Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

The efficacy and safety of antiepileptics in the prophylaxis of pediatric migraine: the meta-analysis of randomized controlled trials.

BACKGROUND: Migraine is the most common primary headache among children and adolescents. The aim of this meta-analysis was to evaluate the efficacy and safety of antiepileptic drugs in the prevention of pediatric migraine. METHODS: PubMed, Cochrane Library, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases were searched for eligible published RCTs from January 1970 to June 2020. Migraine frequency and ≥50% response rate were measured as the efficacy outcomes. We used "Risk of Bias" tool for quality assessment and RevMan5.3 software for statistical analysis. RESULTS: Four articles containing 7 RCTs with 794 participants compared the efficacy of AEDs with placebo. Four RCTs assessed topiramate vs. placebo and 3 RCTs evaluated divalproex sodium extended-release (DVPX ER) vs. placebo. The results demonstrated that children receiving antiepileptic drugs had a significant advantage in remitting the mean monthly migraine days compared to those who received placebo, with an MD of -0.48 (n=930, 95% CI: -0.84 to -0.12, Z=2.60, P=0.009). Topiramate significantly reduced monthly migraine days (MD =-0.70, n=489, 95% CI: -1.16 to -0.25, Z=3.01, P=0.003) but failed to improve the ≥50% response rate (MD =-1.50, n=489, 95% CI: 0.70 to 3.22, Z=1.05, P=0.30). DVPX ER did not significantly reduce monthly headache frequency (n=441, 95% CI: -0.70 to 0.47, Z=0.38, P=0.70) or improve the ≥50% response rate (n=441, 95% CI: 0.59 to 1.25, Z=0.82, P=0.41) compared with placebo. Topiramate and DVPX ER were related to higher rates of side effects and adverse reactions. DISCUSSION: Topiramate can reduce monthly headache days in children and adolescents with migraine. However, it failed to improve the ≥50% response rate. DVPX ER showed no difference from placebo in the prophylactic treatment pediatric migraine. Side effects seemed to be more frequent in topiramate and DVPX ER treated children but generally well-tolerated.