Miriam Rodrigues

BACKGROUND: Determining the prevalence of neuromuscular disorders for the general population is important to identify the scope of burden on society and enable comparisons with other health conditions. This systematic review aims to identify and collate the findings of studies published between 1960 and 2013 on the prevalence of all types of muscular dystrophies. SUMMARY: Relevant articles were identified through electronic database searches and manual searches of reference lists. There were 38 articles from across 19 countries that met the inclusion criteria. The total combined prevalence for all muscular dystrophies for studies classified as having a low risk of bias ranged between 19.8 and 25.1 per 100,000 person-years. Myotonic dystrophy (0.5-18.1 per 100,000), Duchenne muscular dystrophy (1.7-4.2) and facioscapulohumeral muscular dystrophy (3.2-4.6 per 100,000) were found to be the most common types of disorder. There was wide variation in study methodology, case ascertainment, and verification procedures and populations studied, all of which may contribute to the wide prevalence range, in addition to the likely variation in prevalence by country. Key Messages: Greater consistency in the conduct and reporting of neuroepidemiological studies is urgently needed to enable comparisons to be made between studies, countries, and over time.

Analyzing 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 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 analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 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).

BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

We examined the effect of exercise training (Ex) without (Ex 0%) or with a 3% workload (Ex 3%) on different cardiac and renal parameters in renovascular hypertensive (2K1C) male Fisher rats weighing 150-200 g. Ex was performed for 5 weeks, 1 h/day, 5 days/week. Ex 0% or Ex 3% induced similar attenuation of baseline mean arterial pressure (MAP, 119 ± 5 mmHg in 2K1C Ex 0%, N = 6, and 118 ± 5 mmHg in 2K1C Ex 3%, N = 11, vs 99 ± 4 mmHg in sham sedentary (Sham Sed) controls, N = 10) and heart rate (HR, bpm) (383 ± 13 in 2K1C Ex 0%, N = 6, and 390 ± 14 in 2K1C Ex 3%, N = 11 vs 371 ± 11 in Sham Sed, N = 10,). Ex 0%, but not Ex 3%, improved baroreflex bradycardia (0.26 ± 0.06 ms/mmHg, N = 6, vs 0.09 ± 0.03 ms/mmHg in 2K1C Sed, N = 11). Morphometric evaluation suggested concentric left ventricle hypertrophy in sedentary 2K1C rats. Ex 0% prevented concentric cardiac hypertrophy, increased cardiomyocyte diameter and decreased cardiac vasculature thickness in 2K1C rats. In contrast, in 2K1C, Ex 3% reduced the concentric remodeling and prevented the increase in cardiac vasculature wall thickness, decreased the cardiomyocyte diameter and increased collagen deposition. Renal morphometric analysis showed that Ex 3% induced an increase in vasculature wall thickness and collagen deposition in the left kidney of 2K1C rats. These data suggest that Ex 0% has more beneficial effects than Ex 3% in renovascular hypertensive rats.