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Alsaggaf R, Pfeiffer RM, Pearce EE, Greene MH, Lochmuller H, Gadalla SM. Mortality Trends and Causes of Death in Myotonic Dystrophy Type 1 Patients From the UK Clinical Practice Research Datalink. Muscle Nerve 2025; 71:229-236. [PMID: 39679826 PMCID: PMC11708454 DOI: 10.1002/mus.28308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 11/18/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION/AIM Patients with myotonic dystrophy type1 (DM1) have reduced lifespan. This study aimed to quantify mortality risks, and evaluate causes and time trends in DM1. METHODS We identified 1021 DM1 patients and 15,104 matched DM1-free controls from the United Kingdom (UK) Clinical Practice Research Datalink. We used Cox proportional hazards regression models to assess differences in all-cause or cause-specific mortality between DM1 patients and matched controls, and computed standardized mortality ratios (SMRs) for comparisons of DM1 patients with the UK general population. RESULTS DM1 patients were at higher risk of death compared with matched DM1-free controls (hazard ratio [HR] = 2.9, 95% confidence interval [CI] = 2.5-3.4) or the general UK population (SMR = 8.1, 95% CI = 7.3-9.1). The excess risk was primarily attributed to deaths from respiratory failure (HR = 26.7, p < 0.001), aspiration pneumonia (HR = 15.8, p < 0.001), arrythmia, and conduction defects (HR = 15.7, p < 0.001). No mortality risk difference between DM1 patients and matched DM1-free cohort was noted for all cancers combined (p = 0.52). No significant calendar time-related changes in overall survival were seen for DM1 patients (p trend = 0.19). In mortality cause-specific analysis, and compared with patients diagnosed before 1993, death from cancer was on the rise (HR = 2.35, and 5.82 for patients diagnosed 1993-2003, and 2004-2016). DISCUSSION Most DM1 patients died of known disease complications. This highlights the need for integrated clinical approaches with more careful and frequent monitoring.
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Affiliation(s)
- Rotana Alsaggaf
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Ruth M. Pfeiffer
- Biostatistics Branch, Division of Cancer Epidemiology & Genetics, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Emily E. Pearce
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Mark H. Greene
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
| | - Hanns Lochmuller
- Children's Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, and Brain and Mind Research InstituteUniversity of OttawaOttawaCanada
| | - Shahinaz M. Gadalla
- Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Cancer InstituteNational Institutes of HealthBethesdaMarylandUSA
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Shear MA, Penon-Portmann M, Shieh JT, Glenn OA, Thiet MP, Chetty S, Sparks TN, Gano D. Fetal Brain MRI Findings in Myotonic Dystrophy and Considerations for Prenatal Genetic Testing. Neurol Genet 2024; 10:e200171. [PMID: 39444647 PMCID: PMC11498903 DOI: 10.1212/nxg.0000000000200171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 07/08/2024] [Indexed: 10/25/2024]
Abstract
Background Congenital myotonic dystrophy type 1 (DM1) is a rare congenital neuromuscular disorder associated with high morbidity and potential early mortality requiring lifelong symptomatic management. Prenatal presentations of DM1 have been associated with nonspecific ultrasound findings such as clubbed foot, polyhydramnios, ventriculomegaly, and decreased fetal movement, but many cases of DM1 have no ultrasound anomalies. Methods We sought to compare the clinical course and prenatal imaging findings in two cases of DM1 using retrospective chart review. Results This report demonstrates potential expansion of the prenatal phenotype of DM1 including fetal SVT and frontal bossing. Both cases shared unique prenatal imaging features of lateral ventricle dilation involving the anterior bodies and frontal horns on fetal MRI. Discussion Because congenital DM1 is most often maternally inherited, attention to maternal symptoms, physical examination, and family history can be helpful in recognizing cases. Molecular diagnosis of DM1 requires specialized testing of the 3' untranslated region of the DMPK gene, and DM1 will not be detected by current standard prenatal genetic testing with microarray, karyotype, or exome sequencing.
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Affiliation(s)
- Matthew A Shear
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Monica Penon-Portmann
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Joseph T Shieh
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Orit A Glenn
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Mari-Paule Thiet
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Shilpa Chetty
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Teresa N Sparks
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
| | - Dawn Gano
- From the Department of Obstetrics, Gynecology, and Reproductive Sciences (M.A.S., M.-P.T., S.C., T.N.S.); Division of Medical Genetics (M.A.S., M.P.-P., J.T.S.), Department of Pediatrics, University of California, San Francisco; Division of Genetic Medicine (M.P.-P.), Department of Pediatrics, University of Washington, Seattle; Fetal Treatment Center (M.A.S., S.C., T.N.S.), Division of Maternal-Fetal Medicine and Reproductive Genetics; Center for Maternal Fetal Precision Medicine (M.A.S., D.G.); Departments of Neurology and Pediatrics (O.A.G., D.G.); and Department of Radiology and Biomedical Imaging (O.A.G.), University of California, San Francisco
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Rönnblom A, Ekbom A. Survival in myotonic dystrophy type 1: a long time follow up-study with special reference to gastrointestinal symptoms. Ups J Med Sci 2024; 129:10663. [PMID: 39376588 PMCID: PMC11457906 DOI: 10.48101/ujms.v129.10663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 10/09/2024] Open
Abstract
Background Myotonic dystrophy type 1 (DM1) is a monogenetic disease affecting many organs. Gastrointestinal symptoms are prevalent and of considerable consequences for affected individuals. The life expectancy is shortened and the objective of the study is to evaluate if gastrointestinal symptoms can predict the outcome of the disease. Method Fifty-one patients with DM1 were interviewed regarding symptoms from the gastrointestinal tract in the mid-1990s. Survival of all patients was evaluated in 2023 and the impact of symptoms on survival was assessed. Results At the beginning of the study, the mean age was 35.9 years, (median 37.0, 9-63). At the end of the study 47 out of the 51 patients were deceased at a mean age of 53.7 years (median 55.7, 32.5-79.0). Patients with the congenital form of DM1 (n = 6) died at an age of 46.0 years (median 45.2, 40.0-53.6). There was no correlation between the gastrointestinal symptoms and survival. Conclusion Albeit prevalent and of considerable clinical consequence, gastrointestinal symptoms are not correlated to survival in myotonic dystrophy type 1.
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Affiliation(s)
- Anders Rönnblom
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Ekbom
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
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Ostojić S, Kovačević G, Meola G, Pešović J, Savić-Pavićević D, Brkušanin M, Kravljanac R, Perić M, Martić J, Pejić K, Ristić S, Perić S. Main features and disease outcome of congenital myotonic dystrophy - experience from a single tertiary center. Neuromuscul Disord 2024; 40:16-23. [PMID: 38810326 DOI: 10.1016/j.nmd.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 04/05/2024] [Accepted: 05/08/2024] [Indexed: 05/31/2024]
Abstract
Congenital myotonic dystrophy type 1 (CDM1) is a rare neuromuscular disease. The aim of our study was to evaluate clinical variability of CDM1 and factors that may influence survival in CDM1. Research included 24 pediatric patients with CDM1. Most of our patients had some form of hypoxic ischemic encephalopathy (HIE) (74 %), from mild to severe. Prolonged and complicated deliveries (75 %), high percentage of children resuscitated at birth (57 %) and respiratory insufficiency (46 %) with consequent hypoxia were the main reasons that could explain high percentage of HIE. Therapeutic hypothermia was applied in three children with poor outcome. Median survival of all CDM1 was 14.2 ± 1.5 years. Six patients had a fatal outcome (25 %). Their mean age of death was 3.0 ± 2.8 years. Poor prognostic factors for the survival of our CDM1 patients were: preterm delivery, resuscitation at birth, severe HIE, hypothermia treatment and permanent mechanical ventilation. Respiratory insufficiency was the main life-threatening factor. Our data clearly indicates the need to develop natural history studies in CDM1 in order to enhance the standards of care and to develop clinical trials investigating causative therapies in pediatric patients with CDM1.
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Affiliation(s)
- Slavica Ostojić
- Neurology Department, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia.
| | - Gordana Kovačević
- Neurology Department, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Giovanni Meola
- Department of Neurorehabilitation Sciences, Casa Di Cura Igea, Department of Biomedical Sciences for Health, University of Milan, Fondazione Malattie Miotoniche-FMM, Milan Italy
| | - Jovan Pešović
- University of Belgrade-Faculty of Biology, Center for Human Molecular Genetics, Belgrade, Serbia
| | - Dušanka Savić-Pavićević
- University of Belgrade-Faculty of Biology, Center for Human Molecular Genetics, Belgrade, Serbia
| | - Miloš Brkušanin
- University of Belgrade-Faculty of Biology, Center for Human Molecular Genetics, Belgrade, Serbia
| | - Ružica Kravljanac
- Neurology Department, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Marina Perić
- Nephrology Department, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Jelena Martić
- Intensive Care Unit, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Katarina Pejić
- Intensive Care Unit, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Snežana Ristić
- Intensive Care Unit, Institute for Mother and Child Health Care of Serbia "Dr. Vukan Cupic", Faculty of Medicine, University of Belgrade, Serbia
| | - Stojan Perić
- Neurology Clinic, University Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Serbia
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Wu Y, Wei Q, Lin J, Shang H, Ou R. Cognitive impairment, neuroimaging abnormalities, and their correlations in myotonic dystrophy: a comprehensive review. Front Cell Neurosci 2024; 18:1369332. [PMID: 38638300 PMCID: PMC11024338 DOI: 10.3389/fncel.2024.1369332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/22/2024] [Indexed: 04/20/2024] Open
Abstract
Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities.
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Affiliation(s)
| | | | | | | | - Ruwei Ou
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
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Aden P, Skarbø AB, Wallace S, Ørstavik K, Rasmussen M. Cognitive function, behaviour and quality of life in children with myotonic dystrophy type 1 in South - Eastern Norway. Eur J Paediatr Neurol 2023; 45:1-6. [PMID: 37209486 DOI: 10.1016/j.ejpn.2023.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/22/2023] [Accepted: 05/07/2023] [Indexed: 05/22/2023]
Abstract
BACKGROUND Cognitive and behavioural problems may be predominant in the clinical picture of myotonic dystrophy (DM1) in childhood. This can lead to a diagnostic delay and thus prevent optimal therapeutic measures. OBJECTIVE To obtain an overview of children with DM1 in our health region and study their cognitive and behavioural function, quality of life and neurological status. METHODS Patients diagnosed with DM1 were recruited to this cross-sectional study through local habilitation teams of our health region. Neuropsychological testing and physical examination were performed for the majority. For some patients information was retrieved from medical records and through telephone interviews. A questionnaire was administered regarding quality of life. RESULTS 27 subjects <18 years diagnosed with DM1 were identified, giving a frequency of DM1 of 4.3/100 000 in this age group. Twenty consented to participate. Five had congenital DM1. Most of the participants had only mild neurological deficits. Two with congenital type had hydrocephalus requiring a shunt. Ten, whereof none with congenital DM1, had a cognitive function within normal range. Three were diagnosed with an autism spectrum disorder, and additional three were reported with autistic traits. Many parents reported social and school problems for their child. CONCLUSIONS Intellectual disability and varying degrees of autistic behaviour were quite common. Motor deficits were most often mild. A strong focus regarding support at school and in social communication is needed for children growing up with DM1.
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Affiliation(s)
- Petra Aden
- Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway.
| | - Anne-Britt Skarbø
- Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway.
| | - Sean Wallace
- Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway; Department of Neurology, Section for Rare Neuromuscular Disorders and EMAN, Oslo University Hospital, Oslo, Norway.
| | - Kristin Ørstavik
- Department of Neurology, Section for Rare Neuromuscular Disorders and EMAN, Oslo University Hospital, Oslo, Norway.
| | - Magnhild Rasmussen
- Department of Clinical Neurosciences for Children, Oslo University Hospital, Oslo, Norway; Department of Neurology, Section for Rare Neuromuscular Disorders and EMAN, Oslo University Hospital, Oslo, Norway.
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Ait Benichou S, Jauvin D, De Serres-Bérard T, Pierre M, Ling KK, Bennett CF, Rigo F, Gourdon G, Chahine M, Puymirat J. Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1. Gene Ther 2022; 29:698-709. [PMID: 35075265 PMCID: PMC9750879 DOI: 10.1038/s41434-022-00316-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/05/2022] [Accepted: 01/12/2022] [Indexed: 01/09/2023]
Abstract
Myotonic dystrophy, or dystrophia myotonica type 1 (DM1), is a multi-systemic disorder and is the most common adult form of muscular dystrophy. It affects not only muscles but also many organs, including the brain. Cerebral impairments include cognitive deficits, daytime sleepiness, and loss of visuospatial and memory functions. The expression of mutated transcripts with CUG repeats results in a gain of toxic mRNA function. The antisense oligonucleotide (ASO) strategy to treat DM1 brain deficits is limited by the fact that ASOs do not cross the blood-brain barrier after systemic administration, indicating that other methods of delivery should be considered. ASO technology has emerged as a powerful tool for developing potential new therapies for a wide variety of human diseases, and its potential has been proven in a recent clinical trial. Targeting DMPK mRNA in neural cells derived from human induced pluripotent stem cells obtained from a DM1 patient with the IONIS 486178 ASO abolished CUG-expanded foci, enabled nuclear redistribution of MBNL1/2, and corrected aberrant splicing. Intracerebroventricular injection of the IONIS 486178 ASO in DMSXL mice decreased the levels of mutant DMPK mRNAs by up to 70% throughout different brain regions. It also reversed behavioral abnormalities following neonatal administration. The present study indicated that the IONIS 486178 ASO targets mutant DMPK mRNAs in the brain and strongly supports the feasibility of a therapy for DM1 patients based on the intrathecal injection of an ASO.
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Affiliation(s)
- Siham Ait Benichou
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada
| | - Dominic Jauvin
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada
- CERVO Research Center, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada
| | - Thiéry De Serres-Bérard
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada
- CERVO Research Center, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada
| | - Marion Pierre
- CERVO Research Center, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada
| | | | | | - Frank Rigo
- Ionis Pharmaceuticals Inc., Carlsbad, CA, USA
| | - Genevieve Gourdon
- Sorbonne Université, Inserm, Association Institut de Myologie, Centre de recherche en Myologie, Paris, France
| | - Mohamed Chahine
- CERVO Research Center, Institut universitaire en santé mentale de Québec, Quebec City, QC, Canada.
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
| | - Jack Puymirat
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
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Jia YX, Dong CL, Xue JW, Duan XQ, Xu MY, Su XM, Li P. Myotonic dystrophy type 1 presenting with dyspnea: A case report. World J Clin Cases 2022; 10:7060-7067. [PMID: 36051128 PMCID: PMC9297391 DOI: 10.12998/wjcc.v10.i20.7060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/04/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular disease involving multiple systems, especially the cardiopulmonary system. The clinical phenotype of DM1 patients is highly variable, which limits early diagnosis and treatment. In the present study, we reported a 35-year-old female DM1 patient with dyspnea as the primary onset clinical manifestation, analyzed her family's medical history, and reviewed related literature.
CASE SUMMARY A 35-year-old woman was admitted to the hospital with dyspnea of 1 mo duration, and sleep apnea for 3 d. Her respiratory pattern and effort were normal, but limb muscle tension was low. Investigation into the patient's medical history revealed that she might have hereditary neuromuscular disease. Electromyography showed that her myotonia potentials were visible in the resting state of the examined muscles, with decreased motor unit potential time limit and amplitude. Genetic testing for DM1 revealed that the cytosine-thymine-guanine (CTG) repeat number of the DMPK gene exceeded 50, while cytosine-CTG expansion in intron 1 of ZNF9 gene was < 30 repeats. The patient was diagnosed with DM1.
CONCLUSION DM1 is a genetic neuromuscular disease involving multiple systems, and the clinical phenotype in DM1 is extremely variable. Some patients with DM1 may be presented at the respiratory department because of dyspnea, which should be cautioned by the pulmonologists. There may be no obvious or specific symptoms in the early stage of disease, and clinicians should improve their understanding of DM1 and make an early diagnosis, which will improve patients’ quality of life.
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Affiliation(s)
- Yu-Xi Jia
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
- Application Demonstration Center of Precision Medicine Molecular Diagnosis, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Chun-Ling Dong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Jia-Wei Xue
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Xiao-Qin Duan
- Department of Rehabilitation Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ming-Yu Xu
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Xiao-Min Su
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Ping Li
- Department of Developmental Pediatrics, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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Dhont S, Callens R, Stevens D, Bauters F, De Bleecker JL, Derom E, Van Braeckel E. Myotonic dystrophy type 1 as a major risk factor for severe COVID-19? Acta Neurol Belg 2021; 121:1761-1765. [PMID: 33052531 PMCID: PMC7556549 DOI: 10.1007/s13760-020-01514-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 09/28/2020] [Indexed: 01/05/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is challenging health care systems worldwide. People with myotonic dystrophy type 1 (DM1) represent a high-risk population during infectious disease outbreaks, little is known about the potential impact of COVID-19 on patients with DM1. We studied the clinical course of COVID‐19 in three hospitalized patients with myotonic dystrophy type 1 or Steinert’s disease, between April 1, 2020‐April 30‐2020. All three had advanced Steinert’s disease receiving non-invasive nocturnal home ventilatory support. Two of them lived in a residential care centre. Two patients had a limited respiratory capacity, whereas one patient had a rather preserved functional capacity but more comorbidities. Two out of three patients were obese, none of them had diabetes mellitus. Two patients received hydroxychloroquine. Despite maximal supportive care with oxygen therapy, antibiotics, intensive respiratory physiotherapy and non-invasive positive pressure ventilation, all three patients eventually died due to COVID-19. Our case series of three patients with DM1 admitted for COVID-19 confirms that they are at high risk for severe disease and poor outcome. Clinical trials are needed to define best practices and determinants of outcomes in this unique population.
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De Serres-Bérard T, Pierre M, Chahine M, Puymirat J. Deciphering the mechanisms underlying brain alterations and cognitive impairment in congenital myotonic dystrophy. Neurobiol Dis 2021; 160:105532. [PMID: 34655747 DOI: 10.1016/j.nbd.2021.105532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/24/2021] [Accepted: 10/11/2021] [Indexed: 12/13/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is a multisystemic and heterogeneous disorder caused by the expansion of CTG repeats in the 3' UTR of the myotonic dystrophy protein kinase (DMPK) gene. There is a congenital form (CDM1) of the disease characterized by severe hypotonia, respiratory insufficiency as well as developmental delays and intellectual disabilities. CDM1 infants manifest important brain structure abnormalities present from birth while, in contrast, older patients with adult-onset DM1 often present neurodegenerative features and milder progressive cognitive deficits. Promising therapies targeting central molecular mechanisms contributing to the symptoms of adult-onset DM1 are currently in development, but their relevance for treating cognitive impairment in CDM1, which seems to be a partially distinct neurodevelopmental disorder, remain to be elucidated. Here, we provide an update on the clinical presentation of CDM1 and review recent in vitro and in vivo models that have provided meaningful insights on its consequences in development, with a particular focus on the brain. We discuss how enhanced toxic gain-of-function of the mutated DMPK transcripts with larger CUG repeats and the resulting dysregulation of RNA-binding proteins may affect the developing cortex in utero. Because the methylation of CpG islets flanking the trinucleotide repeats has emerged as a strong biomarker of CDM1, we highlight the need to investigate the tissue-specific impacts of these chromatin modifications in the brain. Finally, we outline promising potential therapeutic treatments for CDM1 and propose future in vitro and in vivo models with great potential to shed light on this disease.
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Affiliation(s)
- Thiéry De Serres-Bérard
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, Canada; CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, Canada
| | - Marion Pierre
- CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, Canada
| | - Mohamed Chahine
- CERVO Brain Research Center, Institut universitaire en santé mentale de Québec, Quebec City, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada.
| | - Jack Puymirat
- LOEX, CHU de Québec-Université Laval Research Center, Quebec City, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada
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11
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Kambara M, Ibara S. Chylothorax as a complication of congenital myotonic dystrophy: A retrospective cohort study. Early Hum Dev 2021; 158:105396. [PMID: 34029782 DOI: 10.1016/j.earlhumdev.2021.105396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/05/2021] [Accepted: 05/11/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND The association between congenital myotonic dystrophy (CMD) and chylothorax is poorly recognized. AIMS To evaluate the proportion of chylothorax in infants with CMD compared to its prevalence in infants without CMD. STUDY DESIGN Single-center, retrospective, cohort study. SUBJECTS Infants managed at a neonatal intensive care unit from 2003 to 2019. OUTCOME MEASURES CMD was diagnosed using Southern blot for the quantification of CTG repeats in the dystrophia myotonica protein kinase (DMPK) gene. Prenatal and postnatal data of eligible infants with CMD were collected from the patients' medical records. The primary outcome was the proportion of chylothorax. RESULTS While the proportion of chylothorax in eligible infants without CMD was 0.25% (27/10714), that in infants with CMD was 50% (5/10; odds ratio (OR), 386.3; 95% confidence interval (CI), 84.4-1850.8; P < 0.001). The variables that were significantly different between infants with CMD with chylothorax and those without chylothorax were as follows: maternal age (33.0 vs. 24.8; P = 0.005), polyhydramnios (5/5 vs 1/5; P = 0.034), number of CTG repeats (1980 vs. 1500; P = 0.038), duration of invasive mechanical ventilation (220 vs. 2, P = 0.009), and duration of hospitalization (217.2 vs 68.0; P = 0.014). The mortality rate of all eligible infants with CMD was 5/10 (50%). No variables were significantly associated with mortality. CONCLUSIONS The proportion of chylothorax in infants with CMD was significantly higher than that in infants without CMD. Furthermore, the proportion was higher than that reported in previous studies on congenital chylothorax. This suggests that chylothorax may be frequently experienced in the clinical course of CMD.
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Affiliation(s)
- Masanori Kambara
- Department of Neonatology, Perinatal Medical Center, Kagoshima City Hospital, Kagoshima, Japan.
| | - Satoshi Ibara
- Department of Neonatology, Perinatal Medical Center, Kagoshima City Hospital, Kagoshima, Japan
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12
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Quigg KH, Berggren KN, McIntyre M, Bates K, Salmin F, Casiraghi JL, DʼAmico A, Astrea G, Ricci F, McKay MJ, Baldwin JN, Burns J, Campbell C, Sansone VA, Johnson NE. 12-Month progression of motor and functional outcomes in congenital myotonic dystrophy. Muscle Nerve 2021; 63:384-391. [PMID: 33341951 DOI: 10.1002/mus.27147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND We aim to describe 12-mo functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM). METHODS CDM participants performed the 6 Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength, and Lip Force at baseline and 12-mo visits. Parents completed the Vineland Adaptive Behavior Scale. RESULTS Forty-seven participants, aged 0 to 13 y old, with CDM were enrolled. 6MWT, 10 Meter Run, and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-mo performance was an improvement in 6MWT in children 3-6 y old (P = .008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 y, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 y. Participants with CTG repeat lengths <500 did not perform differently than those with repeat lengths >1000. CONCLUSIONS The 6MWT, 10 Meter Run, and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 y old and <3 y is warranted, but this new information will assist planning of clinical trials in the CDM population.
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Affiliation(s)
- Kellen H Quigg
- Department of Neurology, Virginia Commonwealth University Health, Richmond, Virginia, USA
| | - Kiera N Berggren
- Department of Neurology, Virginia Commonwealth University Health, Richmond, Virginia, USA
| | - Melissa McIntyre
- Department of Pediatric Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Kameron Bates
- Department of Neurology, Virginia Commonwealth University Health, Richmond, Virginia, USA
| | - Francesca Salmin
- The NEuroMuscular Omnicentre (NEMO) Clinical Center, Milan, Italy
| | | | - Adele DʼAmico
- Department of Neurosciences, Bambino Gesù Children's Hospital, Unit of Neuromuscular and Neurodegenerative Disorders, Rome, Italy
| | - Guja Astrea
- Department of Developmental Neuroscience, Scientific Institute for Research Hospitalization and Health Care (IRCCS) Stella Maris, Pisa, Italy
| | - Federica Ricci
- Department of Pediatrics, Section of Child and Adolescent Neuropsychiatry, Regina Margherita Children's Hospital, Turin, Italy
| | - Marnee J McKay
- Faculty of Medicine and Health, Sydney School of Health Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Jennifer N Baldwin
- Priority Research Centre for Physical Activity and Nutrition, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Joshua Burns
- Faculty of Medicine and Health, Sydney School of Health Sciences, The University of Sydney, Sydney, New South Wales, Australia
| | - Craig Campbell
- Department of Pediatrics, London Children's Hospital, University of Western Ontario, London, Ontario, Canada
| | | | - Nicholas E Johnson
- Department of Neurology, Virginia Commonwealth University Health, Richmond, Virginia, USA
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13
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Gutiérrez Gutiérrez G, Díaz-Manera J, Almendrote M, Azriel S, Eulalio Bárcena J, Cabezudo García P, Camacho Salas A, Casanova Rodríguez C, Cobo A, Díaz Guardiola P, Fernández-Torrón R, Gallano Petit M, García Pavía P, Gómez Gallego M, Gutiérrez Martínez A, Jericó I, Kapetanovic García S, López de Munaín Arregui A, Martorell L, Morís de la Tassa G, Moreno Zabaleta R, Muñoz-Blanco J, Olivar Roldán J, Pascual Pascual S, Peinado Peinado R, Pérez H, Poza Aldea J, Rabasa M, Ramos A, Rosado Bartolomé A, Rubio Pérez M, Urtizberea J, Zapata-Wainberg G, Gutiérrez-Rivas E. Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert. Neurologia 2020; 35:185-206. [DOI: 10.1016/j.nrl.2019.01.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Accepted: 01/05/2019] [Indexed: 01/18/2023] Open
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14
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Gutiérrez Gutiérrez G, Díaz-Manera J, Almendrote M, Azriel S, Eulalio Bárcena J, Cabezudo García P, Camacho Salas A, Casanova Rodríguez C, Cobo A, Díaz Guardiola P, Fernández-Torrón R, Gallano Petit M, García Pavía P, Gómez Gallego M, Gutiérrez Martínez A, Jericó I, Kapetanovic García S, López de Munaín Arregui A, Martorell L, Morís de la Tassa G, Moreno Zabaleta R, Muñoz-Blanco J, Olivar Roldán J, Pascual Pascual S, Peinado Peinado R, Pérez H, Poza Aldea J, Rabasa M, Ramos A, Rosado Bartolomé A, Rubio Pérez M, Urtizberea J, Zapata-Wainberg G, Gutiérrez-Rivas E. Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. NEUROLOGÍA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.nrleng.2019.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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15
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Abstract
The peripheral nervous system (PNS) is composed of motor neurons, nerve roots, plexuses, peripheral nerves (motor, sensory and autonomic), neuromuscular junction, and skeletal muscles. Disorders of the PNS in neonates most frequently cause weakness, hypotonia, and contractures, which may be generalized or focal. Since these findings may also occur with brain and spinal cord lesions, key features of the history and neurologic exam, together with diagnostic testing, are helpful in reaching a diagnosis. This review covers the diagnostic approach to PNS disorders in the neonate and includes a discussion of representative diseases of the motor neuron, brachial plexus, peripheral nerves, neuromuscular junction, and muscles. The importance of reaching a precise genetic diagnosis is highlighted with a discussion of current and emerging treatments for neonatal PNS diseases, particularly spinal muscular atrophy.
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Affiliation(s)
- Alex J Fay
- Department of Neurology, University of California, San Francisco, San Francisco, CA.
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16
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Henke C, Spiesshoefer J, Kabitz HJ, Herkenrath S, Randerath W, Brix T, Görlich D, Young P, Boentert M. Characteristics of respiratory muscle involvement in myotonic dystrophy type 1. Neuromuscul Disord 2019; 30:17-27. [PMID: 31839403 DOI: 10.1016/j.nmd.2019.10.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 09/05/2019] [Accepted: 10/29/2019] [Indexed: 01/21/2023]
Abstract
The pathophysiology of respiratory muscle weakness in myotonic dystrophy type 1 (DM1) remains incompletely understood. 21 adult patients with DM1 (11 men, 42 ± 13 years) and 21 healthy matched controls underwent spirometry, manometry, and diaphragm ultrasound. In addition, surface electromyography of the diaphragm and the obliquus abdominis muscle was performed following cortical and posterior cervical magnetic stimulation (CMS) of the phrenic nerves or magnetic stimulation of the lower thoracic nerve roots. Magnetic stimulation was combined with invasive recording of the twitch transdiaphragmatic and gastric pressure (twPdi and twPgas) in 10 subjects per group. The following parameters were reduced in DM1 patients compared to control subjects: maximum inspiratory pressure (MIP; 40.3 ± 19.2 vs. 95.8 ± 28.5 cmH2O, p < 0.01), diaphragm thickening ratio (DTR; 2.0 ± 0.4 vs. 2.7 ± 0.6, p < 0.01), twPdi following CMS (10.8 ± 8.3 vs. 21.4 ± 10.1 cmH2O, p = 0.03), and amplitude of diaphragm compound muscle action potentials (0.10 ± 0.25 vs. 0.46 ± 0.35 mV; p = 0.04). MIP and DTR were significantly correlated with the muscular impairment rating scale (MIRS) score. Maximum expiratory pressure (MEP) was reduced in DM1 patients compared to controls (41.3 ± 13.4 vs. 133.8 ± 28.0 cmH2O, p < 0.01) and showed negative correlation with the MIRS score. Pgas following a maximum cough was markedly lower in patients than in controls (71.9 ± 43.2 vs. 102.4 ± 35.5 cmH2O) but without statistical significance (p = 0.06). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength. Axonal phrenic nerve pathology may contribute to diaphragm dysfunction.
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Affiliation(s)
- Carolin Henke
- Respiratory Physiology Laboratory, Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany
| | - Jens Spiesshoefer
- Respiratory Physiology Laboratory, Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany
| | - Hans-Joachim Kabitz
- Department of Pneumology, Cardiology and Intensive Care Medicine, Klinikum Konstanz, Konstanz, Germany
| | - Simon Herkenrath
- Bethanien Hospital gGmbH Solingen, Solingen, Germany; Institute for Pneumology at the University of Cologne, Solingen, Germany
| | - Winfried Randerath
- Bethanien Hospital gGmbH Solingen, Solingen, Germany; Institute for Pneumology at the University of Cologne, Solingen, Germany
| | - Tobias Brix
- Institute of Medical Informatics, University of Muenster, Muenster, Germany
| | - Dennis Görlich
- Insitute for Biostatistics and Clinical Research, University Hospital, Muenster, Germany
| | - Peter Young
- Medical Park Klinik Reithofpark, Bad Feilnbach, Germany
| | - Matthias Boentert
- Respiratory Physiology Laboratory, Institute for Sleep Medicine and Neuromuscular Disorders, University Hospital Muenster, Muenster, Germany.
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17
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Kohno G, Ogawa K, Kushimoto M, Tanaka S, Ikeda J, Nishizawa T, Mitsuke K, Nakayama T, Suzuki Y, Ishihara H, Fujishiro M. Two Adult Siblings With Myotonic Dystrophy Type 1 With Different Phenotypes Presenting With Chronic Respiratory Insufficiency and Sleep Apnea Syndrome. Front Neurol 2019; 10:681. [PMID: 31333559 PMCID: PMC6620565 DOI: 10.3389/fneur.2019.00681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 06/11/2019] [Indexed: 11/18/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by progressive muscle weakness and myotonia along with multiple organ system involvements. Overall, DM1 patients show reduced life expectancy, mainly due to respiratory or cardiac abnormalities. Chronic respiratory impairment is associated with increased morbidity in DM1. The main ventilatory dysfunction etiology in DM1 is complex, consisting of both peripheral respiratory dysfunction and central respiratory drive dysfunction as well as upper airway muscle dysfunction leading to obstructive sleep apnea syndrome (SAS) and aspiration. Advancements in early diagnosis of DM1 and management with non-invasive therapeutic tools have improved life expectancy for DM1 patients. We present herein two siblings with DM1, a thin elder brother and an obese younger sister with visceral fat accumulation. Although neither had voluntary symptoms related to respiratory dysfunction, their apnea-hypopnea indices revealed severe SAS and subsequent arterial blood gases studies showed hypercapnia as well as hypoxia, suggesting central nervous system involvement with peripheral respiratory dysfunction. Non-invasive positive pressure ventilation during sleep was started following pulmonary assessment. Respiratory function should be assessed in DM1 patients, even those free of respiratory symptoms, because respiratory muscle weakness occurs in a high percentage of these patients and will shorten their lives.
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Affiliation(s)
- Genta Kohno
- Division of Diabetes and Metabolic Diseases, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Katsuhiko Ogawa
- Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan.,Division of Neurology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masaru Kushimoto
- Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan
| | - Sho Tanaka
- Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan.,Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Jin Ikeda
- Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan
| | - Tsukasa Nishizawa
- Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Kazutaka Mitsuke
- Division of Neurology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Tomohiro Nakayama
- Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Yutaka Suzuki
- Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan.,Division of Neurology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hisamitsu Ishihara
- Division of Diabetes and Metabolic Diseases, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Midori Fujishiro
- Division of Diabetes and Metabolic Diseases, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.,Department of Internal Medicine, Nihon University Hospital, Tokyo, Japan
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18
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Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert. Med Clin (Barc) 2019; 153:82.e1-82.e17. [DOI: 10.1016/j.medcli.2018.10.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/15/2018] [Accepted: 10/18/2018] [Indexed: 01/19/2023]
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19
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Ho G, Carey KA, Cardamone M, Farrar MA. Myotonic dystrophy type 1: clinical manifestations in children and adolescents. Arch Dis Child 2019; 104:48-52. [PMID: 29871899 DOI: 10.1136/archdischild-2018-314837] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 03/14/2018] [Accepted: 05/11/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Myotonic dystrophy type 1 (DM1) is an autosomal-dominant neuromuscular disease with variable severity affecting all ages; however, current care guidelines are adult-focused. The objective of the present study was to profile DM1 in childhood and propose a framework to guide paediatric-focused management. DESIGN, SETTING AND PATIENTS 40 children with DM1 (mean age 12.8 years; range 2-19) were studied retrospectively for a total of 513 follow-up years at Sydney Children's Hospital. 143 clinical parameters were recorded. RESULTS The clinical spectrum of disease in childhood differs from adults, with congenital myotonic dystrophy (CDM1) having more severe health issues than childhood-onset/juvenile patients (JDM1). Substantial difficulties with intellectual (CDM1 25/26 96.2%; JDM1 9/10, 90.0%), fine motor (CDM1 23/30, 76.6%; JDM1 6/10, 60.0%), gastrointestinal (CDM1 17/30, 70.0%; JDM1 3/10, 30.0%) and neuromuscular function (CDM1 30/30, 100.0%; JDM1 25/30, 83.3%) were evident. CONCLUSION The health consequences of DM1 in childhood are diverse, highlighting the need for paediatric multidisciplinary management approaches that encompass key areas of cognition, musculoskeletal, gastrointestinal, respiratory, cardiac and sleep issues.
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Affiliation(s)
- Genevieve Ho
- Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, New South Wales, Australia
| | - Kate A Carey
- Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, New South Wales, Australia
| | - Michael Cardamone
- Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia
| | - Michelle A Farrar
- Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia
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20
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Hayes HA, Dibella D, Crockett R, Dixon M, Butterfield RJ, Johnson NE. Stepping Activity in Children With Congenital Myotonic Dystrophy. Pediatr Phys Ther 2018; 30:335-339. [PMID: 30277969 DOI: 10.1097/pep.0000000000000537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
PURPOSE The purpose of this study was to investigate the physical activity levels in children with congenital myotonic dystrophy (CDM), and to examine whether patient clinical and functional characteristics correlated to physical activity. METHODS Twenty-five children with CDM were assessed on functional measures, clinical measures, and physical activity levels. RESULTS Results support that children with CDM spend the majority of their time inactive. There was a negative correlation between inactivity and cytosine-thymine-guanine repeats, suggesting increased inactivity with increased CDM severity. Age, body mass index, and lean muscle mass may be factors influencing activity levels. CONCLUSIONS Children in this study received one-third the recommended steps per day. The number of steps per day is not correlated with clinical measures.
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Affiliation(s)
- Heather A Hayes
- Department of Physical Therapy and Athletic Training (Dr Hayes) and Department of Neurology (Mss Dibella and Crockett and Drs Dixon, Butterfield, and Johnson), University of Utah, Salt Lake City, Utah
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21
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Wenninger S, Montagnese F, Schoser B. Core Clinical Phenotypes in Myotonic Dystrophies. Front Neurol 2018; 9:303. [PMID: 29770119 PMCID: PMC5941986 DOI: 10.3389/fneur.2018.00303] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 04/18/2018] [Indexed: 12/22/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled “Beyond Borders: Myotonic Dystrophies—A European Perception.”
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Affiliation(s)
- Stephan Wenninger
- Friedrich-Baur-Institute, Klinikum der Universität München, Munich, Germany
| | | | - Benedikt Schoser
- Friedrich-Baur-Institute, Klinikum der Universität München, Munich, Germany
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22
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Abstract
PURPOSE OF REVIEW In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs. RECENT FINDINGS Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs. Although observing how innovative drugs will change the natural history of these diseases, including respiratory function over time, adequate symptomatic treatment remains meaningful and is strongly recommended. Physicians should systematically take respiratory involvement into account to improve patients' quality of life and prognosis. SUMMARY First, it is outlined in which subtypes of NMD respiratory muscle dysfunction is particularly relevant. Second, new developments regarding diagnostic procedures, including respiratory muscle strength testing, spirometry, and sleep studies, are covered. Third, this article gives an overview on current concepts of ventilatory support and management of secretions in patients with NMD.
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23
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Thomas JD, Oliveira R, Sznajder ŁJ, Swanson MS. Myotonic Dystrophy and Developmental Regulation of RNA Processing. Compr Physiol 2018; 8:509-553. [PMID: 29687899 PMCID: PMC11323716 DOI: 10.1002/cphy.c170002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM disease presentation is highly variable and distinguished by differences in age-of-onset and symptom severity. In the most severe form, DM presents with congenital onset and profound developmental defects. At the molecular level, DM pathogenesis is characterized by a toxic RNA gain-of-function mechanism that involves the transcription of noncoding microsatellite expansions. These mutant RNAs disrupt key cellular pathways, including RNA processing, localization, and translation. In DM, these toxic RNA effects are predominantly mediated through the modulation of the muscleblind-like and CUGBP and ETR-3-like factor families of RNA binding proteins (RBPs). Dysfunction of these RBPs results in widespread RNA processing defects culminating in the expression of developmentally inappropriate protein isoforms in adult tissues. The tissue that is the focus of this review, skeletal muscle, is particularly sensitive to mutant RNA-responsive perturbations, as patients display a variety of developmental, structural, and functional defects in muscle. Here, we provide a comprehensive overview of DM1 and DM2 clinical presentation and pathology as well as the underlying cellular and molecular defects associated with DM disease onset and progression. Additionally, fundamental aspects of skeletal muscle development altered in DM are highlighted together with ongoing and potential therapeutic avenues to treat this muscular dystrophy. © 2018 American Physiological Society. Compr Physiol 8:509-553, 2018.
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Affiliation(s)
- James D. Thomas
- Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, USA
| | - Ruan Oliveira
- Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, USA
| | - Łukasz J. Sznajder
- Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, USA
| | - Maurice S. Swanson
- Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida, USA
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Abstract
PURPOSE OF REVIEW This article describes clinical and electrical myotonia and provides an update on the classification, diagnosis, and management of myotonic disorders. RECENT FINDINGS In the myotonic dystrophies, antisense oligonucleotides provide a general strategy to correct RNA gain of function and modulate the expression of CTG expanded repeats; they are currently being tested in a phase 1-2 randomized controlled trial in patients with adult-onset myotonic dystrophy type 1. New genetic mutations are continuously being identified in the nondystrophic myotonias involving sodium and chloride channels. This contributes to the difficulty in describing genotype-phenotype correlations as the same mutations can give rise to different phenotypes, and the same phenotypes can arise from different mutations. Pharmacologic therapy is moving toward mutation-targeted treatments. SUMMARY This article describes the clinical and diagnostic characteristics and management of the myotonic dystrophies and the nondystrophic myotonias. Clinical features of the congenital, juvenile, and classic adult forms of myotonic dystrophy type 1 are reviewed, and for the adult form, reference is made to the main diagnostic and follow-up tests for which general consensus exists. The different clinical presentations of myotonic dystrophy type 2 and its main differential diagnostic options are also discussed. The clinical spectrum of the sodium and chloride channelopathies is described, and clinical diagnostic clues to differentiate between these two groups are provided. Therapeutic options for patients with nondystrophic myotonias are also presented with reference to literature review and the author's personal experience.
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Myotonic Dystrophies. Neuromuscul Disord 2018. [DOI: 10.1007/978-981-10-5361-0_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide. Atherosclerosis 2017; 267:110-115. [PMID: 29121498 DOI: 10.1016/j.atherosclerosis.2017.10.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 09/19/2017] [Accepted: 10/18/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominant inherited muscular dystrophies with multiple systemic involvement, often producing cardiac injury. This study sought to determine the clinical significance of elevated high sensitivity cardiac troponin T and I (hs-cTnT and hs-cTnI), and N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in this population. METHODS Sixty DM patients (35 men and 25 women; mean age: 45.1 years, range: 12-73 years) underwent clinical cardiac investigations and measurements of serum hs-cTnT, hs-cTnI, creatine kinase (CK), and NT-proBNP. Left ventricular (LV) ejection fraction (EF) was assessed by echocardiography. RESULTS Genetic analysis revealed that 46 of the 60 patients were DM1, and 14 DM2. Blood measurements showed persistent elevation of hs-cTnT and CK in 55/60 DM patients (91.73%). In contrast, hs-cTnI values were persistently normal throughout the study. Only 2 patients showed an EF <50%, being the overall range of this population between 40% and 79%. We found ECG abnormalities in 19 patients. Of these patients, 13 showed first or second-degree atrio ventricular (AV) blocks (PR interval ≥ 200 ms), 4 showed a left bundle branch block (LBBB) prolonged (QRS duration ≥120 ms), and 2 had an incomplete bundle branch block (QRS duration between 110 and 119 ms). After excluding patients with EF <50%, NT-pro-BNP measurement > 125 pg/mL was an independent predictor of ECG abnormalities. CONCLUSIONS NT-pro-BNP levels may be considered to be used clinically to identify DM patients at increased risk of developing myocardial conduction abnormalities.
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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. PLoS One 2017; 12:e0174166. [PMID: 28323905 PMCID: PMC5360313 DOI: 10.1371/journal.pone.0174166] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 03/03/2017] [Indexed: 12/27/2022] Open
Abstract
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.
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Pucillo EM, Dibella DL, Hung M, Bounsanga J, Crockett B, Dixon M, Butterfield RJ, Campbell C, Johnson NE. Physical function and mobility in children with congenital myotonic dystrophy. Muscle Nerve 2017; 56:224-229. [PMID: 27859360 PMCID: PMC5436951 DOI: 10.1002/mus.25482] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 11/11/2016] [Accepted: 11/16/2016] [Indexed: 11/12/2022]
Abstract
INTRODUCTION Congenital myotonic dystrophy (CDM) occurs when symptoms of myotonic dystrophy present at birth. In this study we evaluated the relationship between physical function, muscle mass, and age to provide an assessment of the disease and help prepare for therapeutic trials. METHODS CDM participants performed timed functional tests (TFTs), the first 2 minutes of 6-minute walk tests (2/6MWTs), and myometry tests, and also performed dual-energy X-ray absorption (DEXA) scans. Healthy controls (HCs) performed TFTs, 6MWTs, and myometry. RESULTS Thirty-seven children with CDM and 27 HCs (age range 3-13 years) participated in the study. There were significant differences in the 10-meter walk (11.3 seconds in CDM vs. 6.8 seconds in HC) and 2MWT (91 meters in CDM vs. 193 meters in HCs). DEXA lean mass of the right arm correlated with grip strength (r = 0.91), and lean mass of the right leg correlated with 6MWT (r = 0.62). CONCLUSION Children with CDM have significant limitations in strength and mobility. The tests performed were reliable, and lean muscle mass may serve as a useful biomarker. Muscle Nerve 56: 224-229, 2017.
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Affiliation(s)
- Evan M Pucillo
- Eccles Institute of Human Genetics, Department of Neurology, University of Utah School of Medicine, 15N 2030 East, Salt Lake City, Utah, 84112, USA
| | - Deanna L Dibella
- Eccles Institute of Human Genetics, Department of Neurology, University of Utah School of Medicine, 15N 2030 East, Salt Lake City, Utah, 84112, USA
| | - Man Hung
- Department of Orthopedics, University of Utah, Salt Lake City, Utah, USA.,Division of Public Health, University of Utah, Salt Lake City, Utah, USA
| | - Jerry Bounsanga
- Department of Orthopedics, University of Utah, Salt Lake City, Utah, USA
| | - Becky Crockett
- Eccles Institute of Human Genetics, Department of Neurology, University of Utah School of Medicine, 15N 2030 East, Salt Lake City, Utah, 84112, USA
| | - Melissa Dixon
- Eccles Institute of Human Genetics, Department of Neurology, University of Utah School of Medicine, 15N 2030 East, Salt Lake City, Utah, 84112, USA
| | | | - Craig Campbell
- Department of Pediatrics, Clinical Neurological Sciences and Epidemiology, Western University, London, Ontario, Canada
| | - Nicholas E Johnson
- Eccles Institute of Human Genetics, Department of Neurology, University of Utah School of Medicine, 15N 2030 East, Salt Lake City, Utah, 84112, USA
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Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy. Mol Ther 2016; 24:1378-87. [PMID: 27203440 DOI: 10.1038/mt.2016.97] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 04/26/2016] [Indexed: 12/11/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.
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Mutchnick IS, Thatikunta MA, Gump WC, Stewart DL, Moriarty TM. Congenital myotonic dystrophy: ventriculomegaly and shunt considerations for the pediatric neurosurgeon. Childs Nerv Syst 2016; 32:609-16. [PMID: 26747623 DOI: 10.1007/s00381-015-2993-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/22/2015] [Indexed: 12/13/2022]
Abstract
PURPOSE Ventriculomegaly in infants with congenital myotonic dystrophy (CDM) is common, and the neurosurgical determination of shunting is complex. The natural history of CDM-associated ventriculomegaly from prenatal to natal to postnatal stages is poorly known. The relationship between macrocephaly and ventriculomegaly, incidence of shunt necessity, and early mortality outcomes lack pooled data analysis. This study aims to review clinical features and pathophysiology of CDM, with emphasis on ventriculomegaly progression, ventriculomegaly association with macrocephaly, and incidence of shunting. METHODS This is a literature review with pooled data analysis and case report. RESULTS One hundred four CDM patients were reviewed in 13 articles that mentioned CDM with ventriculomegaly and/or head circumference. Data was very limited: only 7 patients had data on the presence or absence of prenatal ventriculomegaly, 97 on ventriculomegaly at birth, and 32 on whether or not the ventricles enlarged post-natally. Three patients of 7 (43 %) had pre-natally diagnosed ventriculomegaly, 43 of 97 (44 %) had ventriculomegaly at birth, and only 5 of 32 (16 %) had progressive enlargement of ventricles post-natally. Only 5 of 104 patients had a documented shunt placement: 1 for obstructive, 1 for a post-hemorrhagic communicating, 2 for a communicating hydrocephalus without hemorrhage, and 1 with unknown indication. Of 13 macrocephalic patients with data about ventricular size, 12 had ventriculomegaly. CONCLUSIONS Ventriculomegaly occurs regularly with CDM but most often does not require CSF diversion. Decisions regarding neurosurgical intervention will necessarily be based on limited information, but shunting should only occur once dynamic data confirms hydrocephalus.
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Affiliation(s)
- Ian S Mutchnick
- Division of Pediatric Neurosurgery, Norton Neuroscience Institute and Kosair Children's Hospital, 210 East Gray St., Suite 1102, Louisville, KY, 40202, USA.
| | - Meena A Thatikunta
- Department of Neurosurgery, University of Louisville Hospital, Louisville, KY, USA
| | - William C Gump
- Division of Pediatric Neurosurgery, Norton Neuroscience Institute and Kosair Children's Hospital, 210 East Gray St., Suite 1102, Louisville, KY, 40202, USA
| | - Dan L Stewart
- Department of Pediatrics, Neonatology, University of Louisville School of Medicine, Kosair Children's Hospital, Louisville, KY, USA
| | - Thomas M Moriarty
- Division of Pediatric Neurosurgery, Norton Neuroscience Institute and Kosair Children's Hospital, 210 East Gray St., Suite 1102, Louisville, KY, 40202, USA
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Ho G, Cardamone M, Farrar M. Congenital and childhood myotonic dystrophy: Current aspects of disease and future directions. World J Clin Pediatr 2015; 4:66-80. [PMID: 26566479 PMCID: PMC4637811 DOI: 10.5409/wjcp.v4.i4.66] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 08/07/2015] [Accepted: 09/25/2015] [Indexed: 02/06/2023] Open
Abstract
Myotonic dystrophy type 1 (DM1) is multisystem disease arising from mutant CTG expansion in the non-translating region of the dystrophia myotonica protein kinase gene. While DM1 is the most common adult muscular dystrophy, with a worldwide prevalence of one in eight thousand, age of onset varies from before birth to adulthood. There is a broad spectrum of clinical severity, ranging from mild to severe, which correlates with number of DNA repeats. Importantly, the early clinical manifestations and management in congenital and childhood DM1 differ from classic adult DM1. In neonates and children, DM1 predominantly affects muscle strength, cognition, respiratory, central nervous and gastrointestinal systems. Sleep disorders are often under recognised yet a significant morbidity. No effective disease modifying treatment is currently available and neonates and children with DM1 may experience severe physical and intellectual disability, which may be life limiting in the most severe forms. Management is currently supportive, incorporating regular surveillance and treatment of manifestations. Novel therapies, which target the gene and the pathogenic mechanism of abnormal splicing are emerging. Genetic counselling is critical in this autosomal dominant genetic disease with variable penetrance and potential maternal anticipation, as is assisting with family planning and undertaking cascade testing to instigate health surveillance in affected family members. This review incorporates discussion of the clinical manifestations and management of congenital and childhood DM1, with a particular focus on hypersomnolence and sleep disorders. In addition, the molecular genetics, mechanisms of disease pathogenesis and development of novel treatment strategies in DM1 will be summarised.
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Van Den Hende K, Durand S, Mesnage R, Filleron A, Cambonie G. [Congenital myotonic dystrophy type I in a very premature neonate: ethical concerns]. Arch Pediatr 2015; 22:1042-6. [PMID: 26321353 DOI: 10.1016/j.arcped.2015.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/22/2015] [Accepted: 07/06/2015] [Indexed: 10/23/2022]
Abstract
UNLABELLED The congenital form of myotonic dystrophy type I (CDM1) corresponds to a>1500 expansion of an unstable trinucleotide (CTG) repeat. Two prognostic factors predict the risk of death in early infancy: maturity of less than 35 weeks of gestation and neonatal invasive ventilation for more than 30 days. OBSERVATION The case of a 29-week-old premature female infant, conceived by in vitro fertilization, is reported. Generalized hypotonia led to the diagnosis of the disease. Ethical concertation about withdrawal or maintenance of intensive care was engaged, taking into account the prolonged ventilation, the degree of prematurity, and the parental wishes for maximum care. The infant was extubated after 2 months. At 17 months, motor development and precursors of language were delayed, and difficulties in feeding had required a gastrostomy. DISCUSSION Technical advances in neonatal intensive care now allow CDM1 children to survive prolonged ventilation. The signification of such ventilatory needs on patient outcome, particularly for motor handicaps, speech and language delay, and mental deficiency, remains uncertain. The potential impact of in vitro fertilization on disease expression may also be considered. CONCLUSION CDM1 is a severe condition, but variability in clinical manifestations and absence of genotype-phenotype correlation result in problems predicting prognosis at the individual level. Ethical issues about the level of care, notably for tracheostomy and gastrostomy, should be adapted to each case, in partnership with parents.
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Affiliation(s)
- K Van Den Hende
- Département de pédiatrie néonatale et réanimations, pôle hospitalo-universitaire Femme-Mère-Enfant, hôpital Arnaud-de-Villeneuve, centre hospitalier régional universitaire de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
| | - S Durand
- Département de pédiatrie néonatale et réanimations, pôle hospitalo-universitaire Femme-Mère-Enfant, hôpital Arnaud-de-Villeneuve, centre hospitalier régional universitaire de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France.
| | - R Mesnage
- Département de pédiatrie néonatale et réanimations, pôle hospitalo-universitaire Femme-Mère-Enfant, hôpital Arnaud-de-Villeneuve, centre hospitalier régional universitaire de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
| | - A Filleron
- Service de pédiatrie, hôpital Carémeau, centre hospitalier régional universitaire de Nîmes, place du Professeur-Debré, 30029 Nîmes cedex 9, France
| | - G Cambonie
- Département de pédiatrie néonatale et réanimations, pôle hospitalo-universitaire Femme-Mère-Enfant, hôpital Arnaud-de-Villeneuve, centre hospitalier régional universitaire de Montpellier, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
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Bezak BJ, Arce KA, Jacob A, Van Ess J. Orthognathic Surgery in Patients With Congenital Myopathies and Congenital Muscular Dystrophies: Case Series and Review of the Literature. J Oral Maxillofac Surg 2015; 74:601-9. [PMID: 26292175 DOI: 10.1016/j.joms.2015.07.023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 07/27/2015] [Accepted: 07/27/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE This case series examined preoperative findings and the surgical, anesthetic, and postoperative management of 6 patients with congenital myopathies (CMs) and congenital muscular dystrophies (CMDs) treated at a tertiary medical institution with orthognathic surgery over 15 years to describe pertinent considerations for performing orthognathic surgery in these complex patients. MATERIALS AND METHODS According to the institutional review board-approved protocol, chart records were reviewed for all orthognathic surgical patients with a clinical, genetic, or muscle biopsy-proved diagnosis of CM or CMD. RESULTS Six patients (5 male, 1 female) qualified, and they were treated by 4 surgeons in the division of oral and maxillofacial surgery from 1992 through 2007. Average age was 19.5 years at the time of orthognathic surgery. Five patients had Class III malocclusions and 1 patient had Class II malocclusion. All 6 patients had apertognathia with lip incompetence. Nasoendotracheal intubation with a difficulty of 0/3 (0=easiest, 3=most difficult) was performed in all cases. Routine induction and maintenance anesthetics, including halogenated agents and nondepolarizing muscle relaxants, were administered without malignant hyperthermia. All 6 patients underwent Le Fort level osteotomies; 4 also had mandibular setback surgery with or without balancing mandibular inferior border osteotomies. Five patients required planned intensive care unit care postoperatively (average, 18.4 days; range, 4 to 65 days). Postoperative respiratory complications resulting in major blood oxygen desaturations occurred in 5 patients; 4 of these patients required reintubation during emergency code response. Five patients required extended postoperative intubation (average, 4.2 days; range, 3 to 6 days) and ventilatory support. Average hospital length of stay was 21.8 days (range, 6 to 75 days). Average postoperative follow-up interval was 29.8 weeks (range, 6 to 128 weeks). CONCLUSIONS Patients with CMs or CMDs often have characteristic dentofacial malocclusions that contribute to functional problems with feeding and drooling and psychosocial problems. Orthognathic surgery, usually bimaxillary, can be judiciously considered in these patients; these procedures typically require multidisciplinary pre- and postoperative evaluation and care over lengthy hospital stays with a high risk of respiratory complications that bear consideration in treatment planning.
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Affiliation(s)
- Brett J Bezak
- Resident, Division of Oral and Maxillofacial Surgery, Department of Surgery, Mayo Clinic, Rochester, MN.
| | - Kevin A Arce
- Assistant Professor, Department of Surgery, College of Medicine, Mayo Clinic, Rochester, MN
| | - Adam Jacob
- Associate Professor, Department of Anesthesiology, College of Medicine, Mayo Clinic, Rochester, MN
| | - James Van Ess
- Assistant Professor, Department of Surgery, College of Medicine, Mayo Clinic, Rochester, MN
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Sansone VA, Gagnon C. 207th ENMC Workshop on chronic respiratory insufficiency in myotonic dystrophies: management and implications for research, 27-29 June 2014, Naarden, The Netherlands. Neuromuscul Disord 2015; 25:432-42. [PMID: 25728518 DOI: 10.1016/j.nmd.2015.01.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 01/10/2015] [Accepted: 01/26/2015] [Indexed: 01/19/2023]
Affiliation(s)
- V A Sansone
- Centro Clinico NEMO, University of Milan, Milan, Italy.
| | - C Gagnon
- Université de Sherbrooke, Quebec, Canada
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Bouchard JP, Cossette L, Bassez G, Puymirat J. Natural history of skeletal muscle involvement in myotonic dystrophy type 1: a retrospective study in 204 cases. J Neurol 2014; 262:285-93. [PMID: 25380585 DOI: 10.1007/s00415-014-7570-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 10/29/2014] [Accepted: 10/31/2014] [Indexed: 01/28/2023]
Abstract
Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adult. The aim of this study was to investigate the natural history of skeletal muscle weakness in adults, in a cross-sectional, retrospective study. In a cohort of 204 adult DM1 patients, we quantified muscle impairment, handgrip force and physical disability. Muscle strength was similarly affected in the legs and in the arms, the right and left side, and distally more than proximally in patients. The earliest and the most affected skeletal muscles were the digit flexors, foot dorsiflexors and neck flexors; whereas the elbow and knee extensors and flexors were the least affected muscle groups. The rate of decline of the muscle strength was -0.111 units/year. The handgrip values were lower in DM1 patients than the normative values and the rate of decline in handgrip force per year was -0.24 kg. Limitation in mobility or walking is observed in 84 % of DM1 patients but requirement of wheelchair is infrequent (3 %). The decrease in muscle strength, handgrip force and the increase in physical disability were highly correlated with duration of the disease and the number of CTG repeats in the blood. Significant association was found between decline in muscle strength and the age at onset, physical disability and the age of patients at evaluation, handgrip force and gender. Decline in muscle weakness is very slow and although limitation when walking is a common manifestation of DM1 in patients, the requirement of wheelchair is infrequent.
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Affiliation(s)
- Jean-Pierre Bouchard
- Department of Neurological Sciences, CHU de Quebec, Enfant-Jesus Hospital, Quebec, Canada
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Assessment of Premutation in Myotonic Dystrophy Type 1 Affected Family Members by TP-PCR and Genetic Counseling. Case Rep Med 2014; 2014:289643. [PMID: 24715907 PMCID: PMC3970441 DOI: 10.1155/2014/289643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Revised: 12/25/2013] [Accepted: 12/27/2013] [Indexed: 11/28/2022] Open
Abstract
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.
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Abstract
Myotonic dystrophy (DM) encompasses two gene defects, DM1 (myotonic dystrophy type 1) being currently the sole disorder leading to a childhood form of the disease. As consequence of the non coding unstable CTG repeat expansion mutation, DM1 presents as an extremely wide and diverse clinical continuum ranging from antenatal to late adult forms, the complexity of the disease being reinforced by multisystemic involvement. The congenital form appears as the most severe end of the phenotypic spectrum and may include marked neonatal hypotonia, respiratory failure, facial diplegia, contractures, and mental retardation. Brain involvement is the hallmark of childhood-onset DM1, distinguished by a normal neonatal period, with learning difficulties as the main presenting symptom, resulting from various degrees of mental delay, psychopathological manifestations, speech defects, hypersomnolence, and fatigue. In contrast, muscle weakness remains usually moderate in childhood, limited to facial weakness, ptosis, and dysarthria, until a decline from the second decade. Orthopedic manifestations including kyphoscoliosis and equinovarus may require surgery. Other organs involvement includes frequent abdominal symptoms, whereas endocrine disturbance is rare. Symptomatic cardiac arrhythmia, mainly exercise-induced, can be observed. While current treatment is mainly symptomatic, future clinical trials are expected following significant progress in pathophysiology and the recent development of molecular therapy approaches.
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Todd PK, Ackall FY, Hur J, Sharma K, Paulson HL, Dowling JJ. Transcriptional changes and developmental abnormalities in a zebrafish model of myotonic dystrophy type 1. Dis Model Mech 2013; 7:143-55. [PMID: 24092878 PMCID: PMC3882056 DOI: 10.1242/dmm.012427] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Myotonic dystrophy type I (DM1) is a multi-system, autosomal dominant disorder caused by expansion of a CTG repeat sequence in the 3′UTR of the DMPK gene. The size of the repeat sequence correlates with age at onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function, mediated at least in part by sequestering specific RNA splicing proteins, most notably muscleblind-related (MBNL) proteins. However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG)91 repeat-containing mRNA into single-cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities and broad transcriptional changes, as shown by cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG)91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small-molecule therapeutic development.
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Affiliation(s)
- Peter K Todd
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
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Campbell C, Levin S, Siu VM, Venance S, Jacob P. Congenital myotonic dystrophy: Canadian population-based surveillance study. J Pediatr 2013; 163:120-5.e1-3. [PMID: 23415617 DOI: 10.1016/j.jpeds.2012.12.070] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 12/11/2012] [Accepted: 12/20/2012] [Indexed: 01/07/2023]
Abstract
OBJECTIVES To determine the incidence and neonatal morbidity and mortality of congenital myotonic dystrophy (CDM) in Canada. STUDY DESIGN The study has 2 phases. A 5-year prospective monthly surveillance of incident cases of CDM conducted via the Canadian Pediatric Surveillance Program, from March 1, 2005-February 28, 2010, and a 5-year cohort study of eligible incident cases, which is ongoing and not the subject of this report. RESULTS A total of 121 cases were reported, with 38 confirmed as CDM. The incidence of CDM in Canada is 2.1/100,000 (1/47,619) live births. The cases were reported from 8 provinces and 1 territory. The highest reported incidence was Ontario with 15, followed by British Columbia with 7, and Quebec with 6. External validation of cases was performed. The trinucleotide repeat level varied from 550-3100. Twenty-two (58%) of the children were the index cases for their families. Seventeen children are currently enrolled in the ongoing cohort study. CONCLUSION Surveillance and prospective examination of CDM at a population level is important, as the impact of this rare disease is systemic, chronic, and associated with significant morbidity and mortality throughout childhood.
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Affiliation(s)
- Craig Campbell
- Department of Pediatrics, Shulich School of Medicine, London Health Sciences Center, University of Western Ontario, London, Ontario, Canada.
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Panaite PA, Kuntzer T, Gourdon G, Barakat-Walter I. Respiratory failure in a mouse model of myotonic dystrophy does not correlate with the CTG repeat length. Respir Physiol Neurobiol 2013; 189:22-6. [PMID: 23811192 DOI: 10.1016/j.resp.2013.06.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 06/20/2013] [Accepted: 06/20/2013] [Indexed: 01/03/2023]
Abstract
Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion, these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.
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Molecular mechanisms of muscle atrophy in myotonic dystrophies. Int J Biochem Cell Biol 2013; 45:2280-7. [PMID: 23796888 DOI: 10.1016/j.biocel.2013.06.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 06/11/2013] [Accepted: 06/12/2013] [Indexed: 02/01/2023]
Abstract
Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in patients' tissues by targeting RNA-binding proteins such as CUG-binding protein 1 (CUGBP1) and Muscle blind-like protein 1 (MBNL1). Despite overwhelming evidence showing the critical role of RNA-binding proteins in DM1 and DM2 pathologies, the downstream pathways by which these RNA-binding proteins cause muscle wasting and muscle weakness are not well understood. This review discusses the molecular pathways by which DM1 and DM2 mutations might cause muscle atrophy and describes progress toward the development of therapeutic interventions for muscle wasting and weakness in DM1 and DM2. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.
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Dhand UK, Raja F, Aggarwal K. Structural myocardial involvement in adult patients with type 1 myotonic dystrophy. Neurol Int 2013; 5:e5. [PMID: 23717784 PMCID: PMC3661985 DOI: 10.4081/ni.2013.e5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2012] [Revised: 02/23/2013] [Accepted: 02/25/2013] [Indexed: 01/10/2023] Open
Abstract
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 (ECHAO) 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.
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Affiliation(s)
- Upinder K Dhand
- Departments of Neurology, University of Missouri, Columbia MO, USA
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Savić Pavićević D, Miladinović J, Brkušanin M, Šviković S, Djurica S, Brajušković G, Romac S. Molecular genetics and genetic testing in myotonic dystrophy type 1. BIOMED RESEARCH INTERNATIONAL 2013; 2013:391821. [PMID: 23586035 PMCID: PMC3613064 DOI: 10.1155/2013/391821] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 02/05/2013] [Indexed: 12/29/2022]
Abstract
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.
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Affiliation(s)
- Dušanka Savić Pavićević
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Jelena Miladinović
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Miloš Brkušanin
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Saša Šviković
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Svetlana Djurica
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Goran Brajušković
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
| | - Stanka Romac
- Center for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Studentski trg 16, P.O. Box 52, 11000 Belgrade, Serbia
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Kongenitale myotone Dystrophie mit Zwerchfellparese. Monatsschr Kinderheilkd 2012. [DOI: 10.1007/s00112-012-2721-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Panaite PA, Kuntzer T, Gourdon G, Lobrinus JA, Barakat-Walter I. Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy. Dis Model Mech 2012. [PMID: 23180777 PMCID: PMC3634646 DOI: 10.1242/dmm.010512] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
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 problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.
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Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, Woodgett J, Killian J, Timchenko NA, Timchenko LT. GSK3β mediates muscle pathology in myotonic dystrophy. J Clin Invest 2012; 122:4461-72. [PMID: 23160194 DOI: 10.1172/jci64081] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 09/21/2012] [Indexed: 02/01/2023] Open
Abstract
Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease characterized by skeletal muscle wasting, weakness, and myotonia. DM1 is caused by the accumulation of CUG repeats, which alter the biological activities of RNA-binding proteins, including CUG-binding protein 1 (CUGBP1). CUGBP1 is an important skeletal muscle translational regulator that is activated by cyclin D3-dependent kinase 4 (CDK4). Here we show that mutant CUG repeats suppress Cdk4 signaling by increasing the stability and activity of glycogen synthase kinase 3β (GSK3β). Using a mouse model of DM1 (HSA(LR)), we found that CUG repeats in the 3' untranslated region (UTR) of human skeletal actin increase active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β in both DM1 cell culture and mouse models corrected cyclin D3 levels and reduced muscle weakness and myotonia in DM1 mice. Our data predict that compounds normalizing GSK3β activity might be beneficial for improvement of muscle function in patients with DM1.
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Affiliation(s)
- Karlie Jones
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA
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Hilbert JE, Kissel JT, Luebbe EA, Martens WB, McDermott MP, Sanders DB, Tawil R, Thornton CA, Moxley RT. If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD). Contemp Clin Trials 2012; 33:302-11. [PMID: 22155025 PMCID: PMC3357007 DOI: 10.1016/j.cct.2011.11.016] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 10/28/2011] [Accepted: 11/22/2011] [Indexed: 01/28/2023]
Abstract
INTRODUCTION Registries are becoming increasingly important for rare diseases as experimental therapies develop. This report describes the methodology behind the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD) Patients and Family Members to facilitate the development of other rare disease registries. We also highlight data about the pathophysiology and select burdens of DM and FSHD reported at baseline and longitudinally. METHODS The Registry consists of de-identified, patient reported information collected at baseline and annually and information from review of medical records. Investigators can use the Registry to analyze de-identified data and to facilitate recruitment into clinical studies. RESULTS To date, the Registry has enrolled 1611 members, facilitated 24 studies, and collected data annually for up to 8 years. Genetic test results were obtained in 56.2% of enrollees. Approximately one-third of members used assistive devices and another one-third reported psychological problems at baseline. Wheelchair use was reported for both short and long distances by 7.0% of DM and 18.1% of FSHD members. Approximately 60% of members reported their employment was affected by their disease. CONCLUSIONS Strengths of the Registry include large sample sizes, stringent review of clinical and molecular data, annually updated information, and regular interactions between patients and investigators. Registry data provide new insights into the burdens of DM and FSHD, such as, psychological problems and reduced employment. Opportunities abound for investigators to utilize Registry resources to assess the impact of these and other burdens on health care costs, progression of symptoms, and quality of life.
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Affiliation(s)
- James E Hilbert
- Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
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Myotonic Dystrophy Type 1 or Steinert’s Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 724:239-57. [DOI: 10.1007/978-1-4614-0653-2_18] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Lallemand B, Clementy N, Bernard-Brunet A, Pierre B, Corcia P, Fauchier L, Raynaud M, Pellieux S, Babuty D. The evolution of infrahissian conduction time in myotonic dystrophy patients: clinical implications. Heart 2011; 98:291-6. [PMID: 22038543 PMCID: PMC3262987 DOI: 10.1136/heartjnl-2011-300143] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Background Myotonic dystrophy (MD1) is a hereditary autosomal dominant disease with variable penetrance. Cardiac conduction disturbances are frequent and may be responsible for sudden death, but its progression was heretofore unknown. Aims The aim of the study was to analyse the natural history of infrahissian conduction time in patients with a normal first electrophysiological test, and to identify the predictive value of the clinical and ECG factors accompanying an alteration of infrahissian conduction. Methods Among 127 consecutive screened MD patients, 25 were enrolled and underwent a second electrophysiological testing. The second electrophysiological test was carried out on patients showing new symptoms, new atrioventricular conduction disturbances on ECG, or significant modifications of signal-averaged (SA)-ECG, and on asymptomatic patients with a follow-up of at least 60 months since the first electrophysiological test. Results Among the 25 patients, four had new clinical symptoms, four others developed new atrioventricular conduction abnormalities on ECG and six had significant modifications of the SA-ECG. The mean His-ventricle (HV) interval increased significantly between the two electrophysiological studies (initial HV interval 52.1 ms±1.6 ms, final HV interval 61.4 ms±2.2 ms, p<0.005), with a mean increase of 1.2 ms/year. The five patients with HV interval of 70 ms or greater were implanted with a prophylactic dual-chamber pacemaker. Modifications of resting ECG and SA-ECG were strongly associated with HV interval prolongation. Conclusion In patients with a normal initial electrophysiological study, modifications on the resting ECG and/or SA-ECG, on annual check-up, were associated with an alteration of infrahissian conduction.
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Affiliation(s)
- Bénédicte Lallemand
- Cardiology Department, Hospital Trousseau, François Rabelais University, 37044 Tours, France
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