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.

Efficacy of deep brain stimulation of the anterior-medial globus pallidus internus in tic and non-tic related symptomatology in refractory Tourette syndrome.

Introduction: Although refractory Tourette Syndrome (TS) is rare, it poses great challenges in clinical practice. Co-morbid psychiatric symptoms often occur, negatively impacting quality of life. Deep brain stimulation (DBS) targeting different brain structures seems effective for tics, but specific literature regarding response of psychiatric symptoms is more limited.This study aimed to assess the outcome of tics and non-tic related symptomatology in refractory TS treated with antero-medial globus pallidus interna (amGPi) DBS. Methods: We included all patients with refractory TS (January 2013-August 2020) from the Brain Nerve Centre and Steve Biko Academic Hospital, Pretoria, South Africa, treated with bilateral amGPi DBS; retrospective baseline, early (up to 3 months) post-DBS follow-up assessment data, as well as prospective data from the latest follow-up (mean 37.4 months) were collected using standardised scoring tools and scales. Results: Five patients were identified. Tics decreased by 63,9% (p = 0,002); quality of life improved by 39,8% (p = 0,015); self-injurious behaviour ceased; obsessive-compulsive symptoms resolved in all but one. The number of different chronic medications used more than halved. Transient stimulation-related adverse events occurred in four patients. Conclusion: This study contributes to the data of the efficacy of amGPi-targeted DBS in refractory TS, showing improvement in quality of life and both tic- and non-tic-related symptomatology..