206th ENMC International Workshop: Care for a novel group of patients – adults with Duchenne muscular dystrophy Naarden, The Netherlands, 23–25 May 2014
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The suspect of muscular dystrophy may cause anxiety and stress among those affected and their family members. When a definite diagnosis is obtained, the scenario may be very different depending on the genetic cause. This is particularly true in the case of limb-girdle muscular dystrophies, where clinical heterogeneity among and within forms is extreme (1). In the case of Duchenne muscular dystrophy (DMD), such diagnosis corresponds to the certainty of a wheelchair confinement and a shortened life expectancy. But the age and the grade of disease progression has been modified in the course of the last decades, although a causative therapy that restores a functional dystrophin, available for DMD animal models has not yet attained a human application. However, a crucial point to evaluate supportive long life treatments is represented by objective endpoints represented by numbers. The first of these is the true life expectancy of present-day patients with a defined molecular diagnosis of DMD. An important paper (2) published ten years ago measured the mean age of death of DMD boys in Newcastle in the 1960s, which was 14.4 years; after 30 years in 1990s life expectancy was 25.3 years, but only for those receiving ventilatory support. The mean age at which patients lost their ambulation was stable at 9.3 years.
The DMD average lifespan in the course of the years improved all over the world, but both cardiac and respiratory issues must be considered: the presence of cardiomyopathy shortened life expectancy to 16.9 years.
In the current issue of Acta Myologica two papers recalculate this value and confirm the importance of preventing and treating the respiratory failure. In the study of Rall and Grimm (3) survival data were obtained for 94 German DMD patients, born between 1970 and 1980. The median life expectancy was 24 years, but survival with ventilation was 27 years. For those without ventilation it was 19 years. A second larger study (4) reviewed the notes of 835 DMD patients from 1961 to 2006 in Southern Italy. The age of 20 years was reached by 23,3% of patients born in the 1960s, 54% of patients in the 1970s and 59,8% in patients in the 1980s: the 49,2% of DMD patients of this last group were still alive at 25 years of age.
Death occurred on average at 17,7 years in DMD patients without ventilation, but shifted dramatically to 27,9 years using mechanical ventilation. Also in this report the occurrence of cardiomyopathy was very important for life expectancy: the average age of death was 19,6 years, albeit this was improved in the last 15 years.
In this last paper, the Authors propose that DMD should be also considered an adulthood disease, because half of life belongs to adulthood. Nevertheless, the course of children disease remains very severe, with all patients that loss their ambulation before puberty.
But also this may change in the next future. It is today prevalent the use of steroids to treat DMD and some LGMD forms. Steroids slow down muscle disease and improve all objective endpoints of disease. Another crucial point is the medical therapies and the occurrence of cardiomyopathy (5). Among the upcoming possible therapies, the most straightforward are represented by gene replacement strategies (6) Some recent data obtained on hamsters receiving systemic gene therapy reported a worsening of cardiac function, in parallel with skeletal muscle rescue (7-9) This may be not the case with human patients, but the point cannot be ignored considering that these is already a number of antisense oligo trials for DMD boys (10).
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Molecular biology techniques have changed the way in which we now consider a patient with Duchenne muscular dystrophy or Becker muscular dystrophy. Using cDNA probes, it has been shown that approximately 65% of the patients with Duchenne muscular dystrophy or Becker muscular dystrophy have gene deletions. The identification of a deletion allows the disease to be confirmed by noninvasive DNA testing. Furthermore, the identification of the gene defect can help distinguish Becker muscular dystrophy from other clinically similar neuromuscular disorders. Most importantly, the elucidation of the gene defects has resulted in the application of direct carrier and prenatal diagnostics.
Neuromuscular disease
Congenital muscular dystrophy
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Severe Childhood Autosomal Recessive Muscular Dystrophy (SCARMD) is a variant of sarcoglycanopathy resulting from mutation in the sarcoglycan genes. SCARMD is a rare form of muscular dystrophy characterised by severe DMD like phenotype occurring at early ages and affecting boys as well as girls. Here we are reporting a case of 7year old female child born to 3rd degree consanguineous parents presented with proximal muscle weakness beginning in both lower limbs since4 years of age. On thorough clinical examination and laboratory evaluation child turned out to be SCARMD. Hence this case report emphasizes that suspicion of SCARMD has to be made when female children presented with features of DMD, and genetic counselling and prenatal diagnosis should be done to reduce the burden of the disease in the community.
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The gait parameters (speed, stride length and cadence) of nine boys with Duchenne muscular dystrophy were compared with those of 21 normal boys in the same age range. Differences found were due to the altered ability to control their dynamic state and, to a lesser extent, physical limitations of joint range. This simple method of quantifying gait is proposed as a way in which progression or response to treatment in muscular dystrophy might be monitored. The information obtained may alert the clinician to the fact that the progressive muscle weakness and joint contractures have begun to cause compensatory mechanisms during walking to fail. It is also useful to obtain information on gait in clinical treatment trials as there are very few reliable methods for testing function in muscular dystrophy.
Joint Contracture
Muscle contracture
Cadence
Muscle weakness
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Six brothers aged from 15 months to 13 years with confirmed Duchenne's muscular dystrophy are described. The serum creatine kinase levels ranged from 2420 IU/I in the youngest boy to 769 IU/I in the eldest. The diagnosis of Duchenne's muscular dystrophy was only made when the eldest boy was 13 years old, despite the fact that his parents had sought medical advice when he was 5. The importance of early diagnosis, detection of carriers and neonatal screening is discussed in relation to the prevention of Duchenne's muscular dystrophy.
Creatine kinase
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Activity tracker
Goal Attainment Scaling
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Since there is at present no effective form of chemotherapy available to humans affected with the major types of muscular dystrophy, hereditary and experimentally induced animal models have been extensively studied to gain information about beneficial effects of various pharmacological agents and to study nerve-muscle interactions with respect to structure and function. None of the animal models, however, is directly comparable to any of the human dystrophies, and analogies drawn between them can be very misleading. However, the genetically dystrophic chicken provides a convenient model for testing drugs that may be of benefit even though the primary lesions in these animals are unknown and their relevance to human muscular dystrophies is unclear. Despite these drawbacks, the dystrophic-chicken model is an especially promising system for the study of genetically inherited myopathies because the progressive developmental onset of the disease closely mimics the human form of Duchenne muscular dystrophy in the areas of histological signs of muscle degeneration, muscle-enzyme leakage into blood, and progressive loss of functional ability. Because of the large number of similarities that the avian model of muscular dystrophy shares with Duchenne muscular dystrophy, chemotherapeutic trials in chickens can assess quantitative and qualitative parameters before clinical trials are initiated. In this chapter, both morphological and biochemical data will be presented to document a cyto-skeletal defect in avian muscular dystrophy. Isaxonine, a recently synthesized drug, retards the developmental pathological processes in the dystrophic chicken. It will be shown that by daily injection of this chemotherapeutic agent, the cytoskeletal defect in avian muscular dystrophy is corrected.
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Congenital muscular dystrophy
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Duchenne muscular dystrophy is the most frequent neuromuscular disease in children.To determine the causes of delayed diagnosis of the disease.The clinical records of 61 children diagnosed as Duchenne progressive muscular dystrophy were analyzed.the first symptoms of the disease were noticed at a mean age of 1.5 years. Parents consulted at the mean age of 3 years, but the accurate diagnosis was made at a mean age of 5.7 years. In only 15% of children, the disease was diagnosed in the first four years of age. Less than 20% of children were referred for an adequate study and the rest were managed mainly as flat feet.Duchenne dystrophy is the most common neuromuscular disorder in children, with an incidence of 1 in 3679 male newborns. The lack of recognition of non specific symptoms such as retardation in independent walking and frequent falls as forms of presentation, is probably the most important cause of diagnostic delay. Strong recommendation is made to measure creatinphosphokinase and to study every male child that is not walking independently by the age of 18 months.
Neuromuscular disease
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