Epilepsy Genomics: Disease-Causing Sequence Variants

Excerpt

Approximately 1% of 25,000 genes and 25 million single-nucleotide polymorphisms in the genome of modern humans are epilepsy variants. Epilepsy variants are the molecular basis of fatal progressive myoclonus epilepsies, epileptic encephalopathies, and other genetic epilepsies. This chapter annotates the early success and key turning points in the quest to cure fatal epilepsies. The first key turning point occurred in 2018 when “every-2-weeks” intraventricular infusion of cerliponase alfa, enzyme replacement therapy, halted progression of an early childhood progressive myoclonus epilepsy (CLN2 Batten disease), as reported by Schulz et al. In 2021, Schaeffer et al. reported 2 years of intraventricular cerliponase alfa delayed or prevented onset of symptoms in presymptomatic CLN2 infants. Earlier, in 2017, the Food and Drug Administration (FDA) and European Medicines Agency approved Nusinersen, an antisense oligonucleotide, and AVXS-101 (Zolgensma), a viral-mediated gene replacement therapy, as disease halting and potential cures for Werdnig Hoffmann type I spinal muscular atrophy of infancy (SMN1). Even now, breakthrough advances by others include (1) ex vivo HSPC transduction gene therapy in metachromatic keukodystrophy, and (2) genome editing with zinc finger nuclease opening DNA strands and inserting a correct alpha-L-iduronidase into the genome of Hurler mucopolysaccharidoses patients. Recently, the FDA proclaimed that they expect to approve 10–20 cell and gene therapies a year from 2025 onward. As clinical trials raise hopes for cures, vigilance for adverse effects and ethical concerns must not waiver.