Estimating the Global Market Size for Disease-Modifying Therapies in Epilepsy Caused by Haploinsufficiency

ImportanceHaploinsufficiency, a condition where a single functional copy of a gene is insufficient to maintain normal physiological function due to a mutation, represents the most prevalent disease mechanism underlying genetic epilepsies, particularly developmental and epileptic encephalopathies (DEEs). Current therapies for these patients primarily address symptoms and fail to alter the disease trajectory. Given the prospect of targeted gene therapies, accurately quantifying the burden of these disorders is paramount for optimizing resource allocation in patient care and facilitating the development of novel disease-modifying therapies. ObjectiveTo estimate the global and U.S. incidence and prevalence of epilepsy caused by haploinsufficiency. Design, Setting, and ParticipantsFirst, we identified epilepsy genes, focusing on autosomal dominant genes with a high likelihood of haploinsufficiency. Second, we utilized a statistical framework to estimate the birth incidence of patients with protein-truncating variants in these genes, incorporating gene-specific mutation rates and birth rate data. Finally, we calculated prevalence by multiplying annual incidence by an effective disease duration, considering factors like sudden unexpected death in epilepsy. Main Outcomes and MeasuresBirth incidence and prevalence of epilepsy attributable to de novo protein-truncating variants in haploinsufficient genes. ResultsAn estimated 228.81 (90% CI: 206.21-241.93) cases of haploinsufficiency-related epilepsy occur per 100,000 live births globally. This translates to approximately 313,595 new cases annually worldwide and 8,736 in the United States. The estimated global prevalence is 14,343,840 individuals. Conclusions and RelevanceThis study provides the first data-driven estimates of the of haploinsufficiency-related epilepsy burden, highlighting a substantial population potentially benefiting from gene-targeting therapies. These findings have significant implications for research prioritization, resource allocation, and the development of precision medicine approaches for treating these severe neurological disorders.