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Santos Silva C, Nunes Vicente B, Martins B, Fonseca AC, Coelho P, Roque R, Cota de Medeiros F, Oliveira Santos M, de Carvalho M. Ptosis in human immunodeficiency virus-infected patients under long-term antiretroviral treatment. Clin Neurol Neurosurg 2025; 249:108690. [PMID: 39721124 DOI: 10.1016/j.clineuro.2024.108690] [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: 09/15/2024] [Revised: 11/09/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024]
Abstract
OBJECTIVE To present cases of ptosis in HIV-1 patients on long-term antiretroviral therapy (ART) and review the existing literature. METHODS Five HIV-1-positive patients with slowly progressive bilateral ptosis underwent a comprehensive diagnostic evaluation, including imaging studies, neurophysiological testing, muscle biopsy, and genetic analysis. A literature review was conducted. RESULTS On clinical examination, all patients presented with bilateral symmetrical non-fatigable ptosis, three exhibited facial lipoatrophy and two also had mild multidirectional ophthalmoparesis and all had ocular abnormalities in Hess screen test. Additionally, one patient displayed proptosis, three had floppy lower eyelids, and four presented with exotropia. Anti-acetylcholine receptor antibodies were negative in all patients. Brain magnetic resonance imaging (MRI), motor unit potential analysis, and single-fiber electromyography were unremarkable. Orbital MRI revealed introrbital fat expansion in one patient, and limb muscle biopsies were inconclusive in two cases. Blood genetic testing for chronic progressive external ophthalmoplegia was negative in all patients. A total of 30 similar cases have been documented in the literature, with some studies reporting key findings such as muscle histology indicative of mitochondrial myopathy, MRI revealing patchy extraocular muscle hyperintensity, and muscle genetic testing identifying mitochondrial deoxyribonucleic acid (DNA) deletions. Ptosis surgical repair appears to be the most effective treatment. CONCLUSION HIV patients on long-term ART may develop ocular muscle involvement due to mitochondrial dysfunction, with bilateral ptosis being the primary manifestation. Diagnosis is challenging and requires the exclusion of other conditions. Ptosis surgery can significantly improve quality of life.
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Affiliation(s)
- Cláudia Santos Silva
- Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal; Faculdade de Medicina-Instituto de Medicina Molecular, Centro de Estudos Egas Moniz, Universidade de Lisboa, Lisbon, Portugal.
| | | | - Bárbara Martins
- Department of Neurology, Unidade Local de Saúde de São João, Porto, Portugal; Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Ana Cláudia Fonseca
- Department of Ophthalmology, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal
| | - Pedro Coelho
- Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal
| | - Rafael Roque
- Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal
| | - Fábio Cota de Medeiros
- Department of Infectious Diseases, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal; Institute of Microbiology, Institute of Environmental Health, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Miguel Oliveira Santos
- Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal; Faculdade de Medicina-Instituto de Medicina Molecular, Centro de Estudos Egas Moniz, Universidade de Lisboa, Lisbon, Portugal
| | - Mamede de Carvalho
- Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal; Faculdade de Medicina-Instituto de Medicina Molecular, Centro de Estudos Egas Moniz, Universidade de Lisboa, Lisbon, Portugal
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Pascual-Morena C, Cavero-Redondo I, Saz-Lara A, Martínez-García I, Visier-Alfonso ME, Martínez-Vizcaíno V. Intellectual Profile in Myotonic Dystrophy Type 1 and Its Association With Its Onset: A Systematic Review and Meta-Analysis. Pediatr Neurol 2024; 161:9-17. [PMID: 39232462 DOI: 10.1016/j.pediatrneurol.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/14/2024] [Accepted: 08/03/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND Myotonic dystrophy type 1 (DM1) is caused by mutations in the DMPK gene, and it is associated with cognitive deficits and intelligence below normative values. The objective of this systematic review and meta-analysis was to estimate the overall intelligence and proportion of intellectual development disorder (IDD) in the population with DM1 and its association with its onset. METHODS Systematic searches of Medline, Scopus, Web of Science, and Cochrane Library were performed from inception to January 2023. Studies that determined the full intelligence quotient (FIQ) or the IDD proportion in populations with DM1 were included. Meta-analyses of the FIQ and IDD and the FIQ mean difference and IDD prevalence ratios (PRs) by disease onset, inheritance, and genotype were conducted. RESULTS Forty-five studies were included in the meta-analyses, and all were performed in the DM1 population. The FIQ and IDD in DM1 were 77.90 (71.98, 83.81) and 0.44 (0.27, 0.60), respectively. Furthermore, DM1 onset was negatively associated with intelligence. Thus, the comparison "Congenital versus Adult" onsets resulted in an intelligence quotient of -41.61 (-47.81, -35.40) points and a PR of IDD of 9.49 (3.23, 27.89). Finally, maternal inheritance was also negatively associated, but the genotype did not have a statistically significant association. CONCLUSIONS The alterations in intelligence in DM1 are highly associated with the onset of the disease. However, the genotype did not explain these alterations well and there may be other genetic or epigenetic factors that should be considered.
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Affiliation(s)
- Carlos Pascual-Morena
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain; Faculty of Nursing, Universidad de Castilla-La Mancha, Albacete, Spain
| | - Iván Cavero-Redondo
- CarVasCare Research Group (2023-GRIN-34459), Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain; Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile.
| | - Alicia Saz-Lara
- CarVasCare Research Group (2023-GRIN-34459), Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain
| | - Irene Martínez-García
- CarVasCare Research Group (2023-GRIN-34459), Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain
| | | | - Vicente Martínez-Vizcaíno
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain; Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
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3
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Dewald Z, Adesanya O, Bae H, Gupta A, Derham JM, Chembazhi UV, Kalsotra A. Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy. Nat Commun 2024; 15:9062. [PMID: 39433769 PMCID: PMC11494077 DOI: 10.1038/s41467-024-53378-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 10/10/2024] [Indexed: 10/23/2024] Open
Abstract
Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.
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Affiliation(s)
- Zachary Dewald
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | | | - Haneui Bae
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Andrew Gupta
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Jessica M Derham
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Ullas V Chembazhi
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA
| | - Auinash Kalsotra
- Department of Biochemistry, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
- Cancer Center@Illinois, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
- Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
- Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
- Chan Zuckerburg Biohub, Chicago, IL, USA.
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Pascual-Morena C, Martínez-Vizcaíno V, Cavero-Redondo I, Álvarez-Bueno C, Lucerón-Lucas-Torres M, Saz-Lara A, Martínez-García I. A meta-analysis of the prevalence of neuropsychiatric disorders and their association with disease onset in myotonic dystrophy. Acta Neuropsychiatr 2024:1-12. [PMID: 39376198 DOI: 10.1017/neu.2024.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/09/2024]
Abstract
There is a high prevalence of neuropsychiatric disorders in myotonic dystrophy types 1 and 2 (DM1 and DM2), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in DM1, and depression and anxiety in both DMs. The aim of this systematic review and meta-analysis was to estimate the prevalence of ASD, ADHD, depression and anxiety in the population with DM, and their association with disease onset. A systematic search of Medline, Scopus, Web of Science, and the Cochrane Library was conducted from inception to November 2023. Observational studies estimating the prevalence of these disorders in DM1 or DM2 were included. A meta-analysis of the prevalence of these disorders and an association study with disease onset by prevalence ratio meta-analysis were performed. Thirty-eight studies were included. In DM1, the prevalence of ASD was 14%, with congenital onset being 79% more common than juvenile onset, while the prevalence of ADHD was 21%, with no difference between congenital and juvenile onset, and the prevalence of depression and anxiety were 14% and 16%. Depression was more common in the adult onset. Finally, the prevalence of depression in DM2 was 16%. A higher prevalence of neuropsychiatric disorders is observed in individuals with DM1 and DM2 than in the general population. Therefore, actively screening for congenital and juvenile neurodevelopmental disorders in DM1 and emotional disorders in DM1 and DM2 may improve the quality of life of those affected.
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Affiliation(s)
- Carlos Pascual-Morena
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain
- Facultad de Enfermería de Albacete, Universidad de Castilla-La Mancha, Albacete, Spain
| | - Vicente Martínez-Vizcaíno
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Iván Cavero-Redondo
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
- CarVasCare Research Group, Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain
| | - Celia Álvarez-Bueno
- Health and Social Research Center, Universidad de Castilla-La Mancha, Cuenca, Spain
- Universidad Politécnica y Artística del Paraguay, Asunción, Paraguay
| | | | - Alicia Saz-Lara
- CarVasCare Research Group, Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain
| | - Irene Martínez-García
- CarVasCare Research Group, Facultad de Enfermería de Cuenca, Universidad de Castilla-La Mancha, Cuenca, Spain
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5
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Yang Y, Wang Y, Yan Z, Li Z, Guo P. Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2. FEBS Lett 2024; 598:2544-2556. [PMID: 38922834 DOI: 10.1002/1873-3468.14952] [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: 02/25/2024] [Revised: 05/03/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024]
Abstract
Myotonic dystrophy type 2 (DM2) is a neurogenerative disease caused by caprylic/capric triglyceride (CCTG) tetranucleotide repeat expansions in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene. Non-B DNA structures formed by CCTG repeats can promote genetic instability, whereas interrupting motifs of NCTG (N = A/T/G) within CCTG repeats help to maintain genomic stability. However, whether the interrupting motifs can affect DNA structures of CCTG repeats remains unclear. Here, we report that four CCTG repeats with an interrupting 3'-A/T/G residue formed dumbbell structures, whereas a non-interrupting 3'-C residue resulted in a multi-loop structure exhibiting conformational dynamics that may contribute to a higher tendency of escaping from DNA mismatch repair and causing repeat expansions. The results provide new structural insights into the genetic instability of CCTG repeats in DM2.
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Affiliation(s)
- Yingquan Yang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences, China
| | - Yang Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences, China
- School of Materials Science and Engineering, Tianjin University, China
| | - Zhenzhen Yan
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences, China
| | - Zhigang Li
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Pei Guo
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences, China
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6
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Moshirfar M, Brown AH, Manion GN, Moin KA, Hoopes PC. Recurrent Posterior Capsular Opacification in Adults: A Case Report and an Overview of Literature. Int Med Case Rep J 2024; 17:683-693. [PMID: 39071183 PMCID: PMC11283270 DOI: 10.2147/imcrj.s476559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024] Open
Abstract
Posterior capsular opacification (PCO), also known as "secondary cataract", is a common complication following cataract surgery that can significantly impair visual acuity. The incidence of PCO varies widely in the literature, influenced by intraocular lens (IOL) type and patient risk factors. Neodymium-doped yttrium-aluminum-garnet (YAG) laser posterior capsulotomy is the standard treatment for PCO-related visual impairment. Recurrence of PCO after initial treatment with YAG capsulotomy, though more common in children, is rare in adults. Its underlying pathophysiological mechanisms are similar to that of primary PCO, which includes proliferation, migration, and/or clustering of lens epithelial cells (LECs), with subsequent reclosure of the posterior aperture. Potential risk factors for PCO recurrence that have been speculated through a comprehensive search of the current literature include younger age, female sex, high myopia, diabetes, vitrectomized status, uveitis, low-diopter IOLs, and certain IOL types with higher water content. We present a case of recurrent PCO in a highly myopic 48-year-old male following cataract surgery and implantable collamer lens (ICL) explantation who received a hydrophobic acrylic lens with 4% water content. Surgical techniques that may reduce recurrent PCO occurrence and appropriate postoperative care are emphasized to assist surgeons in their approach to patients at high-risk for this complication.
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Affiliation(s)
- Majid Moshirfar
- Hoopes Vision Research Center, Hoopes Vision, Draper, UT, USA
- John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT, USA
- Utah Lions Eye Bank, Murray, UT, USA
| | - Alex H Brown
- Department of Ophthalmology, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, USA
| | - Garrett N Manion
- Department of Ophthalmology, Creighton University School of Medicine, Omaha, NE, USA
| | - Kayvon A Moin
- Hoopes Vision Research Center, Hoopes Vision, Draper, UT, USA
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7
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Cobbs LV, Soares RR, Spirn M, Mehta S. PREMATURE EMULSIFICATION OF SILICONE OIL AFTER RETINAL DETACHMENT REPAIR IN THE SETTING OF HIGH-INTENSITY EXERCISE. Retin Cases Brief Rep 2024; 18:486-487. [PMID: 36913668 DOI: 10.1097/icb.0000000000001412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
PURPOSE To describe a rare case of silicone oil emulsification that occurred only three months postoperatively. We discuss the implications for postoperative counseling. METHODS Retrospective chart review of a single patient. RESULTS Thirty-nine-year-old woman who presented with a right eye macula-on retinal detachment that was repaired with scleral buckle, vitrectomy, and silicone oil tamponade. Her course was complicated by extensive silicone oil emulsification within 3 months postoperatively, most likely because of shear forces induced by her daily CrossFit exercise regimen. CONCLUSION Typical postoperative precautions after a retinal detachment repair include no heavy lifting or strenuous activity for one week. These restrictions may need to be more stringent and long-term for patients with silicone oil to prevent early emulsification.
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Affiliation(s)
- Lucy V Cobbs
- Retina Service, Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, Pennsylvania
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8
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Nashabat M, Nabavizadeh N, Saraçoğlu HP, Sarıbaş B, Avcı Ş, Börklü E, Beillard E, Yılmaz E, Uygur SE, Kayhan CK, Bosco L, Eren ZB, Steindl K, Richter MF, Bademci G, Rauch A, Fattahi Z, Valentino ML, Connolly AM, Bahr A, Viola L, Bergmann AK, Rocha ME, Peart L, Castro-Rojas DL, Bültmann E, Khan S, Giarrana ML, Teleanu RI, Gonzalez JM, Pini A, Schädlich IS, Vill K, Brugger M, Zuchner S, Pinto A, Donkervoort S, Bivona SA, Riza A, Streata I, Gläser D, Baquero-Montoya C, Garcia-Restrepo N, Kotzaeridou U, Brunet T, Epure DA, Bertoli-Avella A, Kariminejad A, Tekin M, von Hardenberg S, Bönnemann CG, Stettner GM, Zanni G, Kayserili H, Oflazer ZP, Escande-Beillard N. SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation. Nat Commun 2024; 15:1758. [PMID: 38413582 PMCID: PMC10899626 DOI: 10.1038/s41467-024-45933-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 02/08/2024] [Indexed: 02/29/2024] Open
Abstract
SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.
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Affiliation(s)
- Marwan Nashabat
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Nasrinsadat Nabavizadeh
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Hilal Pırıl Saraçoğlu
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Burak Sarıbaş
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Şahin Avcı
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital, Istanbul, Turkey
| | - Esra Börklü
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital, Istanbul, Turkey
| | | | - Elanur Yılmaz
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Seyide Ecesu Uygur
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Cavit Kerem Kayhan
- Pathology Laboratory, Acıbadem Maslak Hospital, Istanbul, Turkey
- Department of Biotechnology, Nişantaşı University, Istanbul, Turkey
| | - Luca Bosco
- Unit of Muscular and Neurodegenerative Disorders and Developmental Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Science, University "Roma Tre", Rome, Italy
| | - Zeynep Bengi Eren
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey
| | - Katharina Steindl
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
| | | | - Guney Bademci
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anita Rauch
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
- Research Priority Program (URPP) ITINERARE: Innovative Therapies in Rare Diseases, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Zohreh Fattahi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
- Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran
| | - Maria Lucia Valentino
- IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Anne M Connolly
- Division of Neurology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Angela Bahr
- Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
| | - Laura Viola
- Unit of Clinical Pediatrics, State Hospital, San Marino Republic, Italy
| | | | | | - LeShon Peart
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Derly Liseth Castro-Rojas
- Genomics Laboratory, Center of Immunology and Genetics (CIGE), SURA Ayudas Diagnosticas, Medellín, Colombia
| | - Eva Bültmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
| | | | | | - Raluca Ioana Teleanu
- Dr Victor Gomoiu Children's Hospital, Bucharest, Romania
- Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Joanna Michelle Gonzalez
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Antonella Pini
- Neuromuscular Pediatric Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - Ines Sophie Schädlich
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany
| | - Katharina Vill
- Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU Hospital, Ludwig-Maximilians-University, Munich, Germany
- Department of Human Genetics, Technical University of Munich, School of Medicine, Munich, Germany
| | - Melanie Brugger
- Department of Human Genetics, Technical University of Munich, School of Medicine, Munich, Germany
| | - Stephan Zuchner
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
- John P. Hussmann Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Stephanie Ann Bivona
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anca Riza
- Human Genomics Laboratory, University of Medicine and Pharmacy, Craiova, Romania
- Regional Centre of Medical Genetics Dolj, County Clinical Emergency Hospital, Craiova, Romania
| | - Ioana Streata
- Human Genomics Laboratory, University of Medicine and Pharmacy, Craiova, Romania
- Regional Centre of Medical Genetics Dolj, County Clinical Emergency Hospital, Craiova, Romania
| | | | | | | | - Urania Kotzaeridou
- Division of Child Neurology and Inherited Metabolic Diseases, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Theresa Brunet
- Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU Hospital, Ludwig-Maximilians-University, Munich, Germany
- Department of Human Genetics, Technical University of Munich, School of Medicine, Munich, Germany
| | | | | | | | - Mustafa Tekin
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA
- John P. Hussmann Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Carsten G Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Georg M Stettner
- Neuromuscular Center Zurich and Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ginevra Zanni
- Unit of Muscular and Neurodegenerative Disorders and Developmental Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Hülya Kayserili
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital, Istanbul, Turkey
- Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey
| | - Zehra Piraye Oflazer
- Department of Neurology, Koç University Hospital Muscle Center, Istanbul, Turkey
| | - Nathalie Escande-Beillard
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul, Turkey.
- Research Center for Translational Medicine (KUTTAM), Koç University School of Medicine (KUSoM), Istanbul, Turkey.
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Bachurin SS, Yurushkin MV, Slynko IA, Kletskii ME, Burov ON, Berezovskiy DP. Structural peculiarities of tandem repeats and their clinical significance. Biochem Biophys Res Commun 2024; 692:149349. [PMID: 38056160 DOI: 10.1016/j.bbrc.2023.149349] [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: 11/19/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023]
Abstract
While it is well established that a mere 2% of human DNA nucleotides are involved in protein coding, the remainder of the DNA plays a vital role in the preservation of normal cellular genetic function. A significant proportion of tandem repeats (TRs) are present in non-coding DNA. TRs - specific sequences of nucleotides that entail numerous repetitions of a given fragment. In this study, we employed our novel algorithm grounded in finite automata theory, which we refer to as Dafna, to investigate for the first time the likelihood of these nucleotide sequences forming non-canonical DNA structures (NS). Such structures include G-quadruplexes, i-motifs, hairpins, and triplexes. The tandem repeats under consideration in our research encompassed sequences containing 1 to 6 nucleotides per repeated fragment. For comparison, we employed a set of randomly generated sequences of the same length (60 nucleotides) as a benchmark. The outcomes of our research exposed a disparity between the potential for NS formation in random sequences and tandem repeats. Our findings affirm that the propensity of DNA and RNA to form NS is closely tied to various genetic disorders, including Huntington's disease, Fragile X syndrome, and Friedreich's ataxia. In the concluding discussion, we present a proposal for a new therapeutic mechanism to address these diseases. This novel approach revolves around the ability of specific nucleic acid fragments to form multiple types of NS.
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Affiliation(s)
- Stanislav S Bachurin
- Department of General and Clinical Biochemistry N2, Rostov State Medical University, 29 Nakhichevanskiy Lane, Rostov-on-Don, 344022, Russian Federation; LambasLab, Bar Rav Hai David 30, Haifa, 3559203, Israel.
| | | | - Ilya A Slynko
- LambasLab, Bar Rav Hai David 30, Haifa, 3559203, Israel
| | - Mikhail E Kletskii
- Department of Chemistry, Southern Federal University, 7 Zorge Str., Rostov-on-Don, 344090, Russian Federation
| | - Oleg N Burov
- Department of Chemistry, Southern Federal University, 7 Zorge Str., Rostov-on-Don, 344090, Russian Federation
| | - Dmitriy P Berezovskiy
- Department of Forensic Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), Build. 4, 2 Bolshaya Pirogovskaya Str., Moscow, 119435, Russian Federation
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10
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Chen AY, Owens MC, Liu KF. Coordination of RNA modifications in the brain and beyond. Mol Psychiatry 2023; 28:2737-2749. [PMID: 37138184 PMCID: PMC11758487 DOI: 10.1038/s41380-023-02083-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 05/05/2023]
Abstract
Gene expression regulation is a critical process throughout the body, especially in the nervous system. One mechanism by which biological systems regulate gene expression is via enzyme-mediated RNA modifications, also known as epitranscriptomic regulation. RNA modifications, which have been found on nearly all RNA species across all domains of life, are chemically diverse covalent modifications of RNA nucleotides and represent a robust and rapid mechanism for the regulation of gene expression. Although numerous studies have been conducted regarding the impact that single modifications in single RNA molecules have on gene expression, emerging evidence highlights potential crosstalk between and coordination of modifications across RNA species. These potential coordination axes of RNA modifications have emerged as a new direction in the field of epitranscriptomic research. In this review, we will highlight several examples of gene regulation via RNA modification in the nervous system, followed by a summary of the current state of the field of RNA modification coordination axes. In doing so, we aim to inspire the field to gain a deeper understanding of the roles of RNA modifications and coordination of these modifications in the nervous system.
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Affiliation(s)
- Anthony Yulin Chen
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA, 19081, USA
| | - Michael C Owens
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kathy Fange Liu
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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11
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Cheminelle M, Nougues MC, Isapof A, Aubertin G, Corvol H, Beydon N, Taytard J. Respiratory function and sleep in children with myotonic dystrophy type 1. Neuromuscul Disord 2023; 33:263-269. [PMID: 36780729 DOI: 10.1016/j.nmd.2023.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 12/29/2022] [Accepted: 01/27/2023] [Indexed: 01/30/2023]
Abstract
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease in children causing sleep and respiratory disorders that are poorly described in the literature compared to adult forms. This retrospective observational study was performed at the Armand Trousseau University Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France. We retrospectively collected data from lung function tests, nocturnal gas exchange recordings, and polysomnography of 24 children with DM1. 39% of the children with DM1 reported respiratory symptoms indicative of sleep disordered breathing. Three patients (12%) presented with a restrictive respiratory pattern, 10 (42%) with a sleep apnoea syndrome, mainly of obstructive origin (2/10 with severe obstructive sleep apnea syndrome), and 11 (45%) with nocturnal alveolar hypoventilation. Non-invasive ventilation (NIV) was indicated in 9 (37.5%) children, although tolerance was poor. No significant deterioration in respiratory function or nocturnal gas exchange was observed during the NIV-free period. This study provides new and useful insights into DM1 disease evolution in children to better adapt for respiratory follow-up and management. This highlights the need for future research to better understand the origin of respiratory and sleep disorders in patients with DM1.
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Affiliation(s)
- Marie Cheminelle
- Pediatric Pulmonology Department, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France
| | - Marie-Christine Nougues
- Pediatric Neurology Department, Reference Centre for Neuromuscular Diseases, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France
| | - Arnaud Isapof
- Pediatric Neurology Department, Reference Centre for Neuromuscular Diseases, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France
| | - Guillaume Aubertin
- Pediatric Pulmonology Department, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France; Sorbonne University, Centre de Recherche Saint-Antoine (CRSA), Inserm UMR_S938, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Harriet Corvol
- Pediatric Pulmonology Department, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France; Sorbonne University, Centre de Recherche Saint-Antoine (CRSA), Inserm UMR_S938, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Nicole Beydon
- Sorbonne University, Centre de Recherche Saint-Antoine (CRSA), Inserm UMR_S938, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France; Functional Unit of Respiratory and Sleep Physiology and Functional Explorations Armand Trousseau Hospital, AP-HP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France
| | - Jessica Taytard
- Pediatric Pulmonology Department, Armand Trousseau Hospital, APHP, Sorbonne University, 26, avenue du Docteur Arnold Netter, 75012 Paris, France; Sorbonne University, Inserm UMR_S1158, Experimental and clinical respiratory neurophysiology, 47-83 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
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12
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Andronie-Cioară FL, Jurcău A, Jurcău MC, Nistor-Cseppentö DC, Simion A. Cholesterol Management in Neurology: Time for Revised Strategies? J Pers Med 2022; 12:jpm12121981. [PMID: 36556202 PMCID: PMC9784893 DOI: 10.3390/jpm12121981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/18/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022] Open
Abstract
Statin therapy has been extensively evaluated and shown to reduce the incidence of new or recurrent vascular events, ischemic stroke included. As a consequence, each published guideline pushes for lower low-density cholesterol levels in the population at large, recommending increased statin doses and/or adding new cholesterol-lowering molecules. Neurologists find it sometimes difficult to apply these guidelines, having to confront situations such as (1) ischemic strokes, mainly cardioembolic ones, in patients with already low LDL-cholesterol levels; (2) myasthenic patients, whose lifespan has been extended by available treatment, and whose age and cholesterol levels put them at risk for ischemic stroke; (3) patients with myotonic dystrophy, whose disease often associates diabetes mellitus and heart conduction defects, and in whom blood cholesterol management is also not settled. As such, further trials are needed to address these issues.
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Affiliation(s)
- Felicia Liana Andronie-Cioară
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Anamaria Jurcău
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
| | - Maria Carolina Jurcău
- Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
- Correspondence: (M.C.J.); (D.C.N.-C.); Tel.: +40-744-600-833 (M.C.J.)
| | - Delia Carmen Nistor-Cseppentö
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
- Correspondence: (M.C.J.); (D.C.N.-C.); Tel.: +40-744-600-833 (M.C.J.)
| | - Aurel Simion
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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13
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Xu TT, Baratz KH, Fautsch MP, Hodge DO, Mahr MA. Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy. Cornea 2022; 41:1088-1093. [PMID: 35588167 PMCID: PMC9120714 DOI: 10.1097/ico.0000000000002864] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/15/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE The purpose of this study is to quantify cancer risk in patients with Fuchs endothelial corneal dystrophy (FECD). METHODS Using the 2014 to 2016 Medicare Limited 5% Data Sets-Carrier Line File, US Medicare fee-for-service beneficiaries (aged 65 years or older) with FECD and cancer were identified through International Classification of Diseases , ninth and 10th Revision diagnostic codes from January 1, 2014, to December 31, 2016. The main outcome measures were odds ratios (ORs) of cancer at various anatomic locations in patients with versus without FECD. RESULTS Of the 1,462,740 Medicare beneficiaries, 15,534 patients (1.1%) had an International Classification of Disease code for FECD. Compared with US Medicare beneficiaries without FECD, patients with FECD were at increased risk for the following malignancies: breast [OR: 1.32; 95% confidence interval (CI): 1.22-1.43; P < 0.001], cutaneous basal cell (OR: 1.42; 95% CI: 1.35-1.49; P < 0.001), cutaneous melanoma (OR: 1.20; 95% CI: 1.03-1.40; P = 0.02), cutaneous squamous cell (OR: 1.45; 95% CI: 1.38-1.53; P < 0.001), ovarian (OR: 1.84; 95% CI: 1.48-2.30; P < 0.001), and thyroid (OR: 1.32; 95% CI: 1.04-1.68; P = 0.02). By contrast, FECD cases were at lower odds of having lung (OR: 0.81; 95% CI: 0.71-0.93; P = 0.003) and prostate cancer diagnoses (OR: 0.88; 95% CI: 0.81-0.96; P = 0.002). CONCLUSIONS Patients with FECD aged 65 years or older may be at increased risk for cancer at several anatomic locations. Follow-up studies are needed to further explore the association of FECD and malignancy, elucidate potential disease mechanisms, and identify genetic and/or environmental risk factors.
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Affiliation(s)
- Timothy T. Xu
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
| | - Keith H. Baratz
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - David O. Hodge
- Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, USA
| | - Michael A. Mahr
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA
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14
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Pharmacotherapy alleviates pathological changes in human direct reprogrammed neuronal cell model of myotonic dystrophy type 1. PLoS One 2022; 17:e0269683. [PMID: 35776705 PMCID: PMC9249217 DOI: 10.1371/journal.pone.0269683] [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: 11/17/2021] [Accepted: 05/25/2022] [Indexed: 12/02/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat disorder affecting multiple organs. However, most of the research is focused on studying and treating its muscular symptoms. On the other hand, despite the significant impact of the neurological symptoms on patients’ quality of life, no drug therapy was studied due to insufficient reproducibility in DM1 brain-specific animal models. To establish DM1 neuronal model, human skin fibroblasts were directly converted into neurons by using lentivirus expressing small hairpin RNA (shRNA) against poly-pyrimidine tract binding protein (PTBP). We found faster degeneration in DM1 human induced neurons (DM1 hiNeurons) compared to control human induced neurons (ctrl hiNeurons), represented by lower viability from 10 days post viral-infection (DPI) and abnormal axonal growth at 15 DPI. Nuclear RNA foci were present in most of DM1 hiNeurons at 10 DPI. Furthermore, DM1 hiNeurons modelled aberrant splicing of MBNL1 and 2, MAPT, CSNK1D and MPRIP at 10 DPI. We tested two drugs that were shown to be effective for DM1 in non-neuronal model and found that treatment of DM1 hiNeurons with 100 nM or 200 nM actinomycin D (ACT) for 24 h resulted in more than 50% reduction in the number of RNA foci per nucleus in a dose dependent manner, with 16.5% reduction in the number of nuclei containing RNA foci at 200 nM and treatment with erythromycin at 35 μM or 65 μM for 48 h rescued mis-splicing of MBNL1 exon 5 and MBNL 2 exons 5 and 8 up to 17.5%, 10% and 8.5%, respectively. Moreover, erythromycin rescued the aberrant splicing of MAPT exon 2, CSNK1D exon 9 and MPRIP exon 9 to a maximum of 46.4%, 30.7% and 19.9%, respectively. These results prove that our model is a promising tool for detailed pathogenetic examination and novel drug screening for the nervous system.
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15
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Kakouri AC, Koutalianos D, Koutsoulidou A, Oulas A, Tomazou M, Nikolenko N, Turner C, Roos A, Lusakowska A, Janiszewska K, Papadimas GK, Papadopoulos C, Kararizou E, Papanicolaou EZ, Gorman G, Lochmüller H, Spyrou GM, Phylactou LA. Circulating small RNA signatures differentiate accurately the subtypes of muscular dystrophies: small-RNA next-generation sequencing analytics and functional insights. RNA Biol 2022; 19:507-518. [PMID: 35388741 PMCID: PMC8993092 DOI: 10.1080/15476286.2022.2058817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders.
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Affiliation(s)
- Andrea C Kakouri
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Demetris Koutalianos
- Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Anastasis Oulas
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Tomazou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.,Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Nikoletta Nikolenko
- National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, UK
| | - Chris Turner
- National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, UK
| | - Andreas Roos
- Department of Neuropediatrics, University Hospital Essen, Duisburg-Essen University, Germany.,Division of Neurology, Department of Medicine, Childrens Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Anna Lusakowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | - George K Papadimas
- Department of Neurology, Eginitio hospital, Medical School of Athens, Athens, Greece
| | | | - Evangelia Kararizou
- Department of Neurology, Eginitio hospital, Medical School of Athens, Athens, Greece
| | | | - Grainne Gorman
- Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, University of Newcastle, Newcastle, UK
| | - Hanns Lochmüller
- Division of Neurology, Department of Medicine, Childrens Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.,Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.,Centro Nacional de AnálisisGenómico, Center for Genomic Regulation (CNAG-CRG), Barcelona Institute of Science and Technology (Bist), Barcelona, Spain
| | - George M Spyrou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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16
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Karagiannis D, Kontomichos L, Tzimis V, Parikakis E, Batsos G, Karampelas M. Progressive External Ophthalmoplegia Diagnosed in the Glaucoma Clinic: The Importance of a Complete Clinical Examination. CLINICAL OPTOMETRY 2021; 13:335-339. [PMID: 34992483 PMCID: PMC8714969 DOI: 10.2147/opto.s342972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 12/14/2021] [Indexed: 06/14/2023]
Abstract
PURPOSE To present a case of chronic progressive external ophthalmoplegia (CPEO) diagnosis in the setting of a busy glaucoma clinic. MATERIALS AND METHODS Case report. RESULTS A 70-year-old-female presented to our glaucoma clinic concerned on her glaucoma status. She was previously followed-up elsewhere. Her past ophthalmic history included a diagnosis of normal tension glaucoma 10 years earlier for which she was on topical anti-glaucoma medication. On inspection, symmetrical ptosis was noted and when she was asked about her family history, she reported that 4 members of her family had "problems with moving their eyes" as she also had from a young age. Her best corrected visual acuity was 20/100 in her right eye (RE) and 20/80 in her left eye (LE). Optic discs had normal margins with peripapillary atrophy and cup/disc ratio was 0.7 RE and 0.8 LE. Intraocular pressure was 10mmHg bilaterally. Ocular motility examination revealed severe restriction in all directions of gaze. She had mild alternating exotropia but she did not report any diplopia. Based on her family history, bilateral ptosis, ophthalmoplegia and reported symptoms, the diagnosis of CPEO was made. CONCLUSION In the setting of a busy subspecialty clinic, it is common for clinicians to focus on a specific pathology and overlook additional signs and symptoms that represent a second often unrelated condition. Our case highlights the importance of a thorough assessment including history taking (general, ophthalmic and family), good documentation of symptoms and an adequate clinical examination.
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Affiliation(s)
- Dimitrios Karagiannis
- Second Department of Ophthalmology, Ophthalmiatreio Eye Hospital of Athens, Athens, Greece
| | - Loukas Kontomichos
- Second Department of Ophthalmology, Ophthalmiatreio Eye Hospital of Athens, Athens, Greece
| | - Vasileios Tzimis
- Second Department of Ophthalmology, Ophthalmiatreio Eye Hospital of Athens, Athens, Greece
| | - Efstratios Parikakis
- Second Department of Ophthalmology, Ophthalmiatreio Eye Hospital of Athens, Athens, Greece
| | - Georgios Batsos
- Second Department of Ophthalmology, Ophthalmiatreio Eye Hospital of Athens, Athens, Greece
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17
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Koutalianos D, Koutsoulidou A, Mytidou C, Kakouri AC, Oulas A, Tomazou M, Kyriakides TC, Prokopi M, Kapnisis K, Nikolenko N, Turner C, Lusakowska A, Janiszewska K, Papadimas GK, Papadopoulos C, Kararizou E, Spyrou GM, Gourdon G, Zamba Papanicolaou E, Gorman G, Anayiotos A, Lochmüller H, Phylactou LA. miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1. Mol Ther Methods Clin Dev 2021; 23:169-183. [PMID: 34703840 PMCID: PMC8517008 DOI: 10.1016/j.omtm.2021.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022]
Abstract
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, primarily characterized by muscle wasting and weakness. Many biomarkers already exist in the rapidly developing biomarker research field that aim to improve patients' care. Limited work, however, has been performed on rare diseases, including DM1. We have previously shown that specific microRNAs (miRNAs) can be used as potential biomarkers for DM1 progression. In this report, we aimed to identify novel serum-based biomarkers for DM1 through high-throughput next-generation sequencing. A number of miRNAs were identified that are able to distinguish DM1 patients from healthy individuals. Two miRNAs were selected, and their association with the disease was validated in a larger panel of patients. Further investigation of miR-223-3p, miR-24-3p, and the four previously identified miRNAs, miR-1-3p, miR-133a-3p, miR-133b-3p, and miR-206-3p, showed elevated levels in a DM1 mouse model for all six miRNAs circulating in the serum compared to healthy controls. Importantly, the levels of miR-223-3p, but not the other five miRNAs, were found to be significantly downregulated in five skeletal muscles and heart tissues of DM1 mice compared to controls. This result provides significant evidence for its involvement in disease manifestation.
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Affiliation(s)
- Demetris Koutalianos
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Andrie Koutsoulidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Chrystalla Mytidou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Andrea C. Kakouri
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Anastasis Oulas
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Marios Tomazou
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Tassos C. Kyriakides
- Yale Center for Analytical Sciences, Yale School of Public Health, 300 George Street, Suite 555, New Haven, CT 06520, USA
| | - Marianna Prokopi
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, 45 Kitiou Kyprianou Str., 3041 Limassol, Cyprus
- Theramir Ltd, 13 Georgiou Karaiskaki Str., 3032 Limassol, Cyprus
| | - Konstantinos Kapnisis
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, 45 Kitiou Kyprianou Str., 3041 Limassol, Cyprus
| | - Nikoletta Nikolenko
- National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, UK
| | - Chris Turner
- National Hospital for Neurology and Neurosurgery, Queen Square, University College London Hospitals NHS Foundation Trust, London, UK
| | - Anna Lusakowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Katarzyna Janiszewska
- Department of Neurology, Central Hospital of Medical University of Warsaw, Warsaw, Poland
| | - George K. Papadimas
- Department of Neurology, Eginitio Hospital, Medical School of Athens, 74 Vasilissis Sofias, 11528 Athens, Greece
| | - Constantinos Papadopoulos
- Department of Neurology, Eginitio Hospital, Medical School of Athens, 74 Vasilissis Sofias, 11528 Athens, Greece
| | - Evangelia Kararizou
- Department of Neurology, Eginitio Hospital, Medical School of Athens, 74 Vasilissis Sofias, 11528 Athens, Greece
| | - George M. Spyrou
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Geneviève Gourdon
- Inserm, Sorbonne University, Institute of Myology, Center of Research in Myology, Paris, France
| | - Eleni Zamba Papanicolaou
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- Neurology Clinic D, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
| | - Grainne Gorman
- Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, University of Newcastle, Newcastle, UK
| | - Andreas Anayiotos
- Department of Mechanical Engineering and Materials Science and Engineering, Cyprus University of Technology, 45 Kitiou Kyprianou Str., 3041 Limassol, Cyprus
| | - Hanns Lochmüller
- Department of Neuropediatrics and Muscle Disorders, Medical Centre–University of Freiburg, Faculty of Medicine, Freiburg, Germany
- Children’s Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
| | - Leonidas A. Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
- The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371 Ayios Dometios, Nicosia, Cyprus, PO Box 23462, 1683 Nicosia, Cyprus
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18
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Vezina-Dawod S, Angelbello AJ, Choudhary S, Wang KW, Yildirim I, Disney MD. Massively Parallel Optimization of the Linker Domain in Small Molecule Dimers Targeting a Toxic r(CUG) Repeat Expansion. ACS Med Chem Lett 2021; 12:907-914. [PMID: 34141068 PMCID: PMC8201483 DOI: 10.1021/acsmedchemlett.1c00027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 02/23/2021] [Indexed: 12/30/2022] Open
Abstract
RNA contributes to disease pathobiology and is an important therapeutic target. The downstream biology of disease-causing RNAs can be short-circuited with small molecules that recognize structured regions. The discovery and optimization of small molecules interacting with RNA is, however, challenging. Herein, we demonstrate a massively parallel one-bead-one-compound methodology, employed to optimize the linker region of a dimeric compound that binds the toxic r(CUG) repeat expansion [r(CUG)exp] causative of myotonic dystrophy type 1 (DM1). Indeed, affinity selection on a 331,776-member library allowed the discovery of a compound with enhanced potency both in vitro (10-fold) and in DM1-patient-derived myotubes (5-fold). Molecular dynamics simulations revealed additional interactions between the optimized linker and the RNA, resulting in ca. 10 kcal/mol lower binding free energy. The compound was conjugated to a cleavage module, which directly cleaved the transcript harboring the r(CUG)exp and alleviated disease-associated defects.
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Affiliation(s)
- Simon Vezina-Dawod
- Department
of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Alicia J. Angelbello
- Department
of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Shruti Choudhary
- Department
of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
| | - Kye Won Wang
- Department
of Chemistry, Florida Atlantic University, Jupiter, Florida 33458, United States
| | - Ilyas Yildirim
- Department
of Chemistry, Florida Atlantic University, Jupiter, Florida 33458, United States
| | - Matthew D. Disney
- Department
of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
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19
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Hama M, Horie R, Kubota T, Matsumura T, Kimura E, Nakamura H, Takahashi MP, Takada H. Metabolic complications in myotonic dystrophy type 1: A cross-sectional survey using the National Registry of Japan. J Neurol Sci 2021; 427:117511. [PMID: 34082146 DOI: 10.1016/j.jns.2021.117511] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/15/2021] [Accepted: 05/25/2021] [Indexed: 01/30/2023]
Abstract
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting multiple organs, including the eyes, heart, endocrine system, and central nervous system. The broad spectrum of DM1 symptoms has been attributed to the aberrant pre-mRNA splicing of various genes due to an abnormal expansion of the CTG repeat in the 3' untranslated region of the DMPK gene. The current challenge in the clinical care of DM1 is the lack of well-established protocols for the management of each organ disorder or symptom. Moreover, the current status of clinical management has not been adequately explored. Metabolic disturbance in DM1 has been less explored among the DM1 manifestations, even though impaired glucose tolerance is a widely known metabolic disorder associated with DM1. We investigated the metabolic disturbance related to DM1 using the national registry of neuromuscular diseases in Japan, Registry of Muscular Dystrophy (Remudy), and assessed the metabolic complications in DM1 and the current treatments. We obtained comprehensive information on the current status of liver dysfunction and dyslipidemia in a sizeable DM1 cohort (~300). We confirmed that the incidence of liver dysfunction and dyslipidemia, particularly hypertriglyceridemia, as well as impaired glucose tolerance, were significantly higher in DM1 patients. Furthermore, the majority of DM1 patients with dyslipidemia were not receiving pharmacotherapy. Our data highlight the current status of DM1 patients in Japan, which can guide the establishment of the standard of care for metabolic issues consequent to DM1.
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Affiliation(s)
- Manami Hama
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Riho Horie
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Tomoya Kubota
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Tsuyoshi Matsumura
- Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center Toneyama, Toyonaka, Osaka 560-8552, Japan
| | - En Kimura
- Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan
| | - Harumasa Nakamura
- Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8551, Japan
| | - Masanori P Takahashi
- Clinical Neurophysiology, Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Hiroto Takada
- Department of Neurology, National Hospital Organization Aomori National Hospital, Namioka, Aomori 038-1331, Japan.
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20
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Hiramoto A, Jonaitis J, Niki S, Kohsaka H, Fetter RD, Cardona A, Pulver SR, Nose A. Regulation of coordinated muscular relaxation in Drosophila larvae by a pattern-regulating intersegmental circuit. Nat Commun 2021; 12:2943. [PMID: 34011945 PMCID: PMC8134441 DOI: 10.1038/s41467-021-23273-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 04/22/2021] [Indexed: 02/03/2023] Open
Abstract
Typical patterned movements in animals are achieved through combinations of contraction and delayed relaxation of groups of muscles. However, how intersegmentally coordinated patterns of muscular relaxation are regulated by the neural circuits remains poorly understood. Here, we identify Canon, a class of higher-order premotor interneurons, that regulates muscular relaxation during backward locomotion of Drosophila larvae. Canon neurons are cholinergic interneurons present in each abdominal neuromere and show wave-like activity during fictive backward locomotion. Optogenetic activation of Canon neurons induces relaxation of body wall muscles, whereas inhibition of these neurons disrupts timely muscle relaxation. Canon neurons provide excitatory outputs to inhibitory premotor interneurons. Canon neurons also connect with each other to form an intersegmental circuit and regulate their own wave-like activities. Thus, our results demonstrate how coordinated muscle relaxation can be realized by an intersegmental circuit that regulates its own patterned activity and sequentially terminates motor activities along the anterior-posterior axis.
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Affiliation(s)
- Atsuki Hiramoto
- Department of Complexity Science and Engineering, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Julius Jonaitis
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
| | - Sawako Niki
- Department of Complexity Science and Engineering, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
- Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Kohsaka
- Department of Complexity Science and Engineering, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | | | - Albert Cardona
- HHMI Janelia Research Campus, Ashburn, VA, USA
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
- MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Stefan R Pulver
- School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK
| | - Akinao Nose
- Department of Complexity Science and Engineering, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
- Department of Physics, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
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21
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La Rosa P, Petrillo S, Bertini ES, Piemonte F. Oxidative Stress in DNA Repeat Expansion Disorders: A Focus on NRF2 Signaling Involvement. Biomolecules 2020; 10:biom10050702. [PMID: 32369911 PMCID: PMC7277112 DOI: 10.3390/biom10050702] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response.
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22
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Santoro M, Piacentini R, Perna A, Pisano E, Severino A, Modoni A, Grassi C, Silvestri G. Resveratrol corrects aberrant splicing of RYR1 pre-mRNA and Ca 2+ signal in myotonic dystrophy type 1 myotubes. Neural Regen Res 2020; 15:1757-1766. [PMID: 32209783 PMCID: PMC7437583 DOI: 10.4103/1673-5374.276336] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Myotonic dystrophy type 1 (DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1 (RYR1), sarcoplasmatic/endoplasmatic Ca2+-ATPase (SERCA) and α1S subunit of voltage-gated Ca2+ channels (Cav1.1) is related to Ca2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol (RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy (rs9879/14) on May 20, 2014.
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Affiliation(s)
| | - Roberto Piacentini
- Department of Neuroscience, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Alessia Perna
- Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Eugenia Pisano
- Department of Cardiovascular and Thoracic Sciences, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Anna Severino
- Department of Cardiovascular and Thoracic Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Modoni
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gabriella Silvestri
- Department of Neuroscience, Università Cattolica del Sacro Cuore; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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23
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Abstract
There is increasing evidence of central nervous system involvement in numerous neuromuscular disorders primarily considered diseases of skeletal muscle. Our knowledge on cerebral affection in myopathies is expanding continuously due to a better understanding of the genetic background and underlying pathophysiological mechanisms. Intriguingly, there is a remarkable overlap of brain pathology in muscular diseases with pathomechanisms involved in neurodegenerative or neurodevelopmental disorders. A rapid progress in advanced neuroimaging techniques results in further detailed insight into structural and functional cerebral abnormalities. The spectrum of clinical manifestations is broad and includes movement disorders, neurovascular complications, paroxysmal neurological symptoms like migraine and epileptic seizures, but also behavioural abnormalities and cognitive dysfunction. Cerebral involvement implies a high socio-economic and personal burden in adult patients sometimes exceeding the everyday challenges associated with muscle weakness. It is especially important to clarify the nature and natural history of brain affection against the background of upcoming specific treatment regimen in hereditary myopathies that should address the brain as a secondary target. This review aims to highlight the character and extent of central nervous system involvement in patients with hereditary myopathies manifesting in adulthood, however also includes some childhood-onset diseases with brain abnormalities that transfer into adult neurological care.
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Affiliation(s)
- Jens Reimann
- Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Germany
- Center for Rare Diseases, University Hospital Bonn, Germany
| | - Cornelia Kornblum
- Department of Neurology, Section of Neuromuscular Diseases, University Hospital Bonn, Germany
- Center for Rare Diseases, University Hospital Bonn, Germany
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24
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Taylor S, Rodrigues M, Poke G, Wake S, McEwen A. Family communication following a diagnosis of myotonic dystrophy: To tell or not to tell? J Genet Couns 2019; 28:1029-1041. [PMID: 31385417 DOI: 10.1002/jgc4.1156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 07/07/2019] [Accepted: 07/08/2019] [Indexed: 11/06/2022]
Abstract
Family communication about genetic information enables informed medical and reproductive decision-making. The literature suggests that a significant proportion of genetically at-risk family members remain uninformed about genetic risk information as a result of non-disclosure. This study explored the experiences of New Zealand families communicating about a diagnosis of type 1 myotonic dystrophy (DM1). Eligible individuals were identified and recruited from the New Zealand (NZ) MD Prev study, a nationwide study which aimed to determine the prevalence, impact, and costs of genetic muscle disorders across the lifespan. Twelve qualitative semi-structured interviews were conducted with 17 participants. The findings demonstrate diversity among and within families, with several distinct family narratives described. Most participants reported a motivation to tell relatives about their diagnosis to promote autonomy. Women were pivotal throughout communication processes and this was often tied to the concept of maternal responsibility and a desire to promote relatives' reproductive autonomy. The diagnosis of DM1 and the subsequent family communication decisions altered relationships for many, with both positive and negative impacts described. The findings demonstrate that individuals require time to explore the impact of a diagnosis of DM1 on self, family and intimate partner relationships to anticipate unique communication challenges. Genetic counselors can use these findings to inform their approach to counseling families with DM1. Longitudinal genetic counseling may be beneficial as a way to provide individuals with life stage specific support as they communicate with their relatives about a diagnosis of DM1.
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Affiliation(s)
- Shelby Taylor
- The Department of Paediatrics, The University of Melbourne, Melbourne, Australia.,Murdoch Children's Research Institute, Melbourne, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia
| | - Miriam Rodrigues
- Neurology, Auckland District Health Board, Auckland, New Zealand.,Muscular Dystrophy Association of New Zealand, Auckland, New Zealand
| | - Gemma Poke
- Genetic Health Services, Wellington, New Zealand
| | - Samantha Wake
- The Department of Paediatrics, The University of Melbourne, Melbourne, Australia.,Murdoch Children's Research Institute, Melbourne, Australia
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25
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Koga S, Eric Ahlskog J, DeTure MA, Baker M, Roemer SF, Konno T, Rademakers R, Ross OA, Dickson DW. Coexistence of Progressive Supranuclear Palsy With Pontocerebellar Atrophy and Myotonic Dystrophy Type 1. J Neuropathol Exp Neurol 2019; 78:756-762. [PMID: 31216016 PMCID: PMC6640894 DOI: 10.1093/jnen/nlz048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) has been reported as a rare clinical subtype, but the underlying pathology of its cerebellar ataxia remains unclear. Here, we report a patient with the coexistence of PSP with pontocerebellar atrophy and myotonic dystrophy type 1 (DM1). A 73-year-old man who was an asymptomatic carrier of DM1 (66 CTG repeats) started developing ataxic gait with multiple falls, visual blurring, double vision, and word finding difficulty at age 62 and was initially diagnosed with multiple system atrophy (MSA). Subsequently, the diagnosis was changed to PSP due to hypometric downward gaze, reduced blink frequency, symmetric bradykinesia, rigidity, and the absence of autonomic dysfunction. He eventually developed delayed grip opening with percussion myotonia at age 72. At autopsy, severe neuronal degeneration and astrogliosis in the pontocerebellar structures suggested MSA, but immunohistochemistry for α-synuclein did not reveal neuronal or glial cytoplasmic inclusions. Immunohistochemistry for phospho-tau and 4-repeat tau confirmed a neuropathological diagnosis of PSP with exceptionally numerous coiled bodies and threads in the pontine base and cerebellar white matter. This unusual distribution of 4-repeat tau pathology and neuronal degeneration with astrogliosis is a plausible clinicopathological substrate of PSP-C.
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Affiliation(s)
- Shunsuke Koga
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
| | - J Eric Ahlskog
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | | | - Matt Baker
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
| | - Shanu F Roemer
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
| | - Takuya Konno
- Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Rosa Rademakers
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
| | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
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26
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Banez-Coronel M, Ranum LPW. Repeat-associated non-AUG (RAN) translation: insights from pathology. J Transl Med 2019; 99:929-942. [PMID: 30918326 PMCID: PMC7219275 DOI: 10.1038/s41374-019-0241-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 01/29/2019] [Indexed: 12/14/2022] Open
Abstract
More than 40 different neurological diseases are caused by microsatellite repeat expansions. Since the discovery of repeat-associated non-AUG (RAN) translation by Zu et al. in 2011, nine expansion disorders have been identified as RAN-positive diseases. RAN proteins are translated from different types of nucleotide repeat expansions and can be produced from both sense and antisense transcripts. In some diseases, RAN proteins have been shown to accumulate in affected brain regions. Here we review the pathological and molecular aspects associated with RAN protein accumulation for each particular disorder, the correlation between disease pathology and the available in vivo models and the common aspects shared by some of the newly discovered RAN proteins.
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Affiliation(s)
- Monica Banez-Coronel
- Center for NeuroGenetics, University of Florida, Gainesville, FL, 32610, USA
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA
| | - Laura P W Ranum
- Center for NeuroGenetics, University of Florida, Gainesville, FL, 32610, USA.
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 32610, USA.
- Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
- McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
- Genetics Institute, University of Florida, Gainesville, FL, 32610, USA.
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27
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Suh MR, Kim DH, Jung J, Kim B, Lee JW, Choi WA, Kang SW. Clinical implication of maximal voluntary ventilation in myotonic muscular dystrophy. Medicine (Baltimore) 2019; 98:e15321. [PMID: 31045770 PMCID: PMC6504256 DOI: 10.1097/md.0000000000015321] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Patients with myotonic muscular dystrophy type 1 (DM1) tend to exhibit earlier respiratory insufficiency than patients with other neuromuscular diseases at similar or higher forced vital capacity (FVC). This study aimed to analyze several pulmonary function parameters to determine which factor contributes the most to early hypercapnia in patients with DM1.We analyzed ventilation status monitoring, pulmonary function tests (including FVC, maximal voluntary ventilation [MVV], and maximal inspiratory and expiratory pressure), and polysomnography in subjects with DM1 who were admitted to a single university hospital. The correlation of each parameter with hypercapnia was determined. Subgroup analysis was also performed by dividing the subjects into 2 subgroups according to usage of mechanical ventilation.Final analysis included 50 patients with a mean age of 42.9 years (standard deviation = 11.1), 46.0% of whom were male. The hypercapnia was negatively correlated with MVV, FVC, forced expiratory volume in 1 second (FEV1), and their ratios to predicted values in subjects with myotonic muscular dystrophy type 1. At the same partial pressure of carbon dioxide, the ratio to the predicted value was lowest for MVV, then FEV1, followed by FVC. Moreover, the P values for differences in MVV and its ratio to the predicted value between ventilator users and nonusers were the lowest.When screening ventilation failure in patients with DM1, MVV should be considered alongside other routinely measured parameters.
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Affiliation(s)
- Mi Ri Suh
- Department of Rehabilitation Medicine, CHA Bundang Medical Center, CHA University School of Medicine, GyeongGi-do
- Rehabilitation and Regeneration Research Center, CHA University School of Medicine, GyeongGi-do
- Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul
- The Graduate School, Yonsei University College of Medicine, Seoul
| | - Dong Hyun Kim
- Department of Physical Medicine and Rehabilitation, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul
| | - Jiho Jung
- Department of Rehabilitation Medicine and Pulmonary Rehabilitation Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Bitnarae Kim
- Department of Rehabilitation Medicine and Pulmonary Rehabilitation Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
- Department of Physical Therapy, Graduate School of Yonsei University, Gangwon-do
| | - Jang Woo Lee
- Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul
- Department of Physical Medicine and Rehabilitation, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Won Ah Choi
- Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul
- Department of Rehabilitation Medicine and Pulmonary Rehabilitation Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Seong-Woong Kang
- Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul
- Department of Rehabilitation Medicine and Pulmonary Rehabilitation Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
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28
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Intrinsically cell-penetrating multivalent and multitargeting ligands for myotonic dystrophy type 1. Proc Natl Acad Sci U S A 2019; 116:8709-8714. [PMID: 30975744 DOI: 10.1073/pnas.1820827116] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Developing highly active, multivalent ligands as therapeutic agents is challenging because of delivery issues, limited cell permeability, and toxicity. Here, we report intrinsically cell-penetrating multivalent ligands that target the trinucleotide repeat DNA and RNA in myotonic dystrophy type 1 (DM1), interrupting the disease progression in two ways. The oligomeric ligands are designed based on the repetitive structure of the target with recognition moieties alternating with bisamidinium groove binders to provide an amphiphilic and polycationic structure, mimicking cell-penetrating peptides. Multiple biological studies suggested the success of our multivalency strategy. The designed oligomers maintained cell permeability and exhibited no apparent toxicity both in cells and in mice at working concentrations. Furthermore, the oligomers showed important activities in DM1 cells and in a DM1 liver mouse model, reducing or eliminating prominent DM1 features. Phenotypic recovery of the climbing defect in adult DM1 Drosophila was also observed. This design strategy should be applicable to other repeat expansion diseases and more generally to DNA/RNA-targeted therapeutics.
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29
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Araújo R, van de Warrenburg B, Lang A, Lees A, Bloem B. The Waiting Room: neurological observations made outside the movement disorder specialist's consulting office. Pract Neurol 2019; 19:295-301. [PMID: 30872358 DOI: 10.1136/practneurol-2018-002110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/07/2019] [Accepted: 01/28/2019] [Indexed: 11/04/2022]
Abstract
The neurological examination should always begin before the patient enters the doctor's office. Movement disorders in particular lend themselves to a spot diagnosis. In today's busy buzzing world, it seems wasteful not to make use of the various diagnostic clues that can be picked up readily while the patient is still in the waiting room. We present several illustrative examples, drawn from the literature and from our own experience. These are divided according to the different waiting room 'stages': the patient sitting in the waiting room, the response on being summoned to enter the consulting room-including rising from the chair, exchanging initial pleasantries and the way of walking. We also discuss the importance of paying attention to the patient's behaviour, clothing, posture, breathing patterns, facial expression and major gait abnormalities.
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Affiliation(s)
- Rui Araújo
- Neurology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal
| | | | - Anthony Lang
- Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Andrew Lees
- Reta Lila Weston Institute of Neurological Studies, University College London, London, UK
| | - Bastiaan Bloem
- Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands
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Spitalieri P, Talarico RV, Murdocca M, Fontana L, Marcaurelio M, Campione E, Massa R, Meola G, Serafino A, Novelli G, Sangiuolo F, Botta A. Generation and Neuronal Differentiation of hiPSCs From Patients With Myotonic Dystrophy Type 2. Front Physiol 2018; 9:967. [PMID: 30100878 PMCID: PMC6074094 DOI: 10.3389/fphys.2018.00967] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/02/2018] [Indexed: 02/03/2023] Open
Abstract
Human induced pluripotent stem cells (hiPSCs)-patient specific are an innovative tool to reproduce a model of disease in vitro and summarize the pathological phenotype and the disease etiopathology. Myotonic dystrophy type 2 (DM2) is caused by an unstable (CCTG)n expansion in intron 1 of the CNBP gene, leading to a progressive multisystemic disease with muscle, heart and central nervous dysfunctions. The pathogenesis of CNS involvement in DM2 is poorly understood since no cellular or animal models fully recapitulate the molecular and clinical neurodegenerative phenotype of patients. In this study, we generated for the first time, two DM2 and two wild type hiPSC lines from dermal fibroblasts by polycistronic lentiviral vector (hSTEMCCA-loxP) expressing OCT4, SOX2, KLF4, and cMYC genes and containing loxP-sites, excisable by Cre recombinase. Specific morphological, molecular and immunocytochemical markers have confirmed the stemness of DM2 and wild type-derived hiPSCs. These cells are able to differentiate into neuronal population (NP) expressing tissue specific markers. hiPSCs-derived NP cells maintain (CCTG)n repeat expansion and intranuclear RNA foci exhibiting sequestration of MBNL1 protein, which are pathognomonic of the disease. DM2 hiPSCs represent an important tool for the study of CNS pathogenesis in patients, opening new perspectives for the development of cell-based therapies in the field of personalized medicine and drug screening.
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Affiliation(s)
- Paola Spitalieri
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Rosa V. Talarico
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Michela Murdocca
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Luana Fontana
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Marzia Marcaurelio
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Elena Campione
- Division of Dermatology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Roberto Massa
- Division of Neurology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giovanni Meola
- Department of Biomedical Science for Health, Policlinico San Donato (IRCCS), University of Milan, Milan, Italy
| | - Annalucia Serafino
- Institute of Translational Pharmacology, Italian National Research Council, Rome, Italy
| | - Giuseppe Novelli
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Istituto Neurologico Mediterraneo (IRCCS), Pozzilli, Italy
| | - Federica Sangiuolo
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Annalisa Botta
- Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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Sulek A, Lusakowska A, Krysa W, Rajkiewicz M, Kaminska A, Nojszewska M, Kostera-Pruszczyk A, Zdzienicka E, Kubalska J, Rakowicz M, Szirkowiec W, Kwiecinski H, Zaremba J. WITHDRAWN: Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients. Neurol Neurochir Pol 2018:S0028-3843(18)30152-X. [PMID: 29880430 DOI: 10.1016/j.pjnns.2018.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/12/2018] [Indexed: 11/24/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, 10.1016/j.pjnns.2018.02.008. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Anna Sulek
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
| | | | - Wioletta Krysa
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Marta Rajkiewicz
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Anna Kaminska
- Department of Neurology, Medical University, Warsaw, Poland
| | | | | | - Elzbieta Zdzienicka
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Jolanta Kubalska
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Maria Rakowicz
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | | | | | - Jacek Zaremba
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
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Affinity capillary electrophoresis for identification of active drug candidates in myotonic dystrophy type 1. Anal Bioanal Chem 2018; 410:4495-4507. [DOI: 10.1007/s00216-018-1107-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 03/16/2018] [Accepted: 04/24/2018] [Indexed: 12/31/2022]
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Sulek A, Lusakowska A, Krysa W, Rajkiewicz M, Kaminska A, Nojszewska M, Kostera-Pruszczyk A, Zdzienicka E, Kubalska J, Rakowicz M, Szirkowiec W, Kwiecinski H, Zaremba J. Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients. Neurol Neurochir Pol 2018; 52:736-742. [PMID: 29588063 DOI: 10.1016/j.pjnns.2018.02.008] [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: 10/03/2017] [Revised: 02/16/2018] [Accepted: 02/26/2018] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively. METHODS Molecular analyses were performed by PCR and the modified RP-PCR in patients, in their at-risk relatives and prenatal cases. RESULTS The analysis of Polish controls revealed the range of 5-31 CTG repeats for DM1 and 110-228 bp alleles for DM2. Among 318 confirmed probands - 196 (62%) were DM1 and 122 (38%) - DM2. Within DM1families, 10 subjects carried a low expanded CTG tract (< 100 repeats), which resulted in a full mutation in subsequent generations. Two related individuals had unstable alleles-188 bp and 196 bp without common interruptions. CONCLUSION The relative frequencies of DM1/DM2 among Polish patients were 68% and 32%, respectively, with a relatively high proportion of DM2 mutations (1.6:1).
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Affiliation(s)
- Anna Sulek
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
| | - Anna Lusakowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Wioletta Krysa
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Marta Rajkiewicz
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Anna Kaminska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Monika Nojszewska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | - Elzbieta Zdzienicka
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Jolanta Kubalska
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Maria Rakowicz
- Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | | | - Hubert Kwiecinski
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Zaremba
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
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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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Paino L, Blasco N. [What would you do with an adult patient who consults due to head muscle weakness and has dropped head?]. Semergen 2017; 44:135-137. [PMID: 28587920 DOI: 10.1016/j.semerg.2017.04.009] [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: 03/09/2017] [Revised: 04/04/2017] [Accepted: 04/20/2017] [Indexed: 11/26/2022]
Abstract
The dropped head syndrome, whether due to muscle weakness, rigidity, or ankylosis, is not uncommon in the elderly. It is characterised by a "chin-on-chest" reducible kyphosis, which is secondary to head muscle debility. It may be associated with a neuromuscular group of diseases such as polymyositis, chronic Inflammatory demyelinating polyneuropathy, myasthenia gravis, amyotrophic lateral sclerosis, and inclusion-body myositis. Some cases associated with hypothyroidism and hyperparathyroidism have also been described. Prognosis without treatment is poor. Therefore, familiarity with this condition, together with a complete anamnesis and physical examination, should lead us to the clinical suspicion and selection of the appropriate complementary tests. In this article, a case of dropped head syndrome is reported, as well as an algorithm for its diagnosis.
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Affiliation(s)
- L Paino
- Medicina Familiar y Comunitaria, CAP Guineueta, Atención Primaria, Institut Català de la Salut, Barcelona, España.
| | - N Blasco
- Medicina Familiar y Comunitaria, CAP Guineueta, Atención Primaria, Institut Català de la Salut, Barcelona, España
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Abstract
BACKGROUND Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. METHODS Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. RESULTS Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. CONCLUSIONS Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.
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Baptista H, Lopes Cardoso I. Steinert syndrome and repercussions in dental medicine. Arch Oral Biol 2017; 75:37-47. [DOI: 10.1016/j.archoralbio.2016.12.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 12/19/2016] [Accepted: 12/21/2016] [Indexed: 12/12/2022]
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deLorimier E, Hinman MN, Copperman J, Datta K, Guenza M, Berglund JA. Pseudouridine Modification Inhibits Muscleblind-like 1 (MBNL1) Binding to CCUG Repeats and Minimally Structured RNA through Reduced RNA Flexibility. J Biol Chem 2017; 292:4350-4357. [PMID: 28130447 DOI: 10.1074/jbc.m116.770768] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/25/2017] [Indexed: 12/16/2022] Open
Abstract
Myotonic dystrophy type 2 is a genetic neuromuscular disease caused by the expression of expanded CCUG repeat RNAs from the non-coding region of the CCHC-type zinc finger nucleic acid-binding protein (CNBP) gene. These CCUG repeats bind and sequester a family of RNA-binding proteins known as Muscleblind-like 1, 2, and 3 (MBNL1, MBNL2, and MBNL3), and sequestration plays a significant role in pathogenicity. MBNL proteins are alternative splicing regulators that bind to the consensus RNA sequence YGCY (Y = pyrimidine). This consensus sequence is found in the toxic RNAs (CCUG repeats) and in cellular RNA substrates that MBNL proteins have been shown to bind. Replacing the uridine in CCUG repeats with pseudouridine (Ψ) resulted in a modest reduction of MBNL1 binding. Interestingly, Ψ modification of a minimally structured RNA containing YGCY motifs resulted in more robust inhibition of MBNL1 binding. The different levels of inhibition between CCUG repeat and minimally structured RNA binding appear to be due to the ability to modify both pyrimidines in the YGCY motif, which is not possible in the CCUG repeats. Molecular dynamic studies of unmodified and pseudouridylated minimally structured RNAs suggest that reducing the flexibility of the minimally structured RNA leads to reduced binding by MBNL1.
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Affiliation(s)
- Elaine deLorimier
- From the Institute of Molecular Biology, Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403 and
| | - Melissa N Hinman
- From the Institute of Molecular Biology, Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403 and
| | - Jeremy Copperman
- From the Institute of Molecular Biology, Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403 and
| | - Kausiki Datta
- the Center for NeuroGenetics, Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610-3010
| | - Marina Guenza
- From the Institute of Molecular Biology, Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403 and
| | - J Andrew Berglund
- From the Institute of Molecular Biology, Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403 and .,the Center for NeuroGenetics, Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, Florida 32610-3010
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Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, Frank S, Angelini C, Furling D, Rüegg MA, Sinnreich M, Castets P. Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I. J Clin Invest 2017; 127:549-563. [PMID: 28067669 DOI: 10.1172/jci89616] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/17/2016] [Indexed: 12/13/2022] Open
Abstract
Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.
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Nojszewska M, Gawel M, Szmidt-Salkowska E, Kostera-Pruszczyk A, Potulska-Chromik A, Lusakowska A, Kierdaszuk B, Lipowska M, Macias A, Gawel D, Seroka A, Kaminska AM. Abnormal spontaneous activity in primary myopathic disorders. Muscle Nerve 2016; 56:427-432. [PMID: 28000226 DOI: 10.1002/mus.25521] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 12/08/2016] [Accepted: 12/14/2016] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Reproducible non-insertional spontaneous activity (SA), with the exception of endplate activity, is an unequivocal sign of abnormality and is one of the most useful findings obtained on electromyography. METHODS In this retrospective study we analyzed occurrence and distribution of abnormal SA in 151 patients with genetically confirmed myopathies. RESULTS Complex repetitive discharges (CRDs) occurred more frequently than fibrillation potentials (fibs) and positive sharp waves (PSWs) in centronuclear myopathy (CNM) and limb-girdle muscular dystrophy type 2A (LGMD-2A), whereas fibs/PSWs were observed more often in desminopathy and facioscapulohumeral dystrophy (FSHD). Abnormal SA was commonly found in CNM (66.7%) and desminopathy (61.5%), occasionally in Duchenne (DMD) and Becker muscular dystrophy (BMD) (45.2% and 27.6%, respectively), but rarely in FSHD (14.9%) and LGMD-2A (12.0%). CONCLUSIONS Abnormal SA probably occurs more frequently in disorders associated with structural changes in muscle fibers. Screening for SA may be a valuable tool for diagnosis of non-myotonic myopathies. Muscle Nerve 56: 427-432, 2017.
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Affiliation(s)
- Monika Nojszewska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Malgorzata Gawel
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | | | | | - Anna Lusakowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Biruta Kierdaszuk
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Marta Lipowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Macias
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Damian Gawel
- Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, Marymoncka Strasse 99/103, 01-813, Warsaw, Poland
| | - Andrzej Seroka
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Anna M Kaminska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
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Bombelli F, Lispi L, Porrini SC, Giacanelli M, Terracciano C, Massa R, Petrucci A. Neuromuscular transmission abnormalities in myotonic dystrophy type 1: A neurophysiological study. Clin Neurol Neurosurg 2016; 150:84-88. [PMID: 27611986 DOI: 10.1016/j.clineuro.2016.08.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 08/10/2016] [Accepted: 08/21/2016] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result of muscle impairment. However, neuromuscular junction (NMJ) abnormalities could play an additional role in determining these manifestations. We aimed to document the possible NMJ involvement in DM1. PATIENTS AND METHODS In order to substantiate this hypothesis we performed low rate repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), in 14 DM1 subjects. RESULTS RNS resulted abnormal in four patients while SFEMG revealed a pathological jitter in ten. A significative correlation was found between jitter values and decrementing response (p<0.000311; r=0.822). CONCLUSION These results suggest a possible involvement of NMJ in DM1.
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Affiliation(s)
- Francesco Bombelli
- Neuromuscular and Neurological Rare Diseases Centre, Neurology and Neurophysiology Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy
| | - Ludovico Lispi
- Neuromuscular and Neurological Rare Diseases Centre, Neurology and Neurophysiology Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy
| | - Sandro Costanzi Porrini
- Medical Genetics Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy
| | - Manlio Giacanelli
- Neuromuscular and Neurological Rare Diseases Centre, Neurology and Neurophysiology Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy
| | - Chiara Terracciano
- Neuromuscular Centre, Neuroscience, Department of Systems Medicine, University of Rome Tor Vergata, V.le Oxford, 81-00133, Rome, Italy
| | - Roberto Massa
- Neuromuscular Centre, Neuroscience, Department of Systems Medicine, University of Rome Tor Vergata, V.le Oxford, 81-00133, Rome, Italy
| | - Antonio Petrucci
- Neuromuscular and Neurological Rare Diseases Centre, Neurology and Neurophysiology Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy.
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Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival. Sci Rep 2016; 6:31222. [PMID: 27526875 PMCID: PMC4985653 DOI: 10.1038/srep31222] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/14/2016] [Indexed: 12/03/2022] Open
Abstract
Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death.
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Herrendorff R, Faleschini MT, Stiefvater A, Erne B, Wiktorowicz T, Kern F, Hamburger M, Potterat O, Kinter J, Sinnreich M. Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I. J Biol Chem 2016; 291:17165-77. [PMID: 27298317 DOI: 10.1074/jbc.m115.710616] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Indexed: 11/06/2022] Open
Abstract
Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3' UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases.
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Affiliation(s)
- Ruben Herrendorff
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Maria Teresa Faleschini
- the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Adeline Stiefvater
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Beat Erne
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Tatiana Wiktorowicz
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Frances Kern
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Matthias Hamburger
- the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Olivier Potterat
- the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Jochen Kinter
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
| | - Michael Sinnreich
- From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and
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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: 61] [Impact Index Per Article: 6.1] [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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Wheeler TM, Baker JN, Chad DA, Zilinski JL, Verzosa S, Mordes DA. Case Records of the Massachusetts General Hospital. Case 30-2015: A 50-Year-Old Man with Cardiogenic Shock. N Engl J Med 2015; 373:1251-61. [PMID: 26398074 DOI: 10.1056/nejmcpc1415169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A 50-year-old man with a history of cardiomyopathy and progressive muscle weakness was admitted with cardiogenic shock. Electroencephalography showed total suppression of cerebral activity; ventilator support was withdrawn, and he died. An autopsy was performed.
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Liu Q, Zheng YF, Zhu YP, Ling SQ, Li WR. Clinical, pathological and genetic characteristics of a pedigree with myotonic dystrophy type 1. Exp Ther Med 2015; 10:1931-1936. [PMID: 26640575 DOI: 10.3892/etm.2015.2738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 07/23/2015] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the clinical, pathological and molecular genetic characteristics of a pedigree with myotonic dystrophy type 1 (DM1). A series of clinical data from a pedigree with DM1 were collected. Muscle biopsy revealed a typical nuclear ingression within numerous muscle fibers following hematoxylin and eosin staining. Genomic DNA was extracted from the venous blood of two patients and the triplet-primed polymerase chain reaction method was performed to amplify the dystrophia myotonic protein kinase (DMPK) gene. The amplified products were subjected to gene sequencing by capillary fluorescence electrophoresis, and a pathogenic mutation in the DMPK gene comprising >50 cytosine-thymine-guanine repeat sequences was found. DM1 includes multi-system damage, as well as skeletal muscle involvement, and can affect the central nervous system, endocrine glands, skin and heart. A skeletal muscle biopsy and genetic testing can confirm the diagnosis and clarify the severity of the disease. In addition, it is necessary to distinguish DM1 from DM2.
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Affiliation(s)
- Qing Liu
- Department of Neurology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China
| | - Yu-Fei Zheng
- Department of Neurology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China
| | - Yan-Ping Zhu
- Department of Neurology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China
| | - Shi-Qing Ling
- Department of Neurology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China
| | - Wei-Rong Li
- Department of Neurology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi 030009, P.R. China
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Abstract
PURPOSE OF REVIEW Myotonic dystrophies type 1 and type 2 are progressive multisystem genetic disorders with clinical and genetic features in common. Myotonic dystrophy type 1 is the most prevalent muscular dystrophy in adults and has a wide phenotypic spectrum. The average age of death in myotonic dystrophy type 1 is in the fifth decade. In comparison, myotonic dystrophy type 2 tends to cause a milder phenotype with later onset of symptoms and is less common than myotonic dystrophy type 1. Historically, patients with myotonic dystrophy type 1 have not received the medical and social input they need to maximize their quality and quantity of life. This review describes the improved understanding in the molecular and clinical features of myotonic dystrophy type 1 as well as the screening of clinical complications and their management. We will also discuss new potential genetic treatments. RECENT FINDINGS An active approach to screening and management of myotonic dystrophies type 1 and type 2 requires a multidisciplinary medical, rehabilitative and social team. This process will probably improve morbidity and mortality for patients. Genetic treatments have been successfully used in in-vitro and animal models to reverse the physiological, histopathological and transcriptomic features. SUMMARY Molecular therapeutics for myotonic dystrophy will probably bridge the translational gap between bench and bedside in the near future. There will still be a requirement for clinical screening of patients with myotonic dystrophy with proactive and systematic management of complications.
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Nojszewska M, Łusakowska A, Szmidt-Salkowska E, Gaweł M, Lipowska M, Sułek A, Krysa W, Rajkiewicz M, Seroka A, Kaczmarek K, Kamińska AM. Peripheral nerve involvement in myotonic dystrophy type 2 - similar or different than in myotonic dystrophy type 1? Neurol Neurochir Pol 2015; 49:164-70. [PMID: 26048604 DOI: 10.1016/j.pjnns.2015.04.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 03/28/2015] [Accepted: 04/29/2015] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Multisystem manifestations of myotonic dystrophies type 1 (DM1) and 2 (DM2) are well known. Peripheral nerve involvement has been reported in DM1 but not in genetically confirmed DM2. The aim of our study was to assess peripheral nerve involvement in DM2 using nerve conduction studies and to compare these results with findings in DM1. METHODS We prospectively studied patients with genetically confirmed DM2 (n=30) and DM1 (n=32). All patients underwent detailed neurological examination and nerve conduction studies. RESULTS Abnormalities in electrophysiological studies were found in 26.67% of patients with DM2 and in 28.13% of patients with DM1 but the criteria of polyneuropathy were fulfilled in only 13.33% of patients with DM2 and 12.5% of patients with DM1. The polyneuropathy was subclinical, and no correlation was found between its presence and patient age or disease duration. CONCLUSIONS Peripheral nerves are quite frequently involved in DM2, but abnormalities meeting the criteria of polyneuropathy are rarely found. The incidence of peripheral nerve involvement is similar in both types of myotonic dystrophy.
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Affiliation(s)
- Monika Nojszewska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Łusakowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | - Małgorzata Gaweł
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
| | - Marta Lipowska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | - Anna Sułek
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Wioletta Krysa
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Marta Rajkiewicz
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Andrzej Seroka
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
| | | | - Anna M Kamińska
- Department of Neurology, Medical University of Warsaw, Warsaw, Poland
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Koutsoulidou A, Kyriakides TC, Papadimas GK, Christou Y, Kararizou E, Papanicolaou EZ, Phylactou LA. Elevated Muscle-Specific miRNAs in Serum of Myotonic Dystrophy Patients Relate to Muscle Disease Progress. PLoS One 2015; 10:e0125341. [PMID: 25915631 PMCID: PMC4411125 DOI: 10.1371/journal.pone.0125341] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Accepted: 03/13/2015] [Indexed: 01/24/2023] Open
Abstract
The discovery of reliable and sensitive blood biomarkers is useful for the diagnosis, monitoring and potential future therapy of diseases. Recently, microRNAs (miRNAs) have been identified in blood circulation and might have the potential to be used as biomarkers for several diseases and clinical conditions. Myotonic Dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy primarily characterized by muscle myotonia, weakness and atrophy. Previous studies have shown an association between miRNAs and DM1 in muscle tissue and, recently, in plasma. The aim of this study was to detect and assess muscle-specific miRNAs as potential biomarkers of DM1 muscle wasting, an important parameter in the disease’s natural history. Disease stable or progressive DM1 patients with muscle weakness and wasting were recruited and enrolled in the study. RNA isolated from participants’ serum was used to assess miRNA levels. Results suggest that the levels of muscle-specific miRNAs are correlated with the progression of muscle wasting and weakness observed in the DM1 patients. Specifically, miR-1, miR-133a, miR133b and miR-206 serum levels were found elevated in DM1 patients with progressive muscle wasting compared to disease stable DM1 patients. Based on these results, we propose that muscle-specific miRNAs might be useful molecular biomarkers for monitoring the progress of muscle atrophy in DM1 patients.
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Affiliation(s)
- Andrie Koutsoulidou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, P.O. Box 2346, 1683 Nicosia, Cyprus
| | - Tassos C. Kyriakides
- Yale Center for Analytical Sciences,Yale School of Public Health, 300 George Street, Suite 555, New Haven, CT 06520, United States of America
| | - George K. Papadimas
- Department of Neurology, Eginitio hospital, Medical School of Athens, 74 Vasilissis Sofias, 11528, Athens, Greece
| | - Yiolanda Christou
- Neurology Clinic D, Cyprus Institute of Neurology & Genetics, P.O. Box 2346, 1683 Nicosia, Cyprus
| | - Evangelia Kararizou
- Department of Neurology, Eginitio hospital, Medical School of Athens, 74 Vasilissis Sofias, 11528, Athens, Greece
| | - Eleni Zamba Papanicolaou
- Neurology Clinic D, Cyprus Institute of Neurology & Genetics, P.O. Box 2346, 1683 Nicosia, Cyprus
| | - Leonidas A. Phylactou
- Department of Molecular Genetics, Function & Therapy, Cyprus Institute of Neurology & Genetics, P.O. Box 2346, 1683 Nicosia, Cyprus
- * E-mail:
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Campanati A, Giannoni M, Buratti L, Cagnetti C, Giuliodori K, Ganzetti G, Silvestrini M, Provinciali L, Offidani A. Skin features in myotonic dystrophy type 1: an observational study. Neuromuscul Disord 2015; 25:409-13. [PMID: 25813338 DOI: 10.1016/j.nmd.2015.02.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 02/17/2015] [Accepted: 02/27/2015] [Indexed: 10/23/2022]
Abstract
Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0. 01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), macules of hyperpigmentation (p = 0.03) were significantly more frequent in patients compared with controls. In patients with Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p < 0.0001). Our preliminary results seem to rule out an increased prevalence of pre-neoplastic, and neoplastic skin lesions in Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1.
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Affiliation(s)
- A Campanati
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy.
| | - M Giannoni
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - L Buratti
- Neurological Clinic, Department of Neurosciences, Marche Polytechnic University, Ancona, Italy
| | - C Cagnetti
- Neurological Clinic, Department of Neurosciences, Marche Polytechnic University, Ancona, Italy
| | - K Giuliodori
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - G Ganzetti
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - M Silvestrini
- Neurological Clinic, Department of Neurosciences, Marche Polytechnic University, Ancona, Italy
| | - L Provinciali
- Neurological Clinic, Department of Neurosciences, Marche Polytechnic University, Ancona, Italy
| | - A Offidani
- Dermatological Clinic, Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
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