Etiological Role of Parasitic Exposure and Familial Susceptibility in Nodding Syndrome-Related Epilepsies

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Project Summary The K01 application for Dr. Rajarshi Mazumder, a board-certified epileptologist at University of California, Los Angeles, will allow him to establish as an independent investigator in global health and epilepsy research. The K01 will provide Dr. Mazumder support and protect time to achieve the following career development goals: 1) gain expertise in molecular epidemiology-- training in design and conduct of research using genetic data and model the effects of genes and their interactions with environmental factors; 2) Advanced statistical training for population health; 3) Lead research in a resource-constrained setting and training in the responsible conduct of research in global health; 4) Grant writing. To accomplish his career goals, Dr. Mazumder has assembled a team of mentors with complimentary expertise in Uganda and the US. More than 80% of people with epilepsy live in low-to middle-income countries, where despite the high incidences, many commonly occurring epilepsies remain understudied and poorly characterized. Nodding syndrome and related epilepsies are such a constellation of epileptic brain disorder that occurs in several sub-Saharan African countries. Although the etiology of this disease is unknown, several studies have found a consistent association with the parasite, Onchocerca volvulus (OV). As the OV parasite is not neuroinvasive, autoimmunity to Hu-Leiomodin-1, a muscle-associated protein, due to molecular mimicry with OV antigens is thought to play a role in the pathogenesis. Studies have also found that variations in immune responses due to HLA polymorphism might also contribute to the etiology. However, the role of host genetics and its relationship to exposure to OV in the manifestation of epilepsy is yet to be systematically investigated. The central hypothesis of this proposal is that families with NS share common electroclinical features forming a distinct familial epilepsy syndrome and this electroclinical phenotype is conferred by O. volvulus-associated hu-Leiomodin-1 autoimmunity in genetically susceptible individuals. We will pursue the following aims: 1) Characterize the epilepsy sub-phenotypes that aggregate within the NS-affected families; 2) Investigate the role of genetic polymorphism in the human host underlying the pathogenesis of NS-and related epilepsies; 3) Evaluate the relationship between exposure to OV-associated Hu-leiomodin-1 antibody and host susceptibility that jointly confers risk for NS-and related epilepsies. This study has a high global health significance, as it aims to mechanistically understand how a parasitic disease modifies the risk of epilepsy in susceptible individuals. There is an urgent need of this evaluation to further mitigate the risk of a neglected tropical disease. The proposal will prepare Dr. Mazumder as an independent researcher and provide the foundation for future R01 funded studies to prevent acquired epilepsies by early identification of susceptible individuals.