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: Determiningtheprevalence 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.

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.

This study demonstrates distinct virus-inducible enhanson properties for three regions of the human beta interferon (IFN-,B) promoter; maximum vrus inducibility required syngerism among all three enhansons. Expression of the ERF-1 transcription factor differentially increased the expression of plasmids containing (AAGTGA)4 or PRDM (-94 to -78) motifs but was inefficient in the induction of the intact IFN-0 promoter.The human T-cell (11,14,38,41). The contribution of an individual enhanson to overall enhancer activity may vary in a cellspecific manner, reflecting the relative abundance and/or activity of specific transcription factors. Four distinct classes of enhansons have been described. Class A enhansons display strict spacing requirements and exhibit enhancer activity when tandem repeats of the motif are oligomerized. Class B enhansons exhibit no enhancer activity when multimerized on their own but can generate enhancer activity when juxtaposed with class A motifs (to form a proto-enhancer) and then oligomerized. Class C enhansons possess intrinsic proto-enhancer activity and, when oligomerized, form a functional enhancer element without strict spacing requirements between enhansons. Class D enhansons, exemplified by steroid response elements, display enhancer activity once the receptor is bound (14,31,36,41).Virus-induced activation of beta interferon (IFN-P) transcription is mediated by the interaction of regulatory proteins with enhanson elements in the IFN-1 promoter. In particular, a hexameric sequence, AAGTGA, permutations of which are present throughout the IFN-P promoter between -107 and -65 relative to the mRNA start site, can function as a virus-inducible or constitutive enhancer when present in tandem repeats (12,20). Multimers of the AAGTGA hexamer generate the sequence GAAAGT, which * Corresponding author.is thought to represent a high-affinity site for two DNAbinding proteins, 18,19,26,39). Recently, different types of (GAAANN)4 sequences mediating virus inducibility have been described, indicating that different hexameric sequences are not equivalent and that other IRF-like proteins are involved in alpha interferon and IFN-,B induction (37).The natural IFN-P promoter contains an interferon regulatory element (located at -77 to -37) which includes two positive regulatory domains (PRDI and PRDII) and one negative regulatory domain, as defined by mutational analysis and protein-DNA interactions (21,22,33,48,49). The PRDI domain (-77 to -64) is thought to interact with the IRF proteins (19,26,39,48), as well as with other constitutive and inducible factors (33,37,48). The PRDII domain (5'-GGGAAATTCC-3'; -64 to -55) binds NF-KB, a cellular factor involved in the transcriptional activation of several viral and cellular genes (3,6,30,32,40,43 (16,28,34,46

BackgroundSince human diets contain many components that may work synergistically to prevent or promote disease, assessing diet quality may be informative. The purpose of this study was to investigate the association between quality diet, by using Healthy Eating Index (HEI), and metabolic risk indicators in postmenopausal women.MethodsThis cross-sectional study included a total of 173 Brazilian women, aged 45-75 years, seeking healthcare at a public outpatient center. Food consumption assessed by 24 h-recall food inquiry was used to calculate HEI scores: >80 implied diet good, 80-51 diet "needed improvement", and <51 diet poor. Anthropometric data included: body mass index (BMI = weight/height2), waist-circumference (WC), body fat (%BF) and lean mass (%LM). Data on total cholesterol (TC), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), and triglycerides (TG) were also collected. Fisher's Exact test, and logistic regression method (to determine odds ratio, OR) were used in the statistical analysis.ResultsOverweight and obesity were observed in 75.7% of the participants. Excessive %BF (> 35%) was observed in 56.1%, while %LM was reduced (< 70%) in 78.1%. WC was elevated (≥88 cm) in 72.3%. Based on HEI values, diet quality was good in 3% (5/173), needed improvement in 48.5% (84/173), and was poor in 48.5% (84/173) of the cases. In this group, 75% of women had high intakes of lipids (> 35%), predominantly saturated and monounsaturated fat. On average, plasma TC, LDLC, and TG levels were higher than recommended in 57.2%, 79.2% and 45.1% of the women, respectively, while HDLC was low in 50.8%. There was association between HEI scores and the %BF that it was higher among women with HEI score < 80 (p = 0.021). There were not observed significant risk associations between HEI and lipid profile.ConclusionAmong the Brazilian postmenopausal women attending a public outpatient clinic, diet was considered to need improvement or to be of poor quality, attributed to high saturated fat ingestion, which probably caused a negative impact on metabolic risk indicators, namely body composition.

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