Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015-2022): 2022 interim analysis.

OBJECTIVE: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). METHODS: Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. RESULTS: As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. CONCLUSION: Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.

Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil.

OBJECTIVE: To validate the Life Satisfaction Index for Adolescents (LSI-A) scale, parent version and patient version, for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and limb-girdle muscular dystrophy (LGMD). METHODS: The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach's α, ICC, Pearson and the ROC Curve. RESULTS: The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach's α, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. CONCLUSION: According to the validity and reproducibility values, the LSI-A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders.

Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil / Tradução e validação da escala de qualidade de vida para adolescentes com doenças neuromusculares para português do Brasil: LSI-A Brasil

ABSTRACT Objective To validate the Life Satisfaction Index for Adolescents (LSI-A) scale, parent version and patient version, for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and limb-girdle muscular dystrophy (LGMD). Methods The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach's α, ICC, Pearson and the ROC Curve. Results The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach's α, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. Conclusion According to the validity and reproducibility values, the LSI-A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders.

RESUMO Objetivo Validar a escala Life Satisfaction Index for Adolescents (LSI-A) versão pais e versão paciente para doenças neuromusculares. Método O instrumento versão pais foi dividido nos Grupos A,B, C e D; e paciente, em B, C e D. Para cálculo estatístico utilizou-se os testes α de Cronbach, CIC, Pearson e Curva ROC. Resultados Valor de Cronbach versão pais e paciente no escore geral, 0.87 e 0.89; confiabilidade,0.98 e 0.97;reprodutibilidade,entre 0.59 e 0.69 e, entre 0.58 e 0.80; sensibilidade, 0.78 e 0.72; especificidade, 0.5 e 0.69; e acurácia, 64% e 70.4% respectivamente. Conclusão Conforme a validade e reprodutibilidade, o LSI-A Brasil versão pais e paciente é útil clinicamente para avaliar a Qualidade de Vida da Distrofia Muscular de Duchenne, Amiotrofia Espinhal Progressiva ou Distrofia Muscular tipo Cinturas e pode ser usado para outras doenças neuromusculares.

Quantitative Myasthenia Gravis Score: a Brazilian multicenter study for translation, cultural adaptation and validation.

OBJECTIVE: To perform the translation, cross-cultural adaptation and validation of the Quantitative Myasthenia Gravis Score (QMGS) to Brazilian Portuguese in accordance with international ethical standards. METHODS: The following steps were taken: (1) implementation of the translation protocol and transcultural adaptation, (2) validation of the adapted content, and (3) assessment of reliability. To check intra- and inter-observer reproducibility, each patient underwent two interviews with interviewer-A and one with B. The QMGS was compared to the Myasthenia Gravis Composite Scale and Myasthenia-specific Quality of Life Questionnaire. RESULTS: Our study group consisted of 30 patients, with a mean age of 47.6±11.4 years and a mean duration of illness of 11.33±8.49 years. Correlation between the QMGS and MGC was very strong (r = 0.928; p < 0.001) and substantial between the QMGS and MG-QOL 15 (r = 0.737; p < 0.001). CONCLUSION: The Brazilian Portuguese translation, and validation of the QMGS was successfully performed.

Quantitative Myasthenia Gravis Score: a Brazilian multicenter study for translation, cultural adaptation and validation / Teste Quantitativo para Miastenia Gravis: estudo multicêntrico brasileiro para tradução, adaptação cultural e validação

ABSTRACT Objective To perform the translation, cross-cultural adaptation and validation of the Quantitative Myasthenia Gravis Score (QMGS) to Brazilian Portuguese in accordance with international ethical standards. Methods The following steps were taken: (1) implementation of the translation protocol and transcultural adaptation, (2) validation of the adapted content, and (3) assessment of reliability. To check intra- and inter-observer reproducibility, each patient underwent two interviews with interviewer-A and one with B. The QMGS was compared to the Myasthenia Gravis Composite Scale and Myasthenia-specific Quality of Life Questionnaire. Results Our study group consisted of 30 patients, with a mean age of 47.6±11.4 years and a mean duration of illness of 11.33±8.49 years. Correlation between the QMGS and MGC was very strong (r = 0.928; p < 0.001) and substantial between the QMGS and MG-QOL 15 (r = 0.737; p < 0.001). Conclusion The Brazilian Portuguese translation, and validation of the QMGS was successfully performed.

RESUMO Objetivo O objetivo foi realizar a tradução e validação do teste quantitativo para Miastenia Gravis (QMGS) para Português do Brasil, de acordo com as diretrizes internacionais. Métodos Foram realizadas as etapas de implementação do protocolo de tradução e adaptação transcultural, validação do conteúdo adaptado e avaliação da confiabilidade. Para verificar a reprodutibilidade intra e inter-observador cada paciente foi submetido a duas entrevistas por um entrevistador-A e um B. O QMGS foi comparado ao MG Composite Scale e Myasthenia-specific Quality of Life Questionnaire. Resultados O estudo inclui 30 pacientes, com a média de idade de 47,6±11,4 anos e tempo médio de doença de 11,33±8,49 anos. A correlação entre QMGS e MGC apresentou-se muito forte (r = 0,928; p < 0,001) e substancial entre QMGS e MG-QOL 15 (r = 0,737; p < 0,001). Conclusão A tradução, e validação do QMGS para o português do Brasil foi realizada com sucesso.

Hand Function in Muscular Dystrophies.

The aim of this study was to investigate the relationship between Performance of Upper Limb (PUL) and Jebsen-Taylor Test (JTT) to assess and monitor upper limb function progression in patients with muscular dystrophy. Thirty patients diagnosed with Duchenne muscular dystrophy, limb-girdle muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy Type 1, and fascioscapulohumeral dystrophy were submitted to the shoulder, elbow, and wrist domains of PUL, and to JTT subtests. Spearman tests investigated the relationships between PUL and JTT total scores and domains. Correlations were classified as strong ( r ≥ 0.70), moderate (0.40 ≤ r < 0.70), or weak ( r ≤ 0.40). There were strong correlations between the PUL and JTT total scores ( r = -0.706). Although JTT measures time and PUL provides kinesiologic scores, these measures were related. Therefore, muscle synergies, which control the compensatory movements and motor functions involving mainly shoulder, elbow, wrist, and finger movements, are related to timed performance in patients with muscular dystrophies.

Is functional dependence of Duchenne muscular dystrophy patients determinant of the quality of life and burden of their caregivers?

OBJECTIVE: The relationship between functional dependence and quality of life (QOL) in Duchenne muscular dystrophy (DMD) patients and burden and QOL in caregivers is not clear. This study investigated possible relationships between functional dependence/QOL of DMD patients and QOL/burden of caregivers. METHOD: This study included 35 boys (6-17 years) and respective caregivers (above 21 years). Caregivers answered to World Health Organization Quality of Life and Zarit Burden Interview questionnaires. Patients were assessed with the Motor Function Measure and the Autoquestionnaire Qualité de vie Enfant Imagé. Spearman correlations and linear regressions were run to investigate relationships between the variables. RESULTS: The occurrence of lower QOL and higher burden among the caregivers of patients with Duchenne muscular dystrophy was evidenced. The functional dependence of patients was not considered a determinant factor. Higher caregivers' burden was related to lower caregivers' QOL and to higher patients' ages.

Is functional dependence of Duchenne muscular dystrophy patients determinant of the quality of life and burden of their caregivers? / A dependência funcional de pacientes com distrofia muscular de Duchenne é fator determinante na qualidade de vida e na sobrecarga de seus cuidadores?

Objective The relationship between functional dependence and quality of life (QOL) in Duchenne muscular dystrophy (DMD) patients and burden and QOL in caregivers is not clear. This study investigated possible relationships between functional dependence/QOL of DMD patients and QOL/burden of caregivers. Method This study included 35 boys (6-17 years) and respective caregivers (above 21 years). Caregivers answered to World Health Organization Quality of Life and Zarit Burden Interview questionnaires. Patients were assessed with the Motor Function Measure and the Autoquestionnaire Qualité de vie Enfant Imagé. Spearman correlations and linear regressions were run to investigate relationships between the variables. Results The occurrence of lower QOL and higher burden among the caregivers of patients with Duchenne muscular dystrophy was evidenced. The functional dependence of patients was not considered a determinant factor. Higher caregivers’ burden was related to lower caregivers’ QOL and to higher patients’ ages. .

Objetivo A relação entre qualidade de vida e função motora de pacientes com distrofia muscular de Duchenne (DMD) e sobrecarga e qualidade de vida (QV) dos cuidadores não está clara na literatura. Esse estudo investigou possíveis relações entre dependência funcional/QV de pacientes e sobrecarga/QV dos cuidadores em 35 meninos (6-17 anos) com DMD e respectivos cuidadores (acima de 21 anos). Método Cada cuidador respondeu ao questionário de QV da Organização Mundial de Saúde e de sobrecarga de Zarit e o paciente foi avaliado com a medida de função motora e o Autoquestionnaire Qualité de vie Enfant Imagé. Correlações de Spearman e regressões lineares investigaram possíveis relações entre as variáveis. Resultados A ocorrência de menor QV e maior sobrecarga entre cuidadores foi evidenciada, enquanto a dependência funcional dos pacientes não foi considerada fator determinante. Conclusão Cuidadores com maior sobrecarga apresentaram menor QV relacionada à maior idade dos pacientes. .

Compensatory movements during functional activities in ambulatory children with Duchenne muscular dystrophy.

OBJECTIVE: During the transitional phase (ambulatory to non-ambulatory), synergies characterize the evolution of Duchenne muscular dystrophy (DMD). This study was performed to describe and quantify compensatory movements while sitting down on/rising from the floor and climbing up/down steps. METHOD: Eighty videos (5 children × 4 assessments × 4 tasks) were recorded quarterly in the year prior to gait loss. Compensatory movements from the videos were registered based on the Functional Evaluation Scale for DMD. RESULTS: The most frequently observed compensatory movements were upper limb support on lower limbs/floor/handrail during all the tasks and lumbar hyperlordosis, trunk support on handrail, equinus foot, increased base of support, non-alternated descent, and pauses while climbing up/down steps. CONCLUSION: Climbing up/down steps showed a higher number of compensatory movements than sitting down on/rising from the floor, which seemed to be lost before climbing up/down steps in ambulatory children with DMD.

Compensatory movements during functional activities in ambulatory children with Duchenne muscular dystrophy / Movimentos compensatorios durante atividades funcionais em criancas deambuladoras com distrofia muscular de Duchenne

Objective: During the transitional phase (ambulatory to non-ambulatory), synergies characterize the evolution of Duchenne muscular dystrophy (DMD). This study was performed to describe and quantify compensatory movements while sitting down on/rising from the floor and climbing up/down steps. Method: Eighty videos (5 children × 4 assessments × 4 tasks) were recorded quarterly in the year prior to gait loss. Compensatory movements from the videos were registered based on the Functional Evaluation Scale for DMD. Results: The most frequently observed compensatory movements were upper limb support on lower limbs/floor/handrail during all the tasks and lumbar hyperlordosis, trunk support on handrail, equinus foot, increased base of support, non-alternated descent, and pauses while climbing up/down steps. Conclusion: Climbing up/down steps showed a higher number of compensatory movements than sitting down on/rising from the floor, which seemed to be lost before climbing up/down steps in ambulatory children with DMD. .

Objetivo: Durante a fase de transição (deambulador – não-deambulador), sinergias musculares caracterizam a evolução da distrofia muscular de Duchenne (DMD). Este estudo visou descrever e quantificar os movimentos compensatórios durante o sentar/levantar do solo, subir/descer degraus. Oitenta vídeos (5 crianças × 4 avaliações × 4 tarefas) foram gravados trimestralmente durante o ano que antecedeu a perda da marcha. Método: Os movimentos compensatórios dos vídeos foram registrados utilizando a Escala de Avaliação Funcional para DMD. Resultados: Os movimentos compensatórios mais frequentemente observados foram apoio de membros superiores nos membros inferiores/solo/corrimão durante todas as tarefas funcionais e hiperlordose lombar, apoio de tronco no corrimão, pés equinos, aumento da base de suporte, descida não alternada e pausas ao subir/descer degraus. Subir/descer degraus apresentou um número maior de movimentos compensatórios do que sentar/levantar do solo. Conclusão: Sentar/levantar do solo foram habilidades perdidas antes de subir/descer degraus em crianças com DMD. .

Comparison of motor strength and function in patients with Duchenne muscular dystrophy with or without steroid therapy.

OBJECTIVE: To compare muscle strength (MS) and motor function in patients with Duchenne muscular dystrophy (DMD) receiving steroids for different times against the natural evolution of DMD described by Scott et al. METHOD: 90 patients with DMD (aged 5- 12 years), receiving steroids for one to seven years, were evaluated by Medical Research Council Scale (MRC) and Hammersmith motor ability score. The relation between MS and motor abilities measurement from our data and Scott's ones were ascertained statistically. RESULTS: The relation between patient's age and Hammersmith scores revealed decrease of 0.76 point per year for age against decrease of 2.23 points on Scott's study. The relation between MRC scale and patient's age showed decrease of 0.80 point per year of age against decrease of 3.65 points on Scott's study. CONCLUSION: In patients with DMD aged five to 12 years the progression of the disease is delayed by steroids and the motor function is less reduced than muscular strength.

Comparison of motor strength and function in patients with Duchenne muscular dystrophy with or without steroid therapy / Comparação da força e função motora em pacientes com distrofia muscular de Duchenne com ou sem corticoterapia

OBJECTIVE: To compare muscle strength (MS) and motor function in patients with Duchenne muscular dystrophy (DMD) receiving steroids for different times against the natural evolution of DMD described by Scott et al. METHOD: 90 patients with DMD (aged 5- 12 years), receiving steroids for one to seven years, were evaluated by Medical Research Council Scale (MRC) and Hammersmith motor ability score. The relation between MS and motor abilities measurement from our data and Scott's ones were ascertained statistically. RESULTS: The relation between patient's age and Hammersmith scores revealed decrease of 0.76 point per year for age against decrease of 2.23 points on Scott's study. The relation between MRC scale and patient's age showed decrease of 0.80 point per year of age against decrease of 3.65 points on Scott's study. CONCLUSION: In patients with DMD aged five to 12 years the progression of the disease is delayed by steroids and the motor function is less reduced than muscular strength.

OBJETIVO: Comparar força muscular e função motora de pacientes com distrofia muscular de Duchenne (DMD) em corticoterapia com a evolução natural da doença descrita por Scott et al. MÉTODO: Noventa pacientes, entre 5 e 12 anos de idade, em corticoterapia por um até sete anos, foram avaliados quanto à força muscular (FM) (escala MRC) e função motora (Hammersmith motor ability score). A relação entre idade, FM e função motora e a comparação com o estudo de Scott et al foram determinadas estatisticamente. RESULTADOS: a relação idade/escore Hammersmith diminuiu 0,76 pontos a cada ano de aumento da idade (2,23 pontos na história natural). A relação idade/MRC decresceu 0,80 pontos a cada ano de aumento da idade (3,65 pontos na história natural). CONCLUSÃO: Nos pacientes em corticoterapia, a progressão da doença é mais lenta que na evolução natural em todas as faixas etárias avaliadas, sendo a FM mais comprometida que a função motora.

Visuospatial attention disturbance in Duchenne muscular dystrophy.

AIM: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to investigate attentional function in individuals with DMD. METHOD: Twenty-five males (mean age 12y; SD 2y 2mo) with DMD and 25 healthy males (mean age 12y; SD 2y) were tested in a visuospatial task (Posner computerized test). They were instructed to respond as quickly as possible to a lateralized visual target stimulus with the ipsilateral hand. Their attention was automatically orientated by a peripheral prime stimulus or, alternatively, voluntarily orientated by a central spatially informative cue. RESULTS: The main result obtained was that the attentional effect (sum of the benefit and the cost of attention) did not differ between the two groups in the case of automatic attention (p=0.846) but was much larger for individuals with DMD than for comparison individuals in the case of voluntary attention (p<0.001). INTERPRETATION: The large voluntary attentional effect exhibited by the participants with DMD seems similar to that of younger children, suggesting that the disease is associated with delayed maturation of voluntary attention mechanisms.

Quantification of muscle strength and motor ability in patients with Duchenne muscular dystrophy on steroid therapy.

OBJECTIVE: An assessment protocol was applied to quantify and describe muscular strength and motor abilities of 32 patients with Duchenne muscular dystrophy (DMD), aged between 5 and 12 years on steroid therapy. METHOD: Assessments were made monthly for the first six months and with intervals of two months thereafter until the 14-month end point. The tests employed included: the Medical Research Council (MRC) scale; the Hammersmith motor ability score; maximum weight lift; timed rise from floor and nine-meter walk. RESULTS: The results showed that loss of muscular strength and motor abilities were slowed in comparison to that observed in the natural evolution of the disease according to the literature. CONCLUSION: We conclude that a swift and objective assessment may be performed using the MRC scale for lower limbs and trunk, the Hammersmith motor ability score, timed nine-meter walk and weight lifts.

Quantification of muscle strength and motor ability in patients with Duchenne muscular dystrophy on steroid therapy

OBJECTIVE: An assessment protocol was applied to quantify and describe muscular strength and motor abilities of 32 patients with Duchenne muscular dystrophy (DMD), aged between 5 and 12 years on steroid therapy. METHOD: Assessments were made monthly for the first six months and with intervals of two months thereafter until the 14-month end point. The tests employed included: the Medical Research Council (MRC) scale; the Hammersmith motor ability score; maximum weight lift; timed rise from floor and nine-meter walk. RESULTS: The results showed that loss of muscular strength and motor abilities were slowed in comparison to that observed in the natural evolution of the disease according to the literature. CONCLUSION: We conclude that a swift and objective assessment may be performed using the MRC scale for lower limbs and trunk, the Hammersmith motor ability score, timed nine-meter walk and weight lifts.

OBJETIVO: Um protocolo de avaliação foi aplicado com o objetivo de quantificar e descrever evolutivamente a força muscular e as habilidades motoras de 32 pacientes com distrofia muscular de Duchenne (DMD), com idades variando de 5 a 12 anos, em corticoterapia. MÉTODO: As avaliações foram aplicadas mensalmente durante os primeiros seis meses e bimensais até completar um período de 14 meses. Os testes empregados foram: escala da "Medical Research Council" (MRC); Hammersmith "motor ability score"; levantamento da carga máxima de peso; cronometragem do tempo para levantar-se do chão e percorrer nove metros. RESULTADOS: Os resultados demonstraram que a perda da força muscular e das habilidades motoras foi mais lenta do que a observada na evolução natural da doença, como descrito na literatura internacional. CONCLUSÃO: Concluímos que uma rápida e objetiva avaliação pode ser executada utilizando a escala MRC para membros inferiores e tronco, Hammersmith motor ability score, cronometragem do tempo para percorrer 9 metros.e o levantamento de peso.

Ullrich congenital muscular dystrophy and Bethlem myopathy: clinical and genetic heterogeneity.

UNLABELLED: Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.

Dystrophin-glycoproteins associated in congenital muscular dystrophy: immunohistochemical analysis of 59 Brazilian cases.

UNLABELLED: The congenital muscular dystrophies (CMD) are heterogeneous muscular diseases with early and dystrophic pattern on muscle biopsy. Many different subtypes have been genetically identified and most phenotypes not yet identified belong to the merosin-positive (MP) CMD subgroup. OBJECTIVE: To analyze the immunohistochemical expression of the main proteins of the dystrophin-glycoproteins associated complex in muscle biopsy of patients with different CMD phenotypes, for investigating a possible correlation with clinical and histopathological data. METHOD: Fifty-nine patients with CMD had clinical, histopathological and immunohistochemical data evaluated: 32 had MP-CMD, 23 CMD with merosin deficiency (MD-CMD), one Ullrich phenotype and three Walker-Warburg disease. RESULTS: Dystrophin and dysferlin were normal in all; among the patients with MD-CMD, merosin deficiency was partial in nine who showed the same clinical severity as those with total deficiency; the reduced expression of alpha-sarcoglycan (SG) and alpha-dystroglycan (DG) showed statistically significant correlation with severe MD-CMD phenotype. CONCLUSION: There is a greater relationship between merosin and the former proteins; among MP-CMD patients, no remarkable immunohistochemical/phenotypical correlations were found, although the reduced expression of beta-DG had showed statistically significant correlation with severe phenotype and marked fibrosis on muscular biopsy.