Genetic Epilepsies: Clinical pearls for early career epileptologists

This review offers a practical look at the most relevant genetic epilepsies that an early-career epileptologist needs to navigate clinical practice, starting with a general overview of molecular genetic mechanisms, then moving to diagnostic testing rationale. The review emphasizes the importance of appropriate pre-testing clinical phenotyping and systematic genetic counseling and provides advice to optimize diagnostic yield and accurate interpretations of findings. Special attention is given to developmental and epileptic encephalopathies, particularly Dravet Syndrome and X-linked epilepsies. An overview of focal epilepsies, from classic syndromes to conditions associated with malformations of cortical development, such as Tuberous Sclerosis Complex and other mTORopathies, highlights advances in the field. The review also reflects on the paradigms of monogenic versus polygenic mechanisms associated with genetic generalized epilepsies. Moreover, critical pearls for diagnosis and management of X-linked epilepsies as well as progressive myoclonic epilepsies are also provided. Finally, an update on precision therapies is provided, ranging from targeting metabolic pathways and cellular signaling mechanisms, to a better understanding of ion channel modulator and repurposing of medications. The former treatments have paved the knowledge to recent breakthroughs on gene-therapies. Now many challenges and promises arise from protein replacement therapies, and gene-based therapies, including anti-sense oligonucleotides (ASOs) and adeno-associated viruses-9 (AAV-9) vectors, that are quickly advancing on multiple clinical trials on this field.