[Show abstract][Hide abstract] ABSTRACT: Analysing the type and frequency of patient specific mutations that give rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. Locus specific databases (LSDBs) allow for the collection, organization, storage and analysis of genetic variants of disease. Here we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analysed genetic data for 7149 DMD mutations held within the database. 5682 large mutations were observed (80% of total mutations), of which 4894 (86%) were deletions (1 exon or larger), and 784 (14%) were duplications (1 exon or larger). There were 1445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Human Mutation 01/2015; 36(4). DOI:10.1002/humu.22758 · 5.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated.
To assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes.
On 17 November 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched reference lists of articles, conference proceedings of relevant conferences, and prospective trial registers. In addition, we contacted manufacturers and researchers in the field.
We considered randomised controlled trials (RCTs) and quasi-RCTs comparing ephedrine as a single or add-on treatment with any other active treatment, placebo, or no treatment in adults or children with autoimmune MG, NMG, or CMSs.
Two review authors independently assessed study design and quality, and extracted data. We contacted study authors for additional information. We collected information on adverse effects from included articles, and contacted authors.
We found no RCTs or quasi-RCTs, and therefore could not establish the effect of ephedrine on MG, NMG and CMSs. We describe the results of 53 non-randomised studies narratively in the Discussion section, including observations of endurance, muscle strength and quality of life. Effects may differ depending on the type of myasthenia. Thirty-seven studies were in participants with CMS, five in participants with MG, and in 11 the precise form of myasthenia was unknown. We found no studies for NMG. Reported adverse effects included tachycardia, sleep disturbances, nervousness, and withdrawal symptoms.
There was no evidence available from RCTs or quasi-RCTs, but some observations from non-randomised studies are available. There is a need for more evidence from suitable forms of prospective RCTs, such as series of n-of-one RCTs, that use appropriate and validated outcome measures.
[Show abstract][Hide abstract] ABSTRACT: Objective
The aim of this study was to evaluate age-related changes in metabolic walking energy expenditure in ambulant boys affected by Duchenne muscular dystrophy over a follow-up period of 12 months.
At baseline (T1) and 12 months later (T2), metabolic walking energy expenditure was assessed during a 6-minute walk test at comfortable speed in 14 ambulant boys with Duchenne (age range: 6.0-12.5 years, mean 8.2). Outcome measures derived from the assessment included the 6-minute comfortable walking distance (m) and net-nondimensional energy cost relative to speed-matched control cost (SMC-EC, %). Statistical comparisons were made using a two-way repeated measures ANOVA (factors: time (T1 versus T2) and age (<8 years of age (yoa) versus ≥8 yoa)).
Over the course of the study, a significant decrease of -28m (−8.2%, p = 0.043) was noted in the walked distance at comfortable speed. Besides, SMC-EC increased with 4.4%, although this change was not significant (p = 0.452). Regarding age groups, boys below 8 yoa showed a smaller annual decrease in the walked distance (−15 m) compared to boys above 8 yoa (−37 m). SMC-EC increased with 10% in the older boys, while in the younger boys it decreased (−2.1%). The main effect of age group on walking distance and SMC-EC however was not significant (p>0.158), and also there were no interaction effects (p>0.248).
The results of our small study suggest that the natural course of walking performance in ambulant boys with Duchenne is characterized by a decrease in comfortable walking distance and an increase in walking energy cost. The rate of energy cost seems to increase with age, while walking distance decreases, which is opposite from the trend in typically developing children.
PLoS ONE 12/2014; 9(12):e115200. DOI:10.1371/journal.pone.01152 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5,2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggest an underlying autoimmune mechanism, supporting the use of immune therapy.
[Show abstract][Hide abstract] ABSTRACT: Becker muscular dystrophy (BMD) presents with limb-girdle distribution of muscle weakness similar to limb girdle muscular dystrophies (LGMDs). To facilitate the differential diagnosis and direct genetic testing clinical markers indicating towards BMD could be helpful in the diagnostic process. We investigated if a combination of muscle testing and MRI could provide a diagnostic marker. Quantitative muscle testing of hip-flexors and extensors, knee-flexors and extensors was performed. To minimize confounding effects of age and weight, mean z-scores for muscle strength of the individual groups was calculated. On 3T MRI the gluteus maximus, iliopsoas, vastus lateralis, medialis and intermedius, rectus femoris, biceps femoris long and short head, semimembranosus, semitendinosus and sartorius were scored for fatty infiltration: 1 = normal, 2 = fatty streaks, 3 = <30%, 4 = 30–60% and 5 = >60%. Eleven patients (mean age 39 years, range 20–63) with variable symptoms ranging from no motor symptoms (n = 3) to wheelchair dependence (n = 1) were tested. Ten patients had negative z-scores and all had fatty infiltration on MRI. Overall knee extension showed the lowest z-score followed by knee flexion, hip extension, while hip flexion was relatively spared. In terms of fatty infiltration the biceps femoris long head was most severely affected and the iliopsoas least. Evaluation of the mean fatty infiltration score of the tested groups showed the highest mean fat score for hip extension muscles followed by knee flexion, knee extension, while hip flexion again appeared relatively spared. We show that in BMD patients hip flexion is spared compared to the other investigated muscles, which is mirrored by the MRI. This could be a valuable clue in the clinical setting as in LGMDs like type 2L and 2A, relatively common in the Netherlands, hip flexion is usually clearly affected. Thus, spared hip flexion on muscle testing or MRI in males with LGMD patters of weakness points to a diagnosis of BMD.
[Show abstract][Hide abstract] ABSTRACT: Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness, with a large variation of disease progression. To investigate possible causes for this diversity it is necessary to compare the disease course between different BMD patients. Due to the rarity of the disease, it is difficult to compose and study large groups of patients of the same age. Therefore we have developed a model to enable comparison of disease severity in BMD patients of different ages. For this purpose, Dutch and Flemish DNA-confirmed BMD patients were interviewed using a standardized questionnaire focusing on the age at reaching five disease milestones: first motor symptoms, difficulty walking stairs, use of a walking aid, wheelchair dependence and mechanical home ventilation. Each patient received 10 points for the age at which a specific milestone was reached and an individual composite score was calculated for each age. Combining the results of all participants, a population mean score was calculated at each age individually. Information was gathered from 113 BMD patients, ranging in age from 6 to 66 (median 39) years. Estimated mean survival for reaching the individual disease milestones was: first motor symptoms 11 years (SE 0.92; n = 109), difficulties walking stairs 25 years (SE 1.5; n = 90), use of a walking aid 37 years (SE 1.8; n = 71), wheelchair dependence 50 years (SE 2.0; n = 35) and mechanical home ventilation 63 years (SE 1.2; n = 5). Out of all individual data a model for disease severity was calculated. The maximum score in this model was 50 points. Mean population scores at age 10, 20, 30, 40, 50 and 60 years respectively were 8.4, 16.7, 20.2, 23.7, 26.8 and 30. When combining these mean scores with their SD, individual Z-scores can be calculated, enabling comparison of disease severity in BMD patients of different ages. As long as no prospectively collected long-term follow-up data are available, this scale could form a useful tool for clinical research in BMD.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES Thymectomy is frequently used in the treatment of myasthenia gravis (MG). But indication, timing or surgical approach remain
controversial. This study reports our experiences with robotic thymectomy and surgical and neurological outcomes in a large
cohort of patients with MG.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 09/2014; 48(1). DOI:10.1093/ejcts/ezu352 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to assess leg muscle quality and give a detailed description of leg muscle involvement in of Duchenne muscular dystrophy patients using quantitative MRI and strength measurements. Fatty infiltration, as well as total and contractile (not fatty infiltrated) cross sectional areas of various leg muscles were determined in 16 Duchenne patients and 11 controls (aged 8 to 15). To determine specific muscle strength, four leg muscle groups (quadriceps femoris, hamstrings, anterior tibialis and triceps surae) were measured and related to the amount of contractile tissue. In patients, the quadriceps femoris showed decreased total and contractile cross sectional area, attributable to muscle atrophy. The total, but not the contractile, cross sectional area of the triceps surae was increased in patients, corresponding to hypertrophy. Specific strength decreased in all four muscle groups of Duchenne patients, indicating reduced muscle quality. This suggests that muscle hypertrophy and fatty infiltration are two distinct pathological processes, differing between muscle groups. Additionally, the quality of remaining muscle fibers is severely reduced in the legs of Duchenne patients. The combination of quantitative MRI and quantitative muscle testing could be a valuable outcome parameter in longitudinal studies and in the follow-up of therapeutic effects.