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1.
Medicine (Baltimore) ; 98(46): e17582, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725606

RESUMO

RATIONALE: Myotonic dystrophy type 1 (DM1) is a slowly progressive multisystem neuromuscular disease characterized by myotonia and muscle weakness and wasting of distal and axial muscles. People with DM1, due to the disease progression, are often concerned about their ability to carry out and participate in the activities of daily living. Rehabilitation approaches in DM1, including moderate-to-intense strength training, have shown not univocal efficacy to face such difficulties. Aim of this case-study was to demonstrate the effects of a combined approach by using conventional plus robotic training in rare neuromuscular diseases, such as DM1. PATIENT CONCERNS: A 46-year-old woman came to our observation complaining of difficulty in opening fist after strong voluntary muscle contraction for about 20 years. Over the years, she referred swallowing difficulties for solid foods, balance impairment complicated by tendency to stumble and falls, fatigability, hand muscle weakness with difficulty to open bottles and lifting weights, and daytime sleepiness DIAGNOSIS:: Paraparesis in DM1. INTERVENTIONS: The patient underwent 2 different trainings. The first period of treatment was carried out by using conventional physiotherapy, 6 times a week (twice a day) for 4 weeks. Then, she underwent a two-month specific task-oriented robotic rehabilitation training for the gait impairment using an overground exoskeleton, namely Ekso-GT, combined to the conventional therapy. OUTCOMES: The patient, after the EKSO training, gained a significant improvement in walking, balance and lower limbs muscle strength, as per 10-meter walking test and Left Lower Limb Motricity Index. Neurophysiological data (electroencephalography and surface electromyography) were also collected to more objectively assess the functional outcomes. LESSONS: Rehabilitation approaches in DM1, including moderate-to-intense strength training, have shown not univocal efficacy. Emerging and advancing robotic technologies can enhance clinical therapeutic outcomes by allowing therapists to activate and/or modulate neural networks to maximize motor and functional recovery.


Assuntos
Exoesqueleto Energizado , Distrofia Miotônica/reabilitação , Plasticidade Neuronal , Modalidades de Fisioterapia , Treinamento de Resistência/métodos , Atividades Cotidianas , Terapia Combinada , Eletromiografia , Feminino , Humanos , Pessoa de Meia-Idade , Distrofia Miotônica/fisiopatologia , Resultado do Tratamento
2.
Genes Dev ; 33(23-24): 1635-1640, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31624084

RESUMO

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.


Assuntos
Processamento Alternativo/genética , Repetições de Microssatélites/genética , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/genética , Distrofia Miotônica/fisiopatologia , Processamento de RNA/genética , Regiões 3' não Traduzidas/genética , Animais , Plexo Corióideo/fisiopatologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Introdução de Genes , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/citologia , Mutação , Miotonina Proteína Quinase/genética , Miotonina Proteína Quinase/metabolismo , Proteínas de Ligação a RNA/genética
3.
Muscle Nerve ; 60(6): 779-789, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509256

RESUMO

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a multisystemic disease caused by expansion of a CTG repeat in the 3' UTR of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. While multiple organs are affected, more than half of mortality is due to muscle wasting. METHODS: It is unclear whether endurance exercise provides beneficial effects in DM1. Here, we show that a 10-week treadmill endurance exercise program leads to beneficial effects in the HSALR mouse model of DM1. RESULTS: Animals that performed treadmill training displayed reduced CUGexp RNA levels, improved splicing abnormalities, an increase in skeletal muscle weight and improved endurance capacity. DISCUSSION: These results indicate that endurance exercise does not have adverse effects in HSALR animals and contributes to beneficial molecular and physiological outcomes.


Assuntos
Treino Aeróbico/métodos , Músculo Esquelético/metabolismo , Distrofia Miotônica/metabolismo , Condicionamento Físico Animal/métodos , Resistência Física/fisiologia , Actinas/genética , Tecido Adiposo , Processamento Alternativo , Animais , Composição Corporal , Densidade Óssea , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Tamanho do Órgão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Expansão das Repetições de Trinucleotídeos
4.
Muscle Nerve ; 60(6): 732-738, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520483

RESUMO

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is caused by a CTG (cytosine-thymine-guanine) trinucleotide repeat expansion. Congenital DM (CDM) presents in the first month of life, whereas individuals with infantile and juvenile DM1 have later onset of symptoms. METHODS: We performed a retrospective chart review of patients with childhood-onset DM1 seen at one of three locations in Dallas, Texas between 1990 and 2018. Symptoms, disease course, cognitive features, and family history were reviewed. RESULTS: Seventy-four patients were included; CDM was diagnosed in 52 patients. There was maternal inheritance in 74% of patients. CTG repeat number ranged from 143 to 2300. Neuropsychiatric and cognitive deficits were common. Over half of the patients had GI disturbances, and orthopedic complications were common. DISCUSSION: Myotonic dystrophy type 1 in children requires a multidisciplinary approach to management. Presenting symptoms vary, and repeat expansion size does not necessarily directly relate to severity of symptoms. A consensus for outcome measures is required.


Assuntos
Distrofia Miotônica/fisiopatologia , Asma/etiologia , Asma/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Doença do Sistema de Condução Cardíaco/etiologia , Doença do Sistema de Condução Cardíaco/fisiopatologia , Criança , Pré-Escolar , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Refluxo Gastroesofágico/etiologia , Refluxo Gastroesofágico/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Herança Materna , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Transtornos do Humor/etiologia , Transtornos do Humor/fisiopatologia , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Miotonina Proteína Quinase/genética , Estudos Retrospectivos , Expansão das Repetições de Trinucleotídeos
5.
Mol Cell Biol ; 39(21)2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383751

RESUMO

Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease without cure. One of the possible therapeutic approaches for DM1 is correction of the RNA-binding proteins CUGBP1 and MBNL1, misregulated in DM1. CUGBP1 activity is controlled by glycogen synthase kinase 3ß (GSK3ß), which is elevated in skeletal muscle of patients with DM1, and inhibitors of GSK3 were suggested as therapeutic molecules to correct CUGBP1 activity in DM1. Here, we describe that correction of GSK3ß with a small-molecule inhibitor of GSK3, tideglusib (TG), not only normalizes the GSK3ß-CUGBP1 pathway but also reduces the mutant DMPK mRNA in myoblasts from patients with adult DM1 and congenital DM1 (CDM1). Correction of GSK3ß in a mouse model of DM1 (HSALR mice) with TG also reduces the levels of CUG-containing RNA, normalizing a number of CUGBP1- and MBNL1-regulated mRNA targets. We also found that the GSK3ß-CUGBP1 pathway is abnormal in skeletal muscle and brain of DMSXL mice, expressing more than 1,000 CUG repeats, and that the correction of this pathway with TG increases postnatal survival and improves growth and neuromotor activity of DMSXL mice. These findings show that the inhibitors of GSK3, such as TG, may correct pathology in DM1 and CDM1 via several pathways.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Distrofia Miotônica/genética , Distrofia Miotônica/fisiopatologia , Animais , Proteínas CELF1/genética , Proteínas CELF1/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Camundongos , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Cultura Primária de Células , RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Tiadiazóis/farmacologia
6.
Muscle Nerve ; 60(5): 575-579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31443127

RESUMO

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting the peripheral nervous system. However, studies evaluating somatic small fiber sensory nerve function, which may contribute to pain in DM1, are lacking. METHODS: Using quantitative sensory testing of the hand and foot, we evaluated Aδ and C-fiber function. Of 20 adult DM1 patients recruited, 16 were analyzed. Their results were compared with those of 32 age- and sex-matched controls. RESULTS: No DM1 patient had diabetes mellitus or clinical evidence of small fiber neuropathy. In DM1, hand (P < .01) and foot (P = 0.02) warm detection thresholds were higher than those of controls. Cool detection thresholds were lower in the foot (P < .001). CONCLUSIONS: Subclinical small sensory fiber dysfunction occurs in DM1 patients without large fiber neuropathy. Further research with other modalities is required to characterize these disturbances as disease modifying therapies are developed.


Assuntos
Distrofia Miotônica/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Limiar Sensorial , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Pé/inervação , Mãos/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Sensação Térmica/fisiologia , Adulto Jovem
7.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466972

RESUMO

A 47-year-old woman presented with sicca symptoms, polyarthralgias, polymyalgias and dysphagia. She was found to have positive antinuclear, anti-SSA-Ro and anti-SSB-La antibodies. Slit lamp exam confirmed the presence of keratoconjunctivitis sicca, and the patient was diagnosed with Sjögren's syndrome. Three years later, she was referred for evaluation of gait instability associated with recent falls. On physical examination, the patient was found to have bilateral ptosis, percussion myotonia, distal upper and lower extremity weakness, and a steppage gait. Electromyography demonstrated electrical myotonia. Genetic testing revealed expanded CTG repeats (733 and 533) in the myotonic dystrophy type 1 (DM1) protein kinase gene, confirming the diagnosis of DM1. Dysphagia, pain and eye discomfort may occur in both Sjögren's syndrome and DM1, and in this case, may have delayed the diagnosis of muscular dystrophy.


Assuntos
Distrofia Miotônica/etiologia , Distrofia Miotônica/genética , Síndrome de Sjogren/complicações , Anticorpos Antinucleares/imunologia , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Eletromiografia/métodos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Ceratoconjuntivite Seca/diagnóstico , Ceratoconjuntivite Seca/tratamento farmacológico , Pessoa de Meia-Idade , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/terapia , Miotonina Proteína Quinase , Proteínas Quinases/genética , Síndrome de Sjogren/sangue , Resultado do Tratamento
8.
BMC Res Notes ; 12(1): 526, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429798

RESUMO

OBJECTIVE: The purpose of this side product of another unpublished research project, was to address the effects of a training program on skeletal muscle adaptations of people with myotonic dystrophy type 1 (DM1), under a multifaceted perspective. The objective of this study was to look at training induced muscular adaptations by evaluating changes in muscle strength, myofiber cross-sectional area (CSA), proportion of myofiber types and with indirect markers of muscle growth [proportion of centrally nucleated fibers (CNF) and density of neutrophils and macrophages]. Two men with DM1 underwent a 12-week strength/endurance training program (18 sessions). Two muscle biopsies were obtained pre- and post-training program. RESULTS: Muscular adaptations occurred only in Patient 1, who attended 72% of the training sessions compared to 39% for Patient 2. These adaptations included increase in the CSA of type I and II myofibers and changes in their proportion. No changes were observed in the percentage of CNF, infiltration of neutrophils and macrophages and muscle strength. These results illustrate the capacity of skeletal muscle cells to undergo adaptations linked to muscle growth in DM1 patients. Also, these adaptations seem to be dependent on the attendance. Trial registration Clinicaltrials.gov NCT04001920 retrospectively registered on June 26th, 2019.


Assuntos
Adaptação Fisiológica , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/terapia , Adulto , Humanos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia
9.
Muscle Nerve ; 60(4): 392-399, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31298737

RESUMO

INTRODUCTION: The prevalence and impact of symptoms affecting individuals with pediatric forms of myotonic dystrophy type-1 (DM1) are not well understood. METHODS: Patients from the United States, Canada, and Sweden completed a survey that investigated 20 themes associated with pediatric-onset DM1. Participants reported the prevalence and importance of each theme affecting their lives. Surveys from participants were matched with surveys from their caregivers for additional analysis. RESULTS: The most prevalent symptomatic themes included problems with hands or fingers (79%) and gastrointestinal issues (75%). Problems with urinary/bowel control and gastrointestinal issues were reported to have the greatest impact on patients' lives. Responses from participants and their caregivers had varying levels of agreement among symptomatic themes. DISCUSSION: Many symptoms have meaningful impact on disease burden. The highest levels of agreement between caregivers and individuals with pediatric forms of myotonic dystrophy were found for physical activity themes.


Assuntos
Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Atividades Cotidianas , Adolescente , Adulto , Cuidadores , Criança , Pré-Escolar , Comunicação , Efeitos Psicossociais da Doença , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Feminino , Dedos/fisiopatologia , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Mãos/fisiopatologia , Humanos , Masculino , Limitação da Mobilidade , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Miotonia/etiologia , Miotonia/fisiopatologia , Distrofia Miotônica/complicações , Medidas de Resultados Relatados pelo Paciente , Adulto Jovem
10.
Med. clín (Ed. impr.) ; 153(2): 82.e1-82.e17, jul. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-183369

RESUMO

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares


Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up


Assuntos
Humanos , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/fisiopatologia , Prognóstico , Seguimentos , Distrofia Miotônica/genética , Neurofisiologia , Planejamento Familiar , Diagnóstico Pré-Natal , Miotonia , Neuroimagem
11.
BMC Neurol ; 19(1): 135, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31216995

RESUMO

BACKGROUND: Myotonic Dystrophy 1 (DM1) causes progressive myopathy of extremity muscles. DM1 may also affect muscles of the trunk. The aim of this study was to investigate fat infiltration and muscle size in trunk muscles in DM1 patients, and in an age and gender matched control group. Further, explore how fat infiltration and degree of atrophy in these muscles are associated with motor and respiratory function in DM1 patients. METHOD: We measured fat infiltration and trunk muscle size by MRI in 20 patients with genetically confirmed classic form of DM1, and compared these cases with 20 healthy, age and gender matched controls. In the DM1 group, we investigated correlations between MRI findings and clinical measures of muscle strength, mobility and respiration. We used sum scores for fat infiltration and muscle size in trunk flexors and trunk extensors in the analysis of group differences and correlations. RESULTS: Significant differences between cases and controls were present for fat infiltration in trunk flexors (p = 0.001) and trunk extensors (p = < 0.001), and for muscle size in trunk flexors (p = 0.002) and trunk extensors (p = 0.030). Fat infiltration in trunk flexors were significant correlated to back extension strength (rho = - 0.523 p = 0.018), while muscle size in trunk flexors was significantly correlated to trunk flexion strength (rho = 0.506 p = 0.023). Fat infiltration in trunk flexors was significantly correlated with lower general mobility (rho = - 0.628, p = 0.003), reduced balance (rho = 0.630, p < 0.003) and forced vital capacity (rho - 0.487 p = 0.040). CONCLUSIONS: Trunk muscles in DM1 patients had significant higher levels of fat infiltration and reduced muscle size compared to age and gender matched controls. In DM1 patients, fat infiltration was associated with reduced muscle strength, mobility, balance and lung function, while muscle size was associated with reduced muscle strength and lung function. These findings are of importance for clinical management of the disease and could be useful additional outcome measures in future intervention studies.


Assuntos
Atrofia/patologia , Músculo Esquelético/patologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Respiração , Tronco/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Adulto Jovem
12.
Medicine (Baltimore) ; 98(18): e15321, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045770

RESUMO

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.


Assuntos
Hipercapnia/fisiopatologia , Pulmão/fisiopatologia , Ventilação Voluntária Máxima/fisiologia , Distrofia Miotônica/complicações , Adulto , Dióxido de Carbono/análise , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pressões Respiratórias Máximas/métodos , Pessoa de Meia-Idade , Distrofia Miotônica/classificação , Distrofia Miotônica/fisiopatologia , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/fisiopatologia , Polissonografia/métodos , Valor Preditivo dos Testes , Pressão , Estudos Prospectivos , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Capacidade Vital/fisiologia
13.
Muscle Nerve ; 60(1): 90-95, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30994189

RESUMO

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized mainly by skeletal muscle alterations. Although oropharyngeal dysphagia is a prominent clinical feature of DM1, it remains poorly studied in its early disease stages. METHODS: Dysphagia was investigated in 11 presymptomatic DM1 carriers, 14 patients with DM1 and 12 age-matched healthy controls, by using fiberoptic endoscopic evaluation of swallowing (FEES) and clinical scores. RESULTS: Scores for the FEES variables, delayed pharyngeal reflex, posterior pooling, and postswallow residue were significantly greater in patients with DM1 and in presymptomatic DM1 carriers than in healthy controls (P < 0.05); oropharyngeal dysfunction was more severe in patients than in presymptomatic carriers. Penetration/aspiration was found altered exclusively in patients with DM1 (P < 0.05). DISCUSSION: Swallowing dysfunction occurs in presymptomatic DM1 carriers. Timely diagnosis of dysphagia in preclinical stages of the disease will aid in the timely management of presymptomatic carriers, potentially preventing medical complications. Muscle Nerve, 2019.


Assuntos
Doenças Assintomáticas , Transtornos de Deglutição/fisiopatologia , Distrofia Miotônica/fisiopatologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Transtornos de Deglutição/etiologia , Endoscopia do Sistema Digestório , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Miotonina Proteína Quinase/genética , Adulto Jovem
14.
BMC Musculoskelet Disord ; 20(1): 101, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836978

RESUMO

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a neuromuscular disease characterized by multisystemic involvements including a progressive loss of maximal muscle strength and muscle wasting. Poor lower-limb strength is an important factor explaining disrupted social participation of affected individuals. This review aims to map what is known about the effects of exercise and training programs undertaken to counteract skeletal muscle impairments in DM1 patients. METHODS: Medline, CINAHL and EMBASE databases were searched. Regarding study eligibility, title and abstract of 704 studies followed by 45 full articles were reviewed according to the following eligibility criteria. Inclusion: (1) humans with DM1 and (2) experimental protocol relying on exercise or training. Exclusion: (1) studies that do not evaluate skeletal muscle responses or adaptations, (2) reviews covering articles already included and (3) pharmacological intervention at the same time of exercise or training program. RESULTS: Twenty-one papers were selected for in-depth analysis. Different exercise or training protocols were found including: acute exercise, neuromuscular electric stimulation, strength training, aerobic training, balance training and multiple rehabilitation interventions. Seven studies reported clinical measurements only, five physiological parameters only and nine both types. CONCLUSION: This scoping review offers a complete summary of the current scientific literature on the effect of exercise and training in DM1 and a framework for future studies based on the concomitant evaluation of the several outcomes in present literature. Although there were a good number of studies focusing on clinical measurements, heterogeneity between studies does not allow to identify what are the adequate training parameters to obtain exercise or training-induced positive impacts on muscle function. Scientific literature is even more scarce regarding physiological parameters, where much more research is needed to understand the underlying mechanisms of exercise response in DM1.


Assuntos
Exercício/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Distrofia Miotônica/terapia , Treinamento de Resistência/métodos , Humanos , Músculo Esquelético/diagnóstico por imagem , Distrofia Miotônica/diagnóstico por imagem , Distrofia Miotônica/fisiopatologia , Treinamento de Resistência/tendências , Resultado do Tratamento
15.
Neurol Sci ; 40(6): 1255-1265, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30891637

RESUMO

Myotonic dystrophy type 1 (DM1) is caused by CTG nucleotide repeat expansions in the 3'-untranslated region (3'-UTR) of the dystrophia myotonica protein kinase (DMPK) gene. The expanded CTG repeats encode toxic CUG RNAs that cause disease, largely through RNA gain-of-function. DM1 is a fatal disease characterized by progressive muscle wasting, which has no cure. Regenerative medicine has emerged as a promising therapeutic modality for DM1, especially with the advancement of induced pluripotent stem (iPS) cell technology and therapeutic genome editing. However, there is an unmet need to identify in vitro outcome measures to demonstrate the therapeutic effects prior to in vivo clinical trials. In this study, we examined the muscle regeneration (myotube formation) in normal and DM1 myoblasts in vitro to establish outcome measures for therapeutic monitoring. We found normal proliferation of DM1 myoblasts, but abnormal nuclear aggregation during the early stage myotube formation, as well as myotube degeneration during the late stage of myotube formation. We concluded that early abnormal nuclear aggregation and late myotube degeneration offer easy and sensitive outcome measures to monitor therapeutic effects in vitro.


Assuntos
Núcleo Celular/patologia , Núcleo Celular/fisiologia , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Regeneração , Proliferação de Células , Células Cultivadas , Humanos , Técnicas In Vitro , Mioblastos/fisiologia
16.
Arch Phys Med Rehabil ; 100(9): 1629-1639, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30831092

RESUMO

OBJECTIVE: To describe and compare changes in participation over a 9-year period in women and men with myotonic dystrophy type 1 (DM1). To compare participation restrictions with available reference values from a typical aging population living in the community. DESIGN: Descriptive longitudinal design comparing data from baseline (2002) with data from follow-up (2011). SETTING: Neuromuscular clinic and participant's home. PARTICIPANTS: Adults with DM1 participated in the follow-up study (N=115). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The Assessment of Life Habits measured participation in 10 domains of daily and social activities. The minimal clinically important difference is 0.5 on a 10-point scale for participation accomplishment level. RESULTS: A total of 62% of participants were women, and the mean age was 52.3±10.3 years. A decline (P<.01) was observed with increasing difficulty and assistance required in global participation (mean ± SD, -0.5±0.9), social activities subscore (-0.6±1.2), nutrition (-0.7±1.4), fitness (-1.0±1.6), personal care (-0.7±1.2), mobility (-0.5±1.9), community life (-0.8±1.9), and recreation (-1.5±3.0). More life areas are disrupted over time: 8 domains were below reference values from a population aged 55-64 years at follow-up compared with 2 domains at baseline. Satisfaction with participation remains high and stable over time. CONCLUSION: As disease duration increases, global participation and more daily and social domains were restricted with increasing difficulty and assistance required. Adults with DM1 showed not only age-associated but disease-specific changes in participation. Description over time of participation could improve clinical assessment and guide interdisciplinary management of DM1, leading to higher rehabilitation success. Further investigation of the factors influencing changes in participation is required to support disease management and services planning.


Assuntos
Atividades Cotidianas , Progressão da Doença , Distrofia Miotônica/fisiopatologia , Participação Social , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Estado Nutricional , Aptidão Física , Recreação , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo
17.
Muscle Nerve ; 59(6): 683-687, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30895625

RESUMO

INTRODUCTION: Respiratory failure is one of the most common causes of mortality in myotonic dystrophy type 1 (DM1). The variation in the DM1 phenotype causes difficulty in clinically predicting the severity of respiratory involvement, and variables such as daytime somnolence are insensitive for identifying patients who require continuous or bilevel nocturnal positive airway pressure (NPAP). METHODS: We retrospectively analyzed a cohort of 126 adult onset patients with DM1 at the point of their first respiratory assessment to identify significant factors in predicting ventilator requirement. RESULTS: Triplet repeat years score and Muscle Impairment Rating Scale were significantly linearly related to NPAP and, thus, formed the model. DISCUSSION: We devised a simple model to aid clinicians in predicting at first visit those patients with DM1 who are likely to require NPAP. We also describe the causes of failure to tolerate NPAP in DM1. Muscle Nerve 59:683-687, 2019.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/estatística & dados numéricos , Hipoventilação/terapia , Distrofia Miotônica/terapia , Insuficiência Respiratória/terapia , Apneia Obstrutiva do Sono/terapia , Adulto , Idoso , Feminino , Humanos , Hipoventilação/etiologia , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/complicações , Distrofia Miotônica/fisiopatologia , Fenótipo , Respiração Artificial , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Estudos Retrospectivos , Apneia Obstrutiva do Sono/etiologia , Capacidade Vital , Adulto Jovem
18.
BMC Neurol ; 19(1): 45, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922263

RESUMO

BACKGROUND: The aim of this study was to explore perceived fatigue, experienced functional limitations due to fatigue and clinical correlates in patients with Myotonic Dystrophy type 1 (DM1). METHODS: In total, 32 consecutive patients with DM1 (14 women and 18 men) and 30 sex, age and education matched healthy control subjects participated. Perceived fatigue was rated on the Fatigue Impact Scale (FIS). Patients also completed a set of assessments aimed to characterize CTG-repeat size, muscle impairment, depression and cognitive functions. Non-parametric analysis were performed as appropriate, including Mann-Whitney U-test and Spearman correlation test. RESULTS: DM1 patients had higher FIS total score than healthy controls, suggesting higher fatigue levels. More specifically, DM1 patients scored higher on the FIS physical and psychosocial subscales than controls but not on the FIS cognitive scale. Scores on fatigue correlated significantly with muscle impairment and depression. CONCLUSIONS: Perceived fatigue is significantly more common in patients with DM1 than in healthy controls. Higher ratings on depression and muscle impairment were associated with the condition. This indicates that both depression and muscle impairment may contribute to the experience of fatigue in DM1.


Assuntos
Cognição , Fadiga/psicologia , Distrofia Miotônica/fisiopatologia , Adulto , Estudos de Casos e Controles , Depressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Exame Físico , Adulto Jovem
19.
J Neurol ; 266(4): 998-1006, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30788616

RESUMO

OBJECTIVE: The objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder. METHODS: Adults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length]. RESULTS: Our sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor. CONCLUSION: We show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients' lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores.


Assuntos
Efeitos Psicossociais da Doença , Distrofia Miotônica/epidemiologia , Adolescente , Adulto , Idoso , Ensaios Clínicos como Assunto , Estudos Transversais , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Prevalência , Qualidade de Vida , Índice de Gravidade de Doença , Fatores Sexuais , Teste de Caminhada , Adulto Jovem
20.
Neurol Sci ; 40(5): 1035-1040, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30790082

RESUMO

INTRODUCTION: To date, there are only several reports on body composition in myotonic dystrophy type 1 (DM1) and there are no data for myotonic dystrophy type 2 (DM2). The aim was to analyze body composition of patients with DM1 and DM2, and its association with socio-demographic and clinical features of the diseases. METHODS: There were no statistical differences in sociodemographic features between 20 DM1 patients and 12 DM2 patients. Body composition was assessed by DEXA (dual-energy x-ray absorptiometry). A three-compartment model was used: bone mineral content (BMC), fat mass (FM), and lean tissue mass (LTM). RESULTS: Patients with DM1 and DM2 had similar total body mass (TBM), BMC, FM, and LTM. Patients with DM1 had higher trunk-limb fat index (TLFI) in comparison to DM2 patients which indicates visceral fat deposition in DM1 (1.16 ± 0.32 for DM1 vs. 0.87 ± 0.23 for DM2, p < 0.05). Right ribs bone mineral density was lower in DM2 group (0.68 ± 0.07 g/cm2 vs. 0.61 ± 0.09 g/cm2, p < 0.05). Higher percentage of FM in legs showed correlation with lower strength of the upper leg muscles in DM1 (ρ = - 0.47, p < 0.05). Higher muscle strength in DM2 patients was in correlation with higher bone mineral density (ρ = + 0.62, p < 0.05 for upper arm muscles, ρ = + 0.87, p < 0.01 for lower arm muscles, ρ = + 0.72, p < 0.05 for lower leg muscles). CONCLUSION: DM1 patients had visceral obesity, and percentage of FM correlated with a degree of muscle weakness in upper legs. In DM2 patients, degree of muscle weakness was in correlation with higher FM index and lower bone mineral density.


Assuntos
Composição Corporal , Distrofia Miotônica , Absorciometria de Fóton , Adulto , Densidade Óssea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Debilidade Muscular/diagnóstico por imagem , Debilidade Muscular/epidemiologia , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/diagnóstico por imagem , Distrofia Miotônica/epidemiologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Obesidade Abdominal/diagnóstico por imagem , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/patologia , Obesidade Abdominal/fisiopatologia
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