RESUMO
We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.
Assuntos
Distrofina/genética , Distrofia Muscular de Duchenne/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Progressão da Doença , Deleção de Genes , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Fenótipo , Estudos Prospectivos , Avaliação de Sintomas , Adulto JovemRESUMO
INTRODUCTION: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). METHODS: This is a multisite, 1-year, open-label trial of twice-weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4-2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley-III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty-three of 25 participants completed the study. RESULTS: Treated boys gained an average of 0.5 points on the Bayley-III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. DISCUSSION: This study provides evidence that twice-weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow-up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650-657, 2019.
Assuntos
Glucocorticoides/administração & dosagem , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisolona/administração & dosagem , Estudos de Casos e Controles , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Humanos , Lactente , Masculino , Debilidade Muscular/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Aumento de PesoRESUMO
INTRODUCTION: Improved outcome measures are essential to efficiently screen the growing number of potential amyotrophic lateral sclerosis (ALS) therapies. METHODS: This longitudinal study of 100 (70 male) participants with ALS compared Accurate Test of Limb Isometric Strength (ATLIS), using a fixed, wireless load cell, with ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC). RESULTS: Participants enrolled at 5 U.S. sites. Data were analyzed from 66 participants with complete ATLIS, ALSFRS-R, and VC data over at least 3 visits. Change in ATLIS was less variable both within- and among-person than change in ALSFRS-R or VC. Additionally, participants who had normal ALSFRS-R arm and leg function averaged 12 to 32% below expected strength values measured by ATLIS. CONCLUSIONS: ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710-715, 2017.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/fisiopatologia , Dinamômetro de Força Muscular/normas , Capacidade Vital/fisiologia , Feminino , Humanos , Contração Isométrica/fisiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologiaRESUMO
OBJECTIVE: Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker muscular dystrophy (BMD) by altering pre-mRNA splicing to restore an open reading frame, allowing translation of an internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated by skipping of either flanking exon (44 or 46). We sought to predict the impact of these by assessing the clinical severity in dystrophinopathy patients. METHODS: Phenotypic data including clinical diagnosis, age at wheelchair use, age at loss of ambulation, and presence of cardiomyopathy were analyzed from 41 dystrophinopathy patients containing equivalent in-frame deletions. RESULTS: As expected, deletions of either exons 45 to 47 (Δ45-47) or exons 45 to 48 (Δ45-48) result in BMD in 97% (36 of 37) of subjects. Unexpectedly, deletion of exons 45 to 46 (Δ45-46) is associated with the more severe DMD phenotype in 4 of 4 subjects despite an in-frame transcript. Notably, no patients with a deletion of exons 44 to 45 (Δ44-45) were found within the United Dystrophinopathy Project database, and this mutation has only been reported twice before, which suggests an ascertainment bias attributable to a very mild phenotype. INTERPRETATION: The observation that Δ45-46 patients have typical DMD suggests that the conformation of the resultant protein may result in protein instability or altered binding of critical partners. We conclude that in DMD patients with Δ45, skipping of exon 44 and multiexon skipping of exons 46 and 47 (or exons 46-48) are better potential therapies than skipping of exon 46 alone.
Assuntos
Bases de Dados Genéticas , Éxons/genética , Terapia Genética/métodos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular de Duchenne/diagnóstico , Valor Preditivo dos Testes , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. METHODS: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. RESULTS: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. CONCLUSION: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016.
Assuntos
Limitação da Mobilidade , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/fisiopatologia , Participação do Paciente/métodos , Adolescente , Corticosteroides/uso terapêutico , Adulto , Criança , Seguimentos , Força da Mão/fisiologia , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Amplitude de Movimento Articular/fisiologia , Capacidade Vital/fisiologia , Adulto JovemRESUMO
INTRODUCTION: Electrical impedance myography (EIM) is a non-invasive, painless, objective technique to quantify muscle pathology. METHODS: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3-12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand-held dynamometry). RESULTS: EIM was well tolerated and had good inter- and intrarater reliability (intraclass correlation coefficient 0.81-0.96). The averaged EIM phase value from all muscles was higher (P < 0.001) in controls (10.45 ± 2.29) than boys with DMD (7.31 ± 2.23), and correlated (P ≤ 0.001) with 6MWD (r = 0.55), NSAA (r = 0.66), TFTs (r = -0.56), and strength (r = 0.44). CONCLUSION: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted.
Assuntos
Impedância Elétrica , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Dinamômetro de Força Muscular , Miografia , Curva ROC , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. METHODS: Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. RESULTS: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. CONCLUSIONS: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use.
Assuntos
Corticosteroides/uso terapêutico , Mãos/fisiopatologia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Adolescente , Adulto , Criança , Avaliação da Deficiência , Mãos/inervação , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Reprodutibilidade dos Testes , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-ß binding protein 4, was previously discovered in a genome-wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. METHODS: We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes. RESULTS: Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth factor (TGF) ß displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4' role as a regulator of TGFß. INTERPRETATION: LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients.
Assuntos
Predisposição Genética para Doença/genética , Proteínas de Ligação a TGF-beta Latente/genética , Limitação da Mobilidade , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Testes Genéticos , Genótipo , Glucocorticoides/farmacologia , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Proteínas Smad/metabolismoRESUMO
INTRODUCTION: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). METHODS: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. RESULTS: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. CONCLUSIONS: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges.
Assuntos
Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Psicometria , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Avaliação da Deficiência , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/classificação , Reprodutibilidade dos Testes , Adulto JovemRESUMO
INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.
Assuntos
Códon sem Sentido/genética , Distrofina/genética , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Oxidiazóis/uso terapêutico , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Cooperação Internacional , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Fatores de Tempo , CaminhadaRESUMO
BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. METHODS: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)
Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Adolescente , Adulto , Idade de Início , Idoso , Análise de Variância , Criança , Hipersensibilidade a Drogas/etiologia , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Imunoglobulina G/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Capacidade Vital/efeitos dos fármacos , Caminhada , Adulto Jovem , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologiaRESUMO
UNLABELLED: introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. METHODS: The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2-28 years. A comprehensive battery of measures was obtained. RESULTS: A novel composite functional "milestone" scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4 ± 0.39 MMT unit/year, compared with -0.4 ± 0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. CONCLUSIONS: In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy.
Assuntos
Técnicas de Diagnóstico Neurológico , Progressão da Doença , Glucocorticoides/uso terapêutico , Cooperação Internacional , Distrofia Muscular de Duchenne/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Adolescente , Adulto , Pesquisa Biomédica/métodos , Pesquisa Biomédica/normas , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Estudos de Coortes , Estudos Transversais , Técnicas de Diagnóstico Neurológico/normas , Humanos , Estudos Longitudinais , Masculino , Força Muscular/fisiologia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/normas , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. METHODS: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate-determined energy expenditure index, and other exploratory endpoints. RESULTS: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. CONCLUSIONS: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression.
Assuntos
Teste de Esforço , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Caminhada/fisiologia , Progressão da Doença , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Oxidiazóis/uso terapêutico , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
INTRODUCTION: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. METHODS: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. RESULTS: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. CONCLUSION: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials.
Assuntos
Teste de Esforço , Distrofia Muscular de Duchenne/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Caminhada/fisiologia , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Eletromiografia , Glucocorticoides/uso terapêutico , Força da Mão/fisiologia , Humanos , Estudos Longitudinais , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Observação , Oxidiazóis/uso terapêutico , Valor Preditivo dos Testes , Fatores de TempoRESUMO
UNLABELLED: Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. METHODS: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. RESULTS: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). CONCLUSIONS: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics.
Assuntos
Glucocorticoides/uso terapêutico , Cooperação Internacional , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/epidemiologia , Projetos de Pesquisa , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Internacionalidade , Estudos Longitudinais , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: The Accurate Test of Limb Isometric Strength (ATLIS) device can reliably measure the strength of 12 muscle groups using a fixed load cell. The purpose of this study was to analyze ATLIS data from healthy adults to calculate an individual's predicted strength scores. METHODS: ATLIS data were collected from 432 healthy adults. Linear regression models were developed to predict each muscle group's strength. The R-squared statistic assessed variability accounted for by the models. RESULTS: Simple main effects models stratified by gender were used to establish regression equations for each muscle using factors of age, weight, and height. CONCLUSIONS: Normalizing raw strength scores controls for biometric factors, thus enabling meaningful comparisons between subjects and allowing each muscle to contribute equally to a summary score. Normalized scores are easily interpreted for broad clinical uses, and derived summary scores establish individuals' disease progression rates using a common scale, allowing for more efficient clinical trials.
Assuntos
Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Adulto , Idoso , Antropometria , Estatura/fisiologia , Peso Corporal/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
AIM: An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper limb. We report the steps leading to the development of the Performance of the Upper Limb (PUL), a tool specifically designed for assessing upper limb function in ambulant and non-ambulant patients with Duchenne muscular dystrophy (DMD). METHOD: The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma. RESULTS: The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician-reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living. INTERPRETATION: The module was developed using innovative approaches and will be useful for designing clinical trials.
Assuntos
Avaliação da Deficiência , Transtornos dos Movimentos/diagnóstico , Distrofia Muscular de Duchenne/patologia , Psicometria , Extremidade Superior/fisiopatologia , Atividades Cotidianas , Humanos , Transtornos dos Movimentos/etiologia , Distrofia Muscular de Duchenne/complicações , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , CaminhadaRESUMO
BACKGROUND: Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008. OBJECTIVES: To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations & Theses A&I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. We collected adverse event data from included trials. The review authors contacted the authors of the included studies to obtain information not available in the published articles. MAIN RESULTS: We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue AUTHORS' CONCLUSIONS: The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed.
Assuntos
Esclerose Lateral Amiotrófica/terapia , Terapia por Exercício/métodos , Esclerose Lateral Amiotrófica/psicologia , Tolerância ao Exercício , Humanos , Doença dos Neurônios Motores/psicologia , Doença dos Neurônios Motores/terapia , Debilidade Muscular/terapia , Resistência Física , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping.
Assuntos
Códon sem Sentido , Distrofina/genética , Éxons , Distrofia Muscular de Duchenne/genética , Splicing de RNA , Feminino , Humanos , Masculino , Distrofia Muscular de Duchenne/metabolismo , Fenótipo , Splicing de RNA/genéticaRESUMO
INTRODUCTION: Acid maltase deficiency (AMD, or Pompe disease) is an inherited myopathic disorder of glycogen degradation. Diagnosis is often delayed. Muscle ultrasound could improve diagnosis. METHODS: We compared skeletal muscle ultrasound images from adults with AMD (n = 10) to other myopathies (n = 81) and, in AMD, compared qualitative (Heckmatt) and quantitative (backscatter) ultrasound measurements with strength and function. RESULTS: Qualitative ultrasound was abnormal in at least one muscle in all AMD subjects. Ultrasound patterns specific for AMD were: normal triceps brachii despite abnormalities in elbow flexors (89% vs. 17%, P < 0.0001); focal abnormalities affecting deep more than superficial biceps brachii (40% vs. 4%, P = 0.002); and more severe involvement of vastus intermedius than rectus femoris (40 vs. 11%, P = 0.03). In AMD, both qualitative (Heckmatt) and quantitative (backscatter) ultrasound measures increased with decreasing strength and function. CONCLUSIONS: Muscle ultrasound identifies the presence and specific patterns of AMD pathology, measures disease severity, and can help in the diagnosis of AMD.