Physiotherapy and Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe, progressive disease first described by Meryon in 1852 and later by Guillaume Duchene. It is the most common and severe form of childhood muscular dystrophy, affecting 1 in 3500 live male births. Is caused by an X—linked recessive genetic disorder resulting in a deficiency of the dystrophin protein, responsible for linking contractile proteins to the sarcolemma. Diagnosis is not always easy and the first symptoms are often related to weakness and difficulty or delay in acquiring the ability to perform simple activities. Progressive weakness leads to the use of compensatory strategies in order to maintain the ability to walk and perform other activities. Respiratory muscles are also affected and the complications resulting from its impairments are frequently the cause of early death of these patients. The advances in DMD management has increased life expectancy of these children with the need for adequate care in adulthood. DMD manifestations include muscle weakness, contractures, respiratory and cardiac complications. Some authors also refer that one-third of patients have difficulties with learning and delayed global development because the gene that encodes dystrophyn expresses various dystrophin isoforms that are found in Schwann and Purkinje celis in the brain. Body functions and structure impairments like muscle weakness, contractures and reduced range of motion lead to limitations in activities, i.e., impairments affect the performance of tasks by the individual. In a physiotherapist’s point of view analysing these limitations is mandatory because physiotherapy’s final purpose is to restore or preserve the ability to perform ADL and to improve quality of life.

LAMA2 Gene Analysis in a Cohort of 26 Congenital Muscular Dystrophy Patients

Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-alpha2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin-alpha2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750-1713_7899-2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin-alpha2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.

Sleep disorders in boys with Duchenne muscular dystrophy.

Aim:  Determine the frequency and predictors of sleep disorders in boys with Duchenne Muscular Dystrophy (DMD). Method:  Cross-sectional study by postal questionnaire. Sleep disturbances were assessed using the Sleep Disturbance Scale for Children (validated on 1157 healthy children). A total sleep score and six sleep disturbance factors representing the most common sleep disorders were computed. Potential associations between pathological scores and personal, medical and environmental factors were assessed. Results:  Sixteen of 63 boys (25.4%) had a pathological total sleep score compared with 3% in the general population. The most prevalent sleep disorders were disorders of initiating and maintaining sleep (DIMS) 29.7%, sleep-related breathing disorders 15.6% and sleep hyperhydrosis 14.3%. On multivariate analysis, pathological total sleep scores were associated with the need to be moved by a carer (OR = 9.4; 95%CI: 2.2-40.7; p = 0.003) and being the child of a single-parent family (OR = 7.2; 95%CI: 1.5-35.1; p = 0.015) and DIMS with the need to be moved by a carer (OR = 18.0; 95%CI: 2.9-110.6; p = 0.002), steroid treatment (OR = 7.7; 95%CI: 1.4-44.0; p = 0.021) and being the child of a single-parent family (OR = 7.0; 95%CI: 1.3-38.4; p = 0.025). Conclusion:  Sleep disturbances are frequent in boys with DMD and are strongly associated with immobility. Sleep should be systematically assessed in DMD to implement appropriate interventions.

Chest pain and ST-segment elevation in a patient with Duchenne muscular dystrophy, what really happened?

Introduction: Myocardial infarction is rare in children, if it occurs, findings are almost similar to adults. In Ouchenne muscular dystrophy (OMO), ST segment displacement associated with typical chest pain can occur. We report the case of a young boy with OMO presenting symptoms suggestive of myocardial ischemia. Case report: 7 year old boy, diagnosed with OMO, eoming to the emergency department with complaints of acute chest pain, dyspnoea and anxiety the night before. Clinical examination was not remarkable, with exception of findings of the OMO. ECG showed important ST-segment elevation in right precordial leads. Major increase in troponin 1 42.33 mcg/(normal, <0.04 mcg/I) was found. Echocardiography revealed slight yskinesia of postero-septal wall without decrease in ventricular function. As acute pain had happened more han 12 hours before referral and as the child was asymptomatic, he received anti-platelets therapy. The serum level of troponin 1 declined and the ECG normalised in a few days. Cardiac catheterization did not show any coronary anomaly or eardiac dysfunction. Cardiac biopsy revealed myocardial cell damaged compatible with OMO cardiomyopathy. Tc99m myocardial single-photon emission computed tomography (SPECT) did not show any radionuclide uptake defect. Conclusions: ln this particular context of children with OMO, the classical signs of myocardial ischemia could be misleading, standard investigation failed to demonstrate the cause of chest pain and inerease of troponin l, there was also no evidence of myocarditis. Role of late enhancement (LE) signal in eontrast-enhanced MRI in the understanding of the occurring process has to be evaluated.

Marked hemiatrophy in carriers of Duchenne muscular dystrophy.

OBJECTIVE: To describe the clinical and molecular genetic findings in 2 carriers of Duchenne muscular dystrophy (DMD) who exhibited marked hemiatrophy. Duchenne muscular dystrophy is an X-linked disorder in which affected male patients harbor mutations in the dystrophin gene. Female patients with heterozygous mutations may be manifesting carriers. DESIGN: Case study. SETTING: Neurology clinic. PATIENTS: Two manifesting carriers of DMD. INTERVENTIONS: Clinical and radiologic examinations along with histologic and molecular investigations. RESULTS: Both patients had marked right-sided hemiatrophy on examination with radiologic evidence of muscle atrophy and fatty replacement on the affected side. In each case, histologic analysis revealed a reduction in dystrophin staining on the right side. Genetic analysis of the dystrophin gene revealed a tandem exonic duplication in patient 1 and a multiexonic deletion in patient 2 with no further point mutations identified on the other chromosome. CONCLUSIONS: Marked hemiatrophy can occur in DMD manifesting carriers. This is likely to result from a combination of skewed X-inactivation and somatic mosaicism.

Respiratory surveillance of patients with Duchenne and Becker muscular dystrophy.

Duchenne muscular dystrophy is is the most common form of the childhood muscular dystrophies. It follows a predictable clinical course marked by progressive skeletal muscle weakness, lost of ambulation before teen-age and death in early adulthood secondary to respiratory or cardiac failure. Becker muscular dystrophy is less common and has a milder clinical course but also results in respiratory and cardiac failure.Altough recent advances in respiratory care and new technologies have improved the outlook many patients already received only a traditional non-interventional approach. The aims of this work are: to analyse the pathophysiology and natural history of respiratory function in these diseases, to descript their clinical manifestations, to present the diagnostics tools and to provide recommendations for an adequated respiratory care in this particular population based on the updated literature referenced.

Orofacial dysfunction in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) affects orofacial function. Our aim was to evaluate certain characteristics of orofacial function in DMD and relate possible deteriorations to the age of the patients and to the diminished internal structure quality of the masseter muscle. Bite force and finger force were measured in 16 DMD patients (6-20 years old) and 16 age matched controls. The thickness and internal structure quality of the masseter muscle were evaluated ultrasonographically. We found reduced mouth opening but no signs of masticatory muscle tenderness. Bite force values were lower for DMD patients. Masseter thickness showed no significant differences between the two groups, but poorer internal muscle structure quality characterised the elder, non-walking DMD patients explaining their low bite force values. In conclusion, the masseter muscle follows the general progress of the disease. Orofacial function in DMD patients is becoming ever more important as their life expectancy increases.

Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor

In Duchenne muscular dystrophy (DMD), a persistently altered and reorganizing extracellular matrix (ECM) within inflamed muscle promotes damage and dysfunction. However, the molecular determinants of the ECM that mediate inflammatory changes and faulty tissue reorganization remain poorly defined. Here, we show that fibrin deposition is a conspicuous consequence of muscle-vascular damage in dystrophic muscles of DMD patients and mdx mice and that elimination of fibrin(ogen) attenuated dystrophy progression in mdx mice. These benefits appear to be tied to: (i) a decrease in leukocyte integrin α(M)β(2)-mediated proinflammatory programs, thereby attenuating counterproductive inflammation and muscle degeneration; and (ii) a release of satellite cells from persistent inhibitory signals, thereby promoting regeneration. Remarkably, Fib-gamma(390-396A) (Fibγ(390-396A)) mice expressing a mutant form of fibrinogen with normal clotting function, but lacking the α(M)β(2) binding motif, ameliorated dystrophic pathology. Delivery of a fibrinogen/α(M)β(2) blocking peptide was similarly beneficial. Conversely, intramuscular fibrinogen delivery sufficed to induce inflammation and degeneration in fibrinogen-null mice. Thus, local fibrin(ogen) deposition drives dystrophic muscle inflammation and dysfunction, and disruption of fibrin(ogen)-α(M)β(2) interactions may provide a novel strategy for DMD treatment.

Essais thérapeutiques dans la dystrophie musculaire de Duchenne: entre espoirs et désespoirs [Therapeutic trials for Duchenne muscular dystrophy: between hopes and disappointments].

Duchenne muscular dystrophy is an X-linked progressive muscle disease. Since the discovery of the dystrophin gene responsible for the condition, various therapeutic strategies have been elaborated. In this paper we introduce three of them, which are well into clinical trials. The first is based on the ability to read through premature stop codons, the second is based on the technique of exon skipping. Both strategies are examples of "personalized medicines", tailored for specific mutation types. The third approach is a pharmacological one, potentially useful for all Duchenne patients, regardless of their mutation type. These first clinical trials raise many questions for researchers as well as for patients and their families, some of which are discussed.

Sleep disorders in boys with Duchenne muscular dystrophy

Introduction La dystrophie musculaire de Duchenne (DMD) est une myopathie progressive liée au chromosome X qui atteint environ un garçon sur 3500. Des troubles du sommeil (TDS) sont fréquemment rapportés par ces patients Les études effectuées à ce jour se sont essentiellement concentrées sur les troubles respiratoires liés au sommeil. Les TDS débutent toutefois fréquemment avant l'installation d'un trouble ventilatoire nocturne et de nombreux autres facteurs peuvent en être la cause. Objectif L'objectif de cette étude est d'évaluer la fréquence des TDS chez les garçons avec une DMD et d'en identifier les facteurs de risque. Méthode II s'agit d'une étude transversale effectuée par questionnaire postal adressé aux parents de tout garçon âgé de 4-18 ans avec une DMD, suivi dans deux centres tertiaires de réhabilitation pédiatrique (Lausanne et Dublin). Les TDS sont évalués à l'aide de la 'Sleep Disturbance Scale for Children' (SDSC), validée sur 1157 enfants sains. Elle permet d'obtenir un score total et des scores pour six facteurs représentant les TDS les plus fréquents (troubles de l'endormissement et du maintien du sommeil (TEMS), éveil nocturne-cauchemars, transition veille-sommeil, somnolence diurne excessive, troubles respiratoires associés au sommeil (TRS), hyperhidrose du sommeil). Un T- score supérieur à 70 (>2DS) est considéré comme pathologique. Les associations potentielles entre des scores pathologiques et des facteurs individuels (âge, mobilité diurne et nocturne, douleur), thérapeutiques (orthèses nocturnes, ventilation non-invasive, médication) et environnementaux (facteurs socio-familiaux) sont évaluées à l'aide d'analyses univariées (χ2) et de régressions logistiques ascendantes. Résultats Seize garçons sur 63, soit 25.4%, présentent un score total pathologique en comparaison au 3% attendus dans la population générale. Les TEMS (29.7%), les TRS (15.6%) et l'hyperhidrose du sommeil (14.3%) sont les TDS les plus prévalent. Le besoin d'être mobilisé la nuit par un tiers (OR=9.4; 95%CI: 2.2-40.7; p=0.003) et être l'enfant d'une famille monoparentale (OR=7.2; 95%CI: 1.5-35.1; p=0.015) sont des facteurs de risque indépendants pour un score total pathologique. Le besoin d'être mobilisé la nuit par un tiers (OR=18.0; 95%CI: 2.9¬110.6; p=0.002), le traitement par corticostéroïdes (OR=7.7; 95%CI: 1.4-44.0; p-0.021) et être l'enfant d'une famille monoparentale (OR=7.0; 95%CI: 1.3-38.4; p=0.025) sont des facteurs de risque indépendants pour un TEMS. Discussion Cette étude montre une prévalence élevée des TDS chez les garçons avec une DMD (25% contre 3% attendus dans la population générale). Le besoin d'être mobilisé la nuit par un tiers est identifié comme un facteur de risque important pour un score total pathologique et un TEMS. Il reflète vraisemblablement un degré d'atteinte motrice tel qu'il limite les mouvements spontanés et les adaptations posturales du sommeil, ayant pour conséquence une diminution importante de la qualité du sommeil. Les enfants vivant dans un foyer monoparental présentent plus fréquemment un score total pathologique et des TEMS, possiblement en lien avec un stress psychologique plus important dans ces familles. Le traitement par corticostéroïdes est identifié comme facteur de risque pour un TEMS. Une adaptation du schéma ou du dosage permet généralement de limiter cet effet secondaire. Si nécessaire, un traitement par Mélatonine peut être instauré. Aucune association n'a pu être mise en évidence entre les facteurs analysés et les TRS, possiblement en raison du petit nombre de garçons ayant rapporté de tels symptômes et du fait que certains symptômes d'hypoventilation nocturne ne sont pas évalués par la SDSC. Par ailleurs, la valeur prédictive de l'anamnèse, comme celle des fonctions pulmonaires diurnes, est connue pour être limitée, raison pour laquelle une oxy-capnométrie est effectuée de routine en dessous d'une capacité vitale forcée de 50%. Elle permet, si nécessaire, l'instauration précoce d'une ventilation non-invasive, limitant ainsi vraisemblablement l'impact de ('hypoventilation nocturne sur la qualité du sommeil dans notre population. Plusieurs limitations sont à évoquer. Le petit nombre de patients ne permet pas d'exclure d'autres associations potentielles. La nature transversale de l'étude augmente le risque de causalité inverse. Cette étude n'inclut pas de mesure quantitative du sommeil. Les questionnaires adressés aux parents ont toutefois pu être démontrés comme fiables hormis pour les TRS. Un biais de non-réponse ne peut pas être totalement exclu, bien que le taux de réponse soit élevé (86,5%) et qu'il n'y ait pas de différence significative entre les populations de répondeurs et non-répondeurs. Conclusion La prévalence des TDS est élevée chez les garçons avec une DMD et leurs causes sont multiples. Les facteurs de risques sont physiques (immobilité nocturne), pharmacologiques (corticothérapie) et environnementaux (famille monoparentale). Compte tenu de son impact sur la qualité de vie, l'évaluation du sommeil doit être systématique en consultation et ne pas se limiter aux seuls troubles ventilatoires nocturnes.

The TREAT-NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.

Continuous monitoring and quantification of multiple parameters of daily physical activity in ambulatory Duchenne muscular dystrophy patients.

Multiple motor function and strength assessment tools exist for the evaluation of neuromuscular diseases, but most do not directly assess functional ability in the patients' daily physical activity in their home environment. In this study our aim was to assess: 1) the feasibility and accuracy of physical activity monitoring during two days in a home environment of five DMD patients using a non-commercialized monitor containing a 3D accelerometer and a gyroscope, 2) if a difference in the physical activity parameters could be measured before and one month after starting prednisolone. We reliably quantified the time spend sitting, standing, lying, walking, the number of steps taken, the cadence, the number of walking episodes and their duration as well as how these were distributed over the day. Parameters possibly reflecting endurance, such as the duration of the walking episodes or the succession of two or three walking episodes lasting more than 30 s were the most improved after prednisolone treatment. This degree of detailed determination of physical activity in a home environment has not been previously reported in neuromuscular disorders to our knowledge and some of the reported parameters are potential new outcome measures in clinical trials.