Duchenne muscular dystrophy: an historical treatment review / Distrofia muscular de Duchenne: revisão histórica do tratamento

ABSTRACT In this review, we discuss the therapies used in the treatment of patients with Duchenne muscular dystrophy since the first description of the disease. A short description is given of the various theories based on disease pathogenesis, which give the substrates for the many therapeutic interventions. A brief review of the methods of evaluation used in therapeutic trials is made. Of all the treatments, the only drugs that are still considered able to modify the course of the disease are the corticosteroids (prednisone/prednisolone/deflazacort). Other drugs (coenzyme Q10 and creatine) have had a little effect in a few functions without adverse reactions. Idebenone seems to improve the respiratory function in the long term. The trials with mRNA transcription, through nonsense mutations or exon 51 skipping, show some beneficial results in a few functional tests, but they are limited to a small set of DMD patients.

RESUMO Nesta revisão são discutidas as terapêuticas empregadas no tratamento da distrofia muscular de Duchenne desde a descrição da doença. Apresentamos as diversas teorias que fundamentaram as intervenções terapêuticas, com uma breve descrição dos tipos de avaliação empregados nos ensaios terapêuticos. Dentre todos os tratamentos, a única medicação que até agora modificou o curso da doença foram os corticosteroides (prednisona/prednisolona/deflazacort). A coenzima Q10 e creatina tiveram algum efeito pequeno em algumas funções e evolução da doença sem efeitos colaterais. O idebenone mostrou efeito benéfico na função respiratória em longo prazo. As tentativas de intervir no gene da distrofina utilizando técnicas de transcrição do mRNA através das mutações sem sentido e técnicas que pulam o exon 51 mostram resultado muito discreto em algumas provas funcionais e limitado a uma parcela pequena de casos.

Immobilization and therapeutic passive stretching generate thickening and increase the expression of laminin and dystrophin in skeletal muscle

Extracellular matrix and costamere proteins transmit the concentric, isometric, and eccentric forces produced by active muscle contraction. The expression of these proteins after application of passive tension stimuli to muscle remains unknown. This study investigated the expression of laminin and dystrophin in the soleus muscle of rats immobilized with the right ankle in plantar flexion for 10 days and subsequent remobilization, either by isolated free movement in a cage or associated with passive stretching for up to 10 days. The intensity of the macrophage response was also evaluated. One hundred and twenty-eight female Wistar rats were divided into 8 groups: free for 10 days; immobilized for 10 days; immobilized/free for 1, 3, or 10 days; or immobilized/stretched/free for 1, 3, or 10 days. After the experimental procedures, muscle tissue was processed for immunofluorescence (dystrophin/laminin/CD68) and Western blot analysis (dystrophin/laminin). Immobilization increased the expression of dystrophin and laminin but did not alter the number of macrophages in the muscle. In the stretched muscle groups, there was an increase in dystrophin and the number of macrophages after 3 days compared with the other groups; dystrophin showed a discontinuous labeling pattern, and laminin was found in the intracellular space. The amount of laminin was increased in the muscles treated by immobilization followed by free movement for 10 days. In the initial stages of postimmobilization (1 and 3 days), an exacerbated macrophage response and an increase of dystrophin suggested that the therapeutic stretching technique induced additional stress in the muscle fibers and costameres.

Detección de alteraciones numéricas en el gen dys y su asociación con rasgos clínicos / Numeric alterations in the dys gene and their association with clinical features

La distrofia muscular de Duchenne/Becker (DMD/B) es una miopatía hereditaria grave y progresiva. Se relaciona con alteraciones en el gen DYS, ubicado en el cromosoma X, que codifica para la proteína distrofina. Distintas manifestaciones pueden observarse según el impacto de la alteración genética sobre la proteína. Los registros internacionales de mutaciones refieren una elevada frecuencia (65-70%) de deleciones/duplicaciones de uno o más exones del gen DYS. En este trabajo presentamos el estudio de alteraciones numéricas en los 79 exones del gen DYS. El estudio fue realizado en 59 individuos pertenecientes a 31 familias no relacionadas. La metodología utilizada fue Multiplex Ligation Dependent Probe Amplification (MLPA). En los 31 casos independientes se estableció además el score clínico, se realizó el test de Raven y se determinaron los valores de creatininfosfoquinasa (CPK) en sangre. Nuestros datos revelan una frecuencia de alteraciones numéricas en el gen DYS del 61.3%, provocando un corrimiento del marco de lectura en el 100% de los casos. Se observó una región con mayor tendencia a presentar alteraciones que involucran un solo exón. La tasa de mutación de novo identificada fue del 35.2%. Se halló, a su vez, una asociación significativa entre afectados con alteraciones numéricas y valores del test de Raven de bajo rendimiento. Estos resultados aportan datos a los conocimientos regionales sobre las alteraciones genéticas y su impacto fenotípico en la enfermedad de Duchenne/Becker.

The Duchen ne/Becker muscular dystrophy is a hereditary miopathy with a recessive sex-linked pattern. The related gene is called DYS and the coded protein plays a crucial role in the anchorage between the cytoskeleton and the cellular membrane in muscle cells. Different clinical manifestations are observed depending on the impact of the genetic alteration on the protein. The global register of mutations reveals an enhanced frequency for deletions/duplications of one or more exons affecting the DYS gene. In the present work, numeric alterations have been studied in the 79 exons of the DYS gene. The study has been performed on 59 individuals, including 31 independent cases and 28 cases with a familial link. The applied methodology was Multiplex Ligation Dependent Probe Amplification (MLPA). In the 31 independent cases clinical data were established: i.e. the clinical score, the Raven test percentiles, and the creatininphosphokinase (CPK) blood values. Our results reveal a 61.3% frequency of numeric alterations affecting the DYS gene in our population, provoking all of them a reading frame shift. The rate for de novo mutations was identified as 35.2%. Alterations involving a specific region of one exon were observed with high frequency, affecting a specific region. A significant association was found between numeric alterations and a low percentile for the Raven test. These data contribute to the local knowledge of genetic alterations and their phenotypic impact for the Duchenne/Becker disease.

Carrier Woman of Duchenne Muscular Dystrophy Mimicking Inflammatory Myositis

Carrier woman of Duchenne muscular dystrophy (DMD) can mimic the inflammatory myositis in presenting symptoms. Two diseases should be differentiated by the clinical history, muscle biopsy and genetic study. There are few reports in which both histochemical and genetic study showed the possible link of overlapping inflammatory pathophysiology with dystrophinopathy. We report a 40-yr-old woman who presented with subacute proximal muscle weakness and high serum level of creatine kinase. She had a history of Graves' disease and fluctuation of serum liver aminotransferase without definite cause. MRI, EMG and NCV were compatible with proximal muscle myopathy. Muscle biopsy on vastus lateralis showed suspicious perifascicular atrophy and infiltration of mono-macrophage lineage cells complicating the diagnosis. Dystrophin staining showed heterogeneous diverse findings from normal to interrupted mosaic pattern. Multiple ligation probe amplification and X chromosome inactivation test confirmed DMD gene deletion mutation in exon 44 and highly skewed X inactivation.

The expression of dystrophin in human viral myocarditis and dilated cardiomyopathy / 法医学杂志

OBJECTIVE@#In order to improve the accuracy and reliability in sudden cardiac death, the pathogenesis and relationship between the viral myocarditis and dilated cardiomyopathy were investigated.@*METHODS@#Improved immunohistochemical technique was adopted to detect the expression of the dystrophin in myocardium from 25 viral myocarditis, 28 dilated cardiomyopathy and 17 control cases including normal, coronary atherosclerotic heart disease and hypertension heart disease as control.@*RESULTS@#The positive rate of dystrophin protein expression in control group was 100%, that in viral myocarditis was 88%, and that in dilated cardiomyopathy was 57%, There were significant differences among three groups (P<0.05), and the correlation between viral myocarditis and dilated cardiomyopathy group (r = -0.526)were also found.@*CONCLUSION@#The myocardial cytoskeletal protein is disrupted in viral myocarditis and dilated cardiomyopathy, and the dystrophin protein may be involved in the pathogenesis of viral myocarditis and dilated cardiomyopathy. The viral infect and impair heart functions by cleaving host dystrophin proteins may ultimately contributes to the viral myocarditis to the converting from dilated cardiomyopathy.

Immunohistochemical alterations of dystrophin in congenital muscular dystrophy

Foi estudada a distribuiçäo da distrofina na membrana plasmática das fibras musculares em 22 crianças com distrofia muscular congênita, através de técnicas de imuno-histoquímica. A distrofina foi identificada nas biópsias musculares processadas a fresco, por técnicas de imunofluorescência utilizando anticorpos policlonais. Todos os casos tinham interrupçöes da imunofluorescência na membrana plasmática. Em 17 elas eram grandes, em 12 eram pequenas e em 7 eram de ambos os tipos. Fibras com interrupçöes pequenas e constantes, como um rosário, foram vistas em 15 casos. Essas anormalidades estavam presentes em todas as fibras em 5 casos, eeram freqüentes em 8, ocasionais em 5 e raras em 4. Cinco casos mostraram fibras sem distrofina. Esses dados sugerem que a expressäo da distrofina é anormal nesse grupo de crianças. Essas anormalidades podem também ser encontradas em casos precoces de distrofia muscular de Becker e distrofia autossômica recessiva da infância. Portanto, isoladamente a imuno-histoquímica näo permite a diferenciaçäo