Low intensity training provokes adaptations on muscle fibrosis of a muscular dystrophy model / El entrenamiento de baja intensidad provoca adaptaciones en la fibrosis muscular de un modelo de distrofia muscular

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder with progressive clinical signs until death, around the second decade of life. Mdx is the most used animal model to pre-clinical studies of DMD. Parameters of exercise on this muscular disease are still unknown. This research aimed to investigate if the low intensity treadmill training would exacerbate the markers of muscle injury, fibrosis, and the composition of the extracellular matrix by type I and III collagens of the mdx model. Dystrophic 11-week-old male mice were separated in exercised (mdxE, n=8) and sedentary (mdxC, n=8) groups. Wild-type mice were used as control (WT, n=8). Exercised group underwent a LIT protocol (9 m/min, 30min, 3days/week, 60 days) on a horizontal treadmill. Gastrocnemius muscle was collected at day 60 and processed to morphological and morphometric analyzes. Sedentary mdx animals presented inflammatory infiltrate and necrotic fibers. Histochemical analysis revealed that the perimysium of the mdxC group is organized into thick and clustered collagen fibers, which generates a larger area of intramuscular collagen fibers for these animals. Histomorphometry attested that fraction area of collagen fibers of mdxC group was higher than mdxE group (p=0.04) and mdxE group values similar to WT group (p=1.00). Centrally located nuclei fibers and the variance coefficient (VC) of minimal Feret's diameter was similar in mdxE and mdxC groups (p=1.00) and both groups presented higher mean values than WT group (p<0.00). Immunohistochemistry revealed the presence of type I collagen mainly in the mdxC group. LIT protocol had not exacerbated muscle injuries resulting from the dystrophindeficiency membrane fragility at the same time that had reduced the intramuscular collagen deposition. LIT had positively influenced these markers of dystrophic muscle injury on gastrocnemius muscle of mdx model.

La distrofia muscular de Duchenne (DMD) es un trastorno neuromuscular genético con signos clínicos progresivos hasta la muerte, alrededor de la segunda década de la vida. Mdx es el modelo animal más utilizado para estudios preclínicos de DMD. Los parámetros del ejercicio en esta enfermedad muscular aún se desconocen. Esta investigación tuvo como objetivo investigar si el entrenamiento de cinta de baja intensidad exacerbaría los marcadores de lesión muscular, fibrosis y la composición de la matriz extracelular por colágenos tipo I y III del modelo mdx. Ratones machos de 11 semanas de edad con distrofia se separaron en grupos ejercitados (mdxE, n = 8) y sedentarios (mdxC, n = 8). Se usaron ratones de tipo salvaje como control (WT, n = 8). El grupo sometido a ejercicio se sometió a un protocolo LIT (9 m / min, 30 min, 3 días / semana, 60 días) en una cinta de trotar horizontal. El músculo gastrocnemio se retiró el día 60 y se procesó para realizar análisis morfológicos y morfométricos. Los animales sedentarios mdx presentaron infiltrado inflamatorio y fibras necróticas. El análisis histoquímico reveló que el perimisio del grupo mdxC está organizado en fibras de colágeno gruesas y agrupadas, lo que genera una mayor área de fibras de colágeno intramusculares para estos animales. La histomorfometría indicó que el área de fracción de las fibras de colágeno del grupo mdxC era más alta que el grupo mdxE (p = 0,04) y los valores del grupo mdxE eran similares al grupo WT (p = 1,00). Las fibras de los núcleos ubicados centralmente y el coeficiente de varianza (VC) del diámetro mínimo de Feret fueron similares en los grupos mdxE y mdxC (p = 1,00) y ambos grupos presentaron valores medios más altos que el grupo WT (p <0,00). La inmunohistoquímica reveló la presencia de colágeno tipo I principalmente en el grupo mdxC. El protocolo LIT no había agravado las lesiones musculares resultantes de la fragilidad de la membrana con deficiencia de distrofina al mismo tiempo que había reducido la deposición intramuscular de colágeno. LIT ha influido positivamente en estos marcadores de lesión muscular distrófica en el músculo gastrocnemio del modelo mdx.

Análise comparativa de qualidade de vida em indivíduos portadores da distrofia muscular de Duchenne (DMD) e distrofia muscular de cinturas (DMC) / Comparative analysis of quality of life in individuals with Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD)

Objetivo - Analisar a qualidade de vida dos pacientes com diagnóstico de distrofia muscular de Duchenne (DMD) e distrofia muscular de cinturas (DMC); compreender as experiências e necessidades dos portadores, e assim desenvolveu-se cuidados específicos e programas adequados, não somente para a reabilitação física, mas criando oportunidades para desenvolvimento da vida social. Métodos - O instrumento utilizado para avaliação desses indivíduos foi o questionário Medical Outcomes Studies 36-item Short-Form (MOS SF-36). Foram analisados oito questionários de indivíduos portadores de distrofias musculares, sendo que 3 indivíduos são portadores de DMD e 3 indivíduos de DMC. A análise dos índices foram realizadas através do cálculo do Raw Scale de forma individual. Resultados - Os indivíduos com DMD possuem menor pontuação em todos os itens descritos na escala, quando comparados aos indivíduos com DMC, que somente apresentaram alteração consideráveis no item referente a capacidade funcional. Conclusão - Os portadores de DMD apresentam pior qualidade de vida comparados aos portadores de DMC.

Objective - To analyse the quality of life of patients with Duchenne muscular distrophy (DMD) and limb-girdle muscular distrophy (LGMD); comprehend the experiences and needs of these people. The specific care develops, with appropriate programs, not only for physical rehabilitation, create opportunities for the development of a social life. Methods - The instrument used for evaluation of these individuals was the Medical Outcomes Studies 36-item Short-Form (MOS SF-36). Eight questionnaires were analyzed from patients with muscular dystrophies,and three individuals are carriers of DMD and three individuals from LGMD. The analysis of indices were performed by calculating the Raw Scale individually. Results - Individuals with DMD have lower scores on all items listed on the scale, when compared with patients with LGMD, which only showed significant changes in the item relating to functional capacity. Conclusion - DMD patients have a worse quality of life compared to patients with LGMD.

Perfil comportamental e competência social de crianças e adolescentes com distrofia muscular de Duchenne / Behavior profile and social competence in children and adolescents with Duchenne muscular dystrophy

A distrofia muscular de Duchenne é uma doença genética caracterizada por enfraquecimento muscular progressivo e degeneração irreversível, acompanhados por danos sensoriais e neuropsicológicos. Os objetivos do estudo consistiram em avaliar o perfil comportamental de crianças/adolescentes com DMD e a influência do prejuízo motor, da idade no início do uso de cadeira de rodas e da idade no diagnóstico. Participaram 34 pacientes e 20 controles. Os pacientes formaram dois grupos conforme o quociente de inteligência (QI). Os pais responderam ao Inventário de Comportamentos da Infância e da Adolescência. Pacientes com DMD obtiveram escores mais baixos em Atividades e Sociabilidade (p < 0,01; ANCOVA). Os pacientes com QI < 80 apresentaram menores índices de Escolaridade. O prejuízo motor e as idades referentes à cadeira e ao diagnóstico correlacionaram-se com sintomas psiquiátricos/somáticos e problemas escolares. Os achados enfatizam a necessidade de programas educacionais acerca da doença como base para o desenvolvimento de estratégias de inclusão social.

Duchenne Muscular Dystrophy is a genetic disease characterized by progressive muscle weakness and degeneration, which are accompanied by sensory and neuropsychological losses. The aims of this study were to evaluate the behavior profile of DMD children and adolescents and examine the influence of motor impairment, age at start using a wheelchair, and age at diagnosis on behavioral characteristics. Thirty-five patients and 20 controls participated. DMD patients formed two different groups according to the intelligence quotient (IQ). Participants' parents completed the Child Behavior Checklist. DMD groups scored lower on the Activities and the Social scales. Patients with QI < 80 presented lower indices in the School scale (p < 0.01, ANCOVA). Motor impairment and age at start using a wheelchair and at diagnosis correlated with psychiatric/somatic symptoms and school problems. The findings highlight the need of educational programs concerning the disease as a basis for the development of social inclusion strategies.

Treinamento físico na distrofia muscular de becker associada à insuficiência cardíaca / Physical training in becker muscular dystrophy associated with heart failure / Entrenamiento físico en la distrofia muscular de becker asociada a la insuficiencia cardíaca

A distrofia muscular de Becker (DMB) integra as distrofinopatias que ocorrem devido a mutações genéticas que expressam a proteína distrofina no cromossomo X. O início dos sintomas neuromusculares normalmente precede o comprometimento da função cardíaca, podendo acontecer inversamente pela insuficiência cardíaca (IC). O treinamento físico é bem estabelecido na IC, porém, quando associada à DMB, é controverso e sem fundamento científico. Apresentamos o caso de um paciente com DMB associada à IC em fila de transplante cardíaco submetido a um programa de treinamento físico.

Becker muscular dystrophy (BMD) integrates dystrophy occurring due to genetic mutations that express the dystrophin protein in chromosome X. The onset of neuromuscular symptoms usually precedes the impairment of cardiac function, and may conversely happen by heart failure (HF). Physical training is well established in HF, however, when combined with BMD, it is controversial and without any scientific basis. This study presents the case of a patient with BMD associated with HF in cardiac transplant waiting list undergoing a physical training program.

La distrofia muscular de Becker (DMB) integra las distrofinopatías que ocurren debido a mutaciones genéticas que expresan la proteína distrofina en el cromosoma X. El inicio de los síntomas neuromusculares normalmente precede el compromiso de la función cardíaca, pudiendo acontecer inversamente por la insuficiencia cardíaca (IC). El entrenamiento físico es bien establecido en la IC, sin embargo, cuando está asociada a la DMB, es controvertido y sin fundamento científico. Presentamos el caso de un paciente con DMB asociada a la IC en fila de transplante cardíaco sometido a un programa de entrenamiento físico.

Existem diferenças nos parâmetros hematológicos e bioquímicos séricos entre fêmeas normais e portadoras do modelo experimental GRMD (golden retriever muscular dystrophy)? / There are differences in hematological and biochemical parameters between carriers and not carriers of experimental model of GRMD (golden retriever muscular dystrophy)?

A proposta deste estudo foi avaliar se existem alterações nos padrões hematológicos e bioquímicos de cadelas da raça Golden Retriever portadoras do gene da distrofia muscular progressiva em comparação aos valores obtidos em cadelas não portadoras de mesma raça e idade. Foram analisados 33 animais, distribuídos em dois grupos, um composto por 19 cadelas Golden Retrievers não portadoras (GRNP) e outro composto por 14 cadelas Golden Retrievers portadoras do gene da distrofia muscular (GRP). Os dois grupos foram submetidos aos mesmos testes hematológicos e bioquímicos, com a mesma frequência e durante o mesmo intervalo de tempo. Apesar de existir diferença estatisticamente significativa entre os grupos para alguns parâmetros hematológicos avaliados, todos os resultados obtidos estavam de acordo com os valores de referência utilizados. Na avaliação dos parâmetros bioquímicos séricos a dosagem de ALT no grupo GRNP ficou levemente acima da média, porém sem grandes significados clínicos A CK também apresentou níveis elevados no grupo GRP, devido à degeneração e necrose muscular característicos da doença, as alterações encontradas nessa análise já eram esperadas. Os demais parâmetros não se alteraram.

The purpose of this study was to evaluate whether there are alterations in hematological and biochemical patterns of female Golden Retriever dogs carrying the gene for progressive muscular dystrophy compared to not carriers dogs of the same breed, age and gender. We analyzed 33 animals, divided into two groups; one consisting of 13 not carriers dogs Golden Retrievers (GRNP) and the other composed of 14 dogs Golden Retrievers carrying the gene for muscular dystrophy (GRP). Animals of both groups underwent biochemical and hematological tests with the same frequency and at the same time interval. Although there is a statistically significant difference between groups for some hematological parameters evaluated, all results were in line with the benchmarks used. In the assessment of serum biochemical parameters in the determination of ALT GRS group was slightly above average, but without major clinical significance CK also showed high levels in GRP group, due to muscle degeneration and necrosis characteristic of the disease, the changes found in this analysis were already expected. The other parameters did not change.

Ultrasonido: una alternativa en la evaluación del diafragma en niños con distrofia muscular de Duchenne / Ultrasound, an alternative in the evaluation of the diaphragm in children with Duchenne muscular dystrophy

The outcome of children with Duchenne muscular dystrophy (DMD) depends on respiratory involvement, so a timely assessment of the diaphragm is required. We propose ultrasound (US) imaging as an alternative in the evaluation of the diaphragm in children with DMD, correlating diaphragmatic thickness and excursion values yielded by the US study with pulmonary function tests. We conducted a case-control study including 27 children, 15 controls and 12 patients. Excursion and thickness of both hemidiaphragms were measured by U.S., and spirometry was performed. The DMD group showed less excursion and a significantly higher thickness of the right hemidiaphragm; 60 percent of patients showed spirometric restrictive pattern and FEV1, FVC, PEF and PIM values were significantly lower. We found a negative trend when correlating diaphragmatic excursion with pulmonary function tests. We conclude that the US technique is suitable for screening alterations in diaphragmatic excursion and thickness in children with DMD, since it provides supporting data to pulmonary function tests.

El pronóstico de los niños con distrofia muscular de Duchenne (DMD) depende del compromiso respiratorio, siendo necesaria la evaluación oportuna del diafragma. Proponemos el ultrasonido (US) como alternativa en la evaluación del diafragma en niños con DMD, correlacionando los valores de excursión y grosor del diafragma obtenido con US, con las pruebas de función pulmonar. Realizamos un estudio de casos y controles, incluyendo 27 niños, 15 controles y 12 pacientes. Se midió excursión y grosor de ambos hemidiafragmas con US; se realizó espirometría y pimometría. El grupo DMD presentó menor excursión y grosor significativamente mayor del hemidiafragma derecho; el 60 por ciento mostró patrón restrictivo en la espirometría y los valores de VEF1, CVF, FEP y PIM fueron significativamente menores. Encontramos una tendencia negativa al correlacionar la excursión diafragmática con las pruebas de función pulmonar. Concluimos que el US es apto para pesquisar alteraciones en la excursión y grosor del diafragma en niños con DMD, apoyando las pruebas de función pulmonar.

Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7 percent of the patients, deletions were found in at least one of the exons; 68 percent of these deletions were in the hot-spot 3' region. Deletions were found in 81.5 percent of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.

As distrofias musculares de Duchenne (DMD) e de Becker (DMB) são doenças causadas por mutação no gene da distrofina. Foram estudados 106 casos com a suspeita diagnóstica de DMD/BMD com a analise de 20 exons do gene da distrofina no sangue e biópsia muscular com imuno-histoquímica para distrofina em alguns casos. Em 71,7 por cento dos casos foi encontrada deleção em pelo menos um dos exons, sendo que 68 por cento das deleções localizam-se na região 3' hot spot. Foram encontradas deleções em 81,5 por cento dos DMD e em todos os BMD, sendo que os sem deleção tinham deficiência de distrofina, incluindo a mulher com DMD. As portadoras sintomáticas não tinham deleções mas anormalidades na distribuição da distrofina no sarcolema. Os outros casos sem deleção, com auxilio da biópsia muscular tiveram outros diagnósticos (atrofia muscular espinhal, miopatia congênita, deficiência de sarcoglicanos, distrofia de cinturas-membros sem classificação). A análise imuno-histoquímica para distrofina na biópsia muscular continua sendo o método mais específico para diagnóstico de DMD/DMB e deve ser utilizado quando não são encontradas deleções do gene da distrophina no sangue.

Qualidade de vida de crianças e adolescentes com distrofia muscular de Duchenne / Quality of life in adolescents and children with Duchenne muscular dystrophy

Objetivo: realizar uma revisão de literatura sobre qualidade de vida (QV) em crianças e adolescentes com distrofia muscular de Duchenne (DMD), doença caracterizada por fraqueza muscular generalizada e progressiva que leva à perda da marcha entre os 8-12 anos e ao óbito, geralmente no final daadolescência...

Utility of dystrophin and utrophin staining in childhood muscular dystrophy.

To determine the utility of dystrophin and utrophin staining in the differential diagnosis of childhood muscular dystrophy. Fifty muscle biopsies of histologically confirmed cases of childhood muscular dystrophy, below 16 years of age, were stained immunohistochemically for dystrophin and utrophin. All the 30 muscle biopsies of patients with Duchenne muscular dystrophy (DMD) showed all or majority of muscle fibers deficient for dystrophin and positive for utrophin. In the 4 female DMD carriers there was mosaic pattern of staining for dystrophin and reciprocal positivity for utrophin. All the muscle biopsies of patients with other childhood onset muscular dystrophies were positive for dystrophin and negative for utrophin. This study shows that dystrophin staining differentiates DMD and DMD carriers from other childhood muscular dystrophies and utrophin staining is of no added value. Utrophin up-regulation may compensate for structural deficiency in dystrophic muscle.

Valley sign in duchenne muscular dystrophy: importance in patients with inconspicuous calves.

Several patients of Duchenne muscular dystrophy (DMD) do not demonstrate clinically remarkable calf hypertrophy. A new clinical sign visible behind the shoulders, which may be called 'valley sign', was tested for its utility in such cases as clinical diagnosis becomes difficult in these patients. Out of 142 DMD patients seen in the last 7 years, 12 were found to have inconspicuous calves. All the 12 patients had clinical, biochemical and/or genetic evidence of DMD. The new sign was examined by 3 independent observers in these 12 DMD patients and in 10 patients with other neuromuscular diseases. Eight DMD patients and none of the others showed positive sign. This signifies importance of this sign in the clinical diagnosis of DMD in those children in whom the calf muscle bulk is apparently normal.