Precision medicine for developmental and epileptic encephalopathies in Africa – strategies for a resource-limited setting

Abstract

Purpose: Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this aetiology is buried under the burden of infections and perinatal insults, in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs), are most severely affected by this diagnostic gap in Africa, as the rate of actionable findings is highest in DEE-associated genes. Methods: We tested 235 genetically naive South African children diagnosed with/possible DEE, using gene panels, exome sequencing and chromosomal microarray. Statistical comparison of electroclinical features in children with and without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results: Of 41/235 children with likely/pathogenic variants, 26/235 had variants supporting precision therapy. Multivariate regression modelling highlighted neonatal or infantile-onset seizures and movement abnormalities as predictive of a positive genetic finding. We used this, coupled with an emphasis on precision medicine outcomes, to propose the pragmatic Think-Genetics strategy for early recognition of a possible genetic aetiology. Conclusion: Our findings emphasise the importance of an early genetic diagnosis in DEE. We designed the Think-Genetics strategy for early recognition, appropriate interim management and genetic testing for DEE in resource-constrained settings.