluca; Malandrini, Alex; Tosi, Gian Marco; Caporossi, Aldo

    2006-11-01

    Two case reports of recurrent granular dystrophy in corneal grafts after penetrating keratoplasty are presented. Slit-lamp examination and confocal microscopy (HRT II) were performed in two patients with recurrent granular dystrophy. All confocal microscopic findings of granular dystrophy were evaluated in the graft. Dystrophic lesions of the donor cornea presented the same confocal microscopic aspects in both eyes, and were similar to granular dystrophy lesions. Confocal microscopy is an imaging method that may provide new information on corneal microanatomy in dystrophies. It may be particularly useful in improving the early diagnosis of dystrophic lesions in corneal grafts.

  16. Muscle wasting in myotonic dystrophies: a model of premature aging.

    Science.gov (United States)

    Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

    2015-01-01

    Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular

  17. Muscle wasting in myotonic dystrophies: a model of premature aging.

    Directory of Open Access Journals (Sweden)

    Alba Judith eMateos-Aierdi

    2015-07-01

    Full Text Available Myotonic dystrophy type I (DM1 or Steinert’s disease and type II (DM2 are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, and other clinical manifestations such as cardiomyopathy, insulin-resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc., including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTGn triplet expansion in the 3’ untranslated region of the DMPK gene, whereas (CCTGn repeats in the first intron of the CNBP/ZNF9 gene cause DM2. The expansions are transcribed into (CUGn and (CCUGn-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL, forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

  18. Analysis list: TFAP2C [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available TFAP2C Breast,Epidermis,Uterus + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TFA...P2C.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/TFAP2C.5.tsv http://dbarchive....biosciencedbc.jp/kyushu-u/hg19/target/TFAP2C.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFA...P2C.Breast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFAP2C.Epider...mis.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/TFAP2C.Uterus.tsv http://dbarchive.biosciencedb

  19. Analysis list: Kmt2c [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Kmt2c Embryonic fibroblast,Liver,Muscle + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Kmt...2c.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Kmt2c.5.tsv http://dbarch...ive.biosciencedbc.jp/kyushu-u/mm9/target/Kmt2c.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Kmt...2c.Embryonic_fibroblast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Kmt...2c.Liver.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Kmt2c.Muscle.tsv http://dbarchive.biosci

  20. Limb-girdle muscular dystrophy in Brazilian children: clinical, histological and molecular characterization

    Directory of Open Access Journals (Sweden)

    Marco A. Veloso Albuquerque

    2014-06-01

    Full Text Available Limb-girdle muscular dystrophies (LGMD are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Method: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. Results: The initial clinical signs included: frequent falls (22 cases, difficulty in climbing stairs (13 cases, walk on tip toes (2 cases, difficulty in rising from the floor (2 cases and difficulty on walking (1 case. The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5% were classified as sarcoglycanopathies (LGMD2C-F, five (13,5% as dysferlinopathy (LGMD2B, five (13,5% as calpainopathy (LGMD2A. Mutations in LMNA gene (LGMD1B, FKRP gene (LGMDI and caveolin gene (LGMD 1C were identified in two (5,5%, two (5,5% and one patient (2,5%, respectively. In seven of 37 cases (19% it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis

  1. Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.

    Science.gov (United States)

    Swaggart, Kayleigh A; Demonbreun, Alexis R; Vo, Andy H; Swanson, Kaitlin E; Kim, Ellis Y; Fahrenbach, John P; Holley-Cuthrell, Jenan; Eskin, Ascia; Chen, Zugen; Squire, Kevin; Heydemann, Ahlke; Palmer, Abraham A; Nelson, Stanley F; McNally, Elizabeth M

    2014-04-22

    Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury.

  2. Idiopathic intracranial hypertension in a child with Duchenne muscular dystrophy.

    Science.gov (United States)

    Weig, Spencer G; Zinn, Matthias M; Howard, James F

    2011-12-01

    Duchenne muscular dystrophy is an X-linked, recessively inherited disorder characterized by progressive weakness attributable to the absence of dystrophin expression in muscle. In multiple studies, the chronic administration of corticosteroids slowed the loss of ambulation that develops in mid to late childhood. Corticosteroids, however, frequently produce unacceptable side effects, including Cushingoid appearance and weight gain. Deflazacort, an oxazoline analogue of prednisolone, produces equivalent benefits on muscle with fewer reported Cushingoid side effects. We present a 9-year-old boy with Duchenne muscular dystrophy who developed morbid obesity and subsequent idiopathic intracranial hypertension after 2 years of receiving deflazacort. Although deflazacort is typically thought to produce less obesity than prednisone, severe Cushingoid side effects may occur in some individuals. To our knowledge, this description is the first of idiopathic intracranial hypertension complicating chronic corticosteroid treatment of Duchenne muscular dystrophy.

  3. Crystalline Subtype of Pre-Descemetic Corneal Dystrophy

    Directory of Open Access Journals (Sweden)

    Rosa Dolz-Marco

    2014-01-01

    Full Text Available Purpose: To report corneal findings in a familial case of the crystalline subtype of pre- Descemetic corneal dystrophy. Case Report: A 19-year-old girl and her 44-year-old mother were found to have asymptomatic, bilateral, punctiform and multi-colored crystalline opacities across the whole posterior layer of the corneas. Endothelial specular microscopy revealed the presence of white round flecks located at different levels anterior to the endothelium. No systemic abnormalities or medications could be related to account for these findings. Conclusion: To the best of our knowledge, this is the third familial report of this rare corneal disorder. Differential diagnosis may include Schnyder corneal dystrophy, cystinosis, Bietti΄s dystrophy and monoclonal gammopathy.

  4. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies.

    Science.gov (United States)

    Kitiratschky, Veronique B D; Grau, Tanja; Bernd, Antje; Zrenner, Eberhart; Jägle, Herbert; Renner, Agnes B; Kellner, Ulrich; Rudolph, Günther; Jacobson, Samuel G; Cideciyan, Artur V; Schaich, Simone; Kohl, Susanne; Wissinger, Bernd

    2008-07-01

    The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

  5. Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming.

    Science.gov (United States)

    Matsakas, Antonios; Yadav, Vikas; Lorca, Sabina; Narkar, Vihang

    2013-10-01

    Treatment of Duchenne muscular dystrophy (DMD) by replacing mutant dystrophin or restoring dystrophin-associated glycoprotein complex (DAG) has been clinically challenging. Instead, identifying and targeting muscle pathways deregulated in DMD will provide new therapeutic avenues. We report that the expression of nuclear receptor estrogen-related receptor-γ (ERRγ), and its metabolic and angiogenic targets are down-regulated (50-85%) in skeletal muscles of mdx mice (DMD model) vs. wild-type mice. Corelatively, oxidative myofibers, muscle vasculature, and exercise tolerance (33%) are decreased in mdx vs. wild-type mice. Overexpressing ERRγ selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERRγ enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33-66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERRγ pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERRγ did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERRγ. In summary, ERRγ-dependent metabolic and angiogenic gene program is defective in DMD, and we demonstrate that its restoration is a potential strategy for treating muscular dystrophy.

  6. Reliability and feasibility of the six minute walk test in subjects with myotonic dystrophy.

    Science.gov (United States)

    Kierkegaard, Marie; Tollbäck, Anna

    2007-12-01

    The objective was to describe test-retest reliability and feasibility of the six minute walk test in adult subjects with myotonic dystrophy type 1. Twelve subjects (28-68 years, mean 44) performed three six minute walk tests on two occasions, one week apart. Relative reliability was high (ICC(2.1)=0.99) and absolute reliability values were low (standard error of measurement 12 m, repeatability 33 m). Feasibility was investigated in a sample of 64 subjects (19-70 years, mean 43). Fifty-two subjects were able to perform two tests on the same day. Subjects with severe proximal weakness had difficulties performing repeated tests. A practice trial followed by a second test on the same day can be recommended for most subjects, and the best test should be used for evaluations. In conclusion, even though the study sample was small, the present study indicates that the six minute walk test is reliable and feasible in subjects with myotonic dystrophy type 1.

  7. The involvement of collagen triple helix repeat containing 1 in muscular dystrophies.

    Science.gov (United States)

    Spector, Itai; Zilberstein, Yael; Lavy, Adi; Genin, Olga; Barzilai-Tutsch, Hila; Bodanovsky, Ana; Halevy, Orna; Pines, Mark

    2013-03-01

    Fibrosis is the main complication of muscular dystrophies. We identified collagen triple helix repeat containing 1 (Cthrc1) in skeletal and cardiac muscles of mice, representing Duchenne and congenital muscle dystrophies (DMD and CMD, respectively), and dysferlinopathy. In all of the mice, Cthrc1 was associated with high collagen type I levels; no Cthrc1 or collagen was observed in muscles of control mice. High levels of Cthrc1 were also observed in biopsy specimens from patients with DMD, in whom they were reversibly correlated with that of β-dystroglycan, whereas collagen type I levels were elevated in all patients with DMD. At the muscle sites where collagen and Cthrc1 were adjacent, collagen fibers appeared smaller, suggesting involvement of Cthrc1 in collagen turnover. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of the transforming growth factor-β signaling, reduced Cthrc1 levels in skeletal and cardiac muscles of mice, representing DMD, CMD, and dysferlinopathy. The myofibroblasts infiltrating the dystrophic muscles of the murine models of DMD, CMD, and dysferlinopathy were the source of Cthrc1. Transforming growth factor-β did not affect Cthrc1 levels in the mdx fibroblasts but decreased them in the control fibroblasts, in association with increased migration of mdx fibroblasts and dystrophic muscle invasion by myofibroblasts. To our knowledge, this is the first demonstration of Cthrc1 as a marker of the severity of the disease progression in the dystrophic muscles, and as a possible target for therapy.

  8. Analysis of human transforming growth factor β-induced gene mutation in corneal dystrophy

    Institute of Scientific and Technical Information of China (English)

    李杨; 孙旭光; 任慧媛; 董冰; 王智群; 孙秀英

    2004-01-01

    Background Corneal dystrophy is a group of inherited blinding diseases of the cornea. This study was to identify the mutations of the keratoepithelin (KE) gene for proper diagnosis of corneal dystrophy. Methods Three families with corneal dystrophy were analysed. Thirteen individuals at risk for corneal dystrophy in family A, the proband and her son in family B, and the proband in family C were examined after their blood samples were obtained. Mutation screening of human transforming growth factor β-induced gene (BIGH3 gene) was performed. Results Five individuals in family A were found by clinical evaluation to be affected with granular corneal dystrophy and carried the BIGH3 mutation W555R. However, both probands in families B and C, also diagnosed with granular corneal dystrophy, harboured the BIGH3 mutation R124H. Conclusion Molecular genetic analysis can improve accurate diagnosis of corneal dystrophy.

  9. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    Science.gov (United States)

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

  10. [Myotonic dystrophy as a contraindication for electroconvulsive therapy?].

    Science.gov (United States)

    Wynhoven, L M L; Scherders, M J W T; van Suijlekom, J A

    2009-01-01

    A 57-year-old woman with medication-resistant major depression was referred to our clinic for electroconvulsive therapy. After an extensive evaluation of our patient's condition we concluded that in this case the comorbid myotonic dystrophy was a contraindication for the performance of electroconvulsive therapy. However, in the current Dutch Psychiatric Association guidelines this illness is not mentioned as a possible contraindication for electroconvulsive therapy. This raises the question of whether myotonic dystrophy should now be incorporated in these guidelines and makes us wonder to what extent our conclusion could have consequences for the treatment of other neuromuscular illnesses.

  11. The paradox of muscle hypertrophy in muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy.

  12. Structural deterioration of tendon collagen in genetic muscular dystrophy.

    Science.gov (United States)

    Stinson, R H

    1975-08-19

    The structure of gastrocnemius tendons from chickens with genetically induced muscular dystrophy has been studied by low-angle X-ray diffraction. Compared with normal samples there is poor alignment of collagen within the tendons. This difference is quite pronounced at eight weeks when the affected birds are still in comparatively good physical condition. Similar changes have been reported for birds with nutritionally induced muscular dystrophy (Bartlett, M. W., Egelstaff, P. A., Holden, T. M., Stinson, R. H. and Sweeny, P. R. (1973) Biochim. Biophys. Acta 328, 213-220).

  13. Regulation of adipogenesis by nucelar receptor PPARγ is modulated by the histone demethylase JMJD2C

    Directory of Open Access Journals (Sweden)

    Lizcano Fernando

    2011-01-01

    Full Text Available A potential strategy to combat obesity and its associated complications involves modifying gene expression in adipose cells to reduce lipid accumulation. The nuclear receptor Peroxisome Proliferator-activated receptor gamma (PPARγ is the master regulator of adipose cell differentiation and its functional activation is currently used as a therapeutic approach for Diabetes Mellitus type 2. However, total activation of PPARγ induces undesirable secondary effects that might be set with a partial activation. A group of proteins that produce histone demethylation has been shown to modify the transcriptional activity of nuclear receptors. Here we describe the repressive action of the jumonji domain containing 2C/lysine demethylase 4 C (JMJD2C/KDM4C on PPARγ transcriptional activation. JMJD2C significantly reduced the rosiglitazone stimulated PPARγ activation. This effect was mainly observed in experiments performed using the Tudor domains that may interact with histone deacetylase class 1 (HDAC and this interaction probably reduces the mediated activation of PPARγ. Trichostatin A, a HDAC inhibitor, reduces the repressive effect of JMJD2C. When JMJD2C was over-expressed in 3T3-L1 cells, a reduction of differentiation was observed with the Tudor domain. In summary, we herein describe JMJD2C-mediated reduction of PPARgamma transcriptional activation as well as preadipocyte differentiation. This novel action of JMJD2C might have an important role in new therapeutic approaches to treat obesity and its complications.

  14. Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism.

    Science.gov (United States)

    Renjini, R; Gayathri, N; Nalini, A; Srinivas Bharath, M M

    2012-04-01

    Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

  15. Identification of a cys-ser substitution in the 5-HT{sub 2C} (HTR2C) receptor gene and allelic association to violent behavior and alcoholism

    Energy Technology Data Exchange (ETDEWEB)

    Lappalainen, J.; Ozaki, N.; Goldman, D. [National Institute on Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

    1994-09-01

    Several lines of evidence suggest that brain serotonergic functions, including behavioral and neurochemical responses to 5-HT{sub 2C} agonist, are abnormal in some individuals with alcoholism and aggressive behaviors. The aim of the present study was to identify coding sequence variants in the human 5-HT{sub 2C} receptor gene which may cause abnormal or variant function of this receptor. Using SSCP analysis, a non-conservative cys-ser substitution was found in the 5-HT{sub 2C} receptor (designated 5-HT{sub 2Ccys} and 5-HT{sub 2Cser}). The polymorphism was typed in CEPH families to genetically map the gene. To test for association of the variant to alcoholism, violent behavior and serotonin function, the 5-HT{sub 2C} genotypes of 151 non-related Finnish male alcoholic violent offenders and impulsive fire setters and 127 Finnish psychiatrically interviewed healthy male volunteers were determined. CSF 5-HIAA concentrations were available for 74 alcoholic violent offenders and 25 healthy volunteers. Linkage analysis placed the 5-HT{sub 2C} gene on Xq21, a region that has been previously shown to contain genes for several mental retardation syndromes. The 5-HT{sub 2Ccys}/5-HT{sub 2Cser} genotype frequencies in alcoholic violent offenders and controls differed significantly (0.90/0.10 and 0.82/0.18, respectively, P=0.048). The association was found to be strongest in the violent offenders who did not fulfill the criteria for antisocial personality disorder (5-HT{sub 2Ccys}/5-HT{sub 2Cser} 0.93/0.07, p=0.021). No association was found between CSF 5-HIAA concentrations and 5-HT{sub 2C} genotype. These results implicate a 5-HT{sub 2C} receptor amino acid substitution in predisposition to alcohol abuse and violent behavior in a subgroup of alcoholics.

  16. Neuropsychological profile of duchenne muscular dystrophy.

    Science.gov (United States)

    Perumal, Anna Roshini; Rajeswaran, Jamuna; Nalini, Atchayaram

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder characterized by progressive muscle wasting. DMD is a fatal X-linked recessive disorder with an estimated prevalence of 1 in 3,500 male live births. This disease has long been associated with intellectual impairment. Research has shown that boys with DMD have variable intellectual performance, indicating the presence of specific cognitive deficits. The aim of the study was to use a battery of intelligence, learning, and memory tests to identify a neuropsychological profile in boys with DMD. A total of 22 boys diagnosed with DMD in the age range of 6 to 10 years old were evaluated using the Wechsler Intelligence Scale for Children-Third Edition, Rey's Auditory Verbal Learning Test, and the Memory for Designs Test. The data were interpreted using means, standard deviations, percentages, and percentiles. Normative data were also used for further interpretation. The results showed that boys with DMD had a significantly lower IQ (88.5). Verbal IQ (86.59) was found to be lower than Performance IQ (92.64). There was evidence of impaired performance on the Processing Speed, Freedom From Distractibility, and Verbal Comprehension Indexes. Specific deficits in information processing, complex attention, immediate verbal memory span, verbal working memory, verbal comprehension, vocabulary, visuoconstruction ability, and verbal learning and encoding were observed. However, perceptional organization, general fund of information, abstract reasoning, visual discrimination and acuity, visual learning and memory, and verbal memory were adequate. The neuropsychological findings support the hypothesis that these children have specific cognitive deficits as opposed to a global intellectual deficit.

  17. Gastrointestinal manifestations in myotonic muscular dystrophy

    Institute of Scientific and Technical Information of China (English)

    Massimo Bellini; Sonia Biagi; Cristina Stasi; Francesco Costa; Maria Gloria Mumolo; Angelo Ricchiuti; Santino Marchi

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness.Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting.A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry,electromyography, functional ultrasonography,scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported.The drugs recommended for treating the gastrointestinal complaints such as prokinetic, antidyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders.Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD.

  18. Late-onset Pompe disease with phenotype of the limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    S. A. Kurbatov

    2015-01-01

    Full Text Available Pompe disease, also known as type II glycogenosis, is a rare autosomal recessive disease. Two main types include early-onset Pompe disease – severe, rapidly progressive multisystem deficency, manifestating on the first year of life, and late-onset Pompe disease (LOPD, with the age of onset ranging from the first year till late adulthood. Both types are caused by the deficiency of lysosomal acid-α-glucosidase due to the mutations in GAA gene, leading to an excessive storage of glycogen in body cells. LOPD is a slowly progressive disease with a primary lesion of a skeletal, respiratory and cardiac muscles, affected in different grade, and moderately elevated сreatine kinase. It is often difficult to perform differential diagnosis with a large group of hereditary and non-hereditary myopathies. We present a case report of LOPD with signs of limb-girdle muscular dystrophy.

  19. Cognitive changes and cranial MRI changes in patients with myotonic dystrophy type 1: a study of 4 cases%四例强直性肌营养不良1型患者认知功能及头颅MRI研究

    Institute of Scientific and Technical Information of China (English)

    侯清华; 许轶; 江桂华; 詹文峰; 黄海浪; 刘海润; 解龙昌; 高庆春

    2012-01-01

    目的 探讨强直性肌营养不良1型(DM1)患者的认知功能、智力和头颅MRI改变.方法 选择广州医学院第二附属医院神经内科自2011年9月至2011年12月间诊治的一家系4例DM1患者为研究对象,采用中国修订韦氏智力量表和韦氏记忆量表检测智力,采用蒙特利尔认知评估量表(MoCA)和神经行为认知状况测试(NCSE)检测认知功能,同时行颅脑MRI检查. 结果 1例患者智商(IQ)和记忆商数(MQ)正常,其余3例患者IQ和MQ有不同程度下降,其中IQ下降以言语智商(VIQ)下降较明显.3例患者MoCA和NCSE检测示其视空间/执行、计算、记忆和抽象能力损害较明显;另1例患者MoCA检测虽然总分正常,但语言分测试中句子复述和词语流畅性检查均失分.MRI检查示3例患者存在不同程度脑萎缩,并以额叶、颞叶萎缩较明显;4例患者均存在不同程度的脑白质病变和颅骨增厚. 结论 DMI患者存在多种认知功能障碍和脑部病变,值得进一步研究.%Objective To investigate the cognitive, intelligent and cranial MRI status of 4 patients with myotonic dystrophy type 1 (DM1). Methods A pedigree of 4 patients,admitted to our hospital from September 2011 to December 2011 and diagnosed as having DM1, were chosen in our study; Chinese edition tests of Wechsler adult intelligence scale and Wechsler memory scale were used to test the intelligence of these patients; Montreal cognitive assessment (MoCA) and Neurobehavioral cognitive status examination (NCSE) were applied to evaluate the patients' cognitive function.All of the 4 patients received a cranial MRI scan. Results Except for 1 patient,the other 3 patients had low intelligent quotient (IQ) and memory quotient (MQ),and their verbal IQs were all lower than performance IQs.Three patients showed impaired visual space/executive skills,calculation,memory,and conceptual thinking abilities; 1 patient showed impaired sentence repetition and verbal fluency on Mo

  20. Granular Corneal Dystrophy Manifesting after Radial Keratotomy

    Directory of Open Access Journals (Sweden)

    Sepehr Feizi

    2008-12-01

    Full Text Available

    PURPOSE: To report manifestation of granular corneal dystrophy after radial keratotomy (RK. CASE REPORT: A 32-year-old man presented with white radial lines in both corneas. He had undergone uncomplicated RK in both eyes 8 years ago. Preoperative refraction had been OD: -3.5 -0.75@180 and OS: -3.0 -0.5@175. Uncorrected visual acuity was OD: 8/10 and OS: 7/10; best corrected visual acuity was 9/10 in both eyes with OD: -0.5 -0.5@60 and OS: -0.75 -0.5@80. Slit lamp examination revealed discrete well-demarcated whitish lesions with clear intervening stroma in the central anterior cornea consistent with granular dystrophy. Similar opacities were present within the RK incisions. CONCLUSION: Granular dystrophy deposits may appear within RK incisions besides other previously reported locations.