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.

Successful Coil Embolization of a Large Anterior Tibial Artery Pseudoaneurysm After Open Reduction Internal Fixation of a Bi-condylar Tibial Plateau Fracture.

Pseudoaneurysms are false aneurysms that consist of turbulent blood flow between the outside layers of the arterial wall, the tunica media and tunica adventitia. Typically, pseudoaneurysms develop after injury to an artery, most often as a result of blunt trauma. Femoral pseudoaneurysms can also develop after catheter-based vascular interventions due to laceration of the artery from access needles, insufficient time or pressure held at the access site after the procedure, amongst other causes. Rarely, arterial injury during orthopedic pinning procedures has been known to cause pseudoaneurysms. There are only two documented cases within the literature in which a patient underwent closed intermedullary nailing of a proximal tibia fracture after trauma and developed an anterior tibial artery pseudoaneurysm. There are few reports of pseudoaneurysm development as the result of external fixation device placement presumably caused by the inability to directly visualize internal anatomy.

Screening for cerebrovascular disease in microcephalic osteodysplastic primordial dwarfism type II (MOPD II): an evidence-based proposal.

Microcephalic osteodysplastic primordial dwarfism type II (OMIM 210720) is a rare autosomal recessive condition frequently associated with early-onset cerebrovascular disease. Presymptomatic detection and intervention could prevent the adverse consequences associated with this. We reviewed published cases of microcephalic osteodysplastic primordial dwarfism type II to ascertain prevalence and characteristics of cerebrovascular disease and use these data to propose an evidence-based approach to cerebrovascular screening. Of 147 cases identified, 47 had cerebrovascular disease (32%), including occlusive arteriopathy (including moyamoya) and cerebral aneurysmal disease. Occlusive disease occurred in younger individuals, and progression can be both rapid and clinically silent. A reasonable screening approach would be magnetic resonance imaging and angiography of the cervical and intracranial circulation at diagnosis, repeated at yearly intervals until 10 years, and every 2 years thereafter, unless clinical concerns occur earlier. At present it would appear that this needs to be life-long. Families and professionals should be alerted to the potential significance of neurologic symptoms and measures should be taken to maintain good vascular health in affected individuals.