Adults with Developmental and Epileptic Encephalopathies in the Precision Treatment Era

Developmental and epileptic encephalopathies (DEEs) are early-onset, severe diseases characterized by neurodevelopmental disorder and some of the most severe forms of epilepsy. A substantial proportion of DEEs are caused by pathogenic variants in a single gene, making them particularly well suited for precision-therapy approaches. Accordingly, a growing number of gene- and mechanism-based therapies (including antisense oligonucleotides, targeted small molecules, and adeno-associated virus (AAV)-mediated gene replacement strategies) are currently in development or clinical trials. However, as these advances rapidly move forward, a critical question remains: where do adults with DEEs fit in this evolving precision-medicine landscape?

Diagnosis of DEEs in Adults

Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are widely regarded as prototypical developmental and epileptic encephalopathies, although they represent only a subset of a much broader and heterogeneous group. Although DS is defined by a characteristic phenotype, its widespread recognition has largely followed the availability of molecular genetic testing, reflecting the fact that more than 85% of cases are caused by haploinsufficiency of the SCN1A gene.¹ Unfortunately, most adults with DS were not clinically diagnosed in childhood and do not receive genetic testing in adulthood. They remain nondiagnosed, and possibly being treated with contraindicated antiseizure medications such as sodium channel blockers.

It is also common that adults with any type of poorly controlled seizures and intellectual disability (ID) received the label of LGS. However, LGS is a very well-defined electroclinical condition with large variety of etiologies, including single gene disorders, copy number variants, hypoxic ischemic encephalopathy, other structural and unknown reasons. GLS and DS are evolving conditions and the phenotype in adults can be different from that in children. Since the overwhelming literature on those conditions is on the pediatric phenotype,² it can be very difficult to properly clinically diagnose adults with those DEEs. In addition to the changing phenotype, there is also a change in nomenclature and classification. For instance, the presence of generalized paroxysmal fast activity (GPFA) on EEG is one of the hallmarks of LGS.³ However, GPFA may be lost as the patient ages, and pediatric EEG reports are not always available. Even when pediatric EEGs are available, the reporting nomenclature at the time may have been different and instead of “generalized paroxysmal fast activity” one may find: “paroxysmal fast rhythms”, “repetitive fast discharges”, “beta band seizure pattern”, etc.

Natural History of DEEs

The advent of next-generation sequencing and the increasing availability of multigene panels, exome and genome sequencing led to a better understanding of different forms of DEEs. Pediatric patients are now properly diagnosed based on the genetic cause of their DEE. Common examples include:STXBP1-related DEE, KCNT1-related DEE, SCN8A-DEE, CDKL5 deficiency disorder, etc.^4-7 Increasingly, different phenotypes linked to the same gene are being recognized depending on whether the abnormal genetic variant leads to a gain- or loss-of-function (GOF or LOF). Common examples include SCN1A LOF leading to (a) Dravet syndrome, (b) epilepsy of infancy with migrating focal seizures, (c) epilepsy with myoclonic atonic features or the milder (d) generalized epilepsy with febrile seizure plus; while SCN1A GOF can lead to (e) neonatal onset DEE with or without movement disorder and arthrogryposis, and (f) familial hemiplegic migraine type 3.⁸Despite these advances, many adults with genetic DEEs continue to carry legacy, phenotype-based diagnoses such as “symptomatic generalized epilepsy,” or “Rett-like syndrome,” rather than definitive gene-specific classifications. In the absence of accurate molecular diagnosis, successive generations of adults with genetic DEEs remain effectively invisible to both research and clinical frameworks, limiting our ability to define adult phenotypes, disease trajectories, and long-term outcomes. Consequently, critical insights into the natural history and aging of these disorders risk being delayed if the field relies solely on pediatric cohorts aging into adulthood.

Importantly, recent adult-focused investigations demonstrate that this delay is neither inevitable nor justified. Studies that have systematically identified and characterized adults with genetically determined DEEs challenge the longstanding assumption that DEEs are static pediatric disorders. Longitudinal and cross-sectional analyses reveal that conditions such as SCN1A-related DS, SYNGAP1-related encephalopathy, STXBP1-DEE and CHD2-related epilepsy remain clinically dynamic across adulthood, with evolving seizure profiles, progressive parkinsonism, gait abnormalities, movement disorders and other motor dysfunctions, as well as cognitive decline.^9-14 These findings not only establish the feasibility of assembling molecularly defined adult DEE cohorts, but also underscore the urgency of extending natural history studies and outcome measures to adult DEE populations.

Beyond demonstrating that developmental and epileptic encephalopathies remain clinically active in adulthood, emerging evidence raises the possibility that at least a subset of DEEs may evolve from primarily neurodevelopmental disorders into conditions with neurodegenerative features later in life. Importantly, neuropathological evidence now provides biological support for this clinical trajectory. A recent post-mortem study in an adult with SCN1A-related DS demonstrated widespread, excessive accumulation of corpora amylacea, p62-positive glial pathology, abnormal aquaporin 4 staining, and markers consistent with impaired proteostasis and disrupted brain waste clearance, suggesting active neurodegenerative processes rather than fixed developmental abnormalities.¹⁵ Similar converging signals, including progressive cerebral and cerebellar atrophy on neuroimaging, late-emerging movement disorders, and age-dependent functional decline, have been reported across multiple genetic DEEs, supporting a model in which early neurodevelopmental disruption is followed by cumulative, age-related neurobiological stress.^14,16,17 Together, these findings suggest that some DEEs may follow a biphasic or progressive trajectory, with important implications for timing, targets, and outcome measures in precision-therapy trials.

The successful translation of precision therapies into adulthood will depend on the development of clear, biologically and clinically meaningful endpoints tailored to adult DEE phenotypes. As adult cohorts demonstrate ongoing disease evolution, trial endpoints must extend beyond seizure reduction to encompass measures of mobility, independence, cognition, and quality of life. Without such endpoints, adult patients risk exclusion from trials or inclusion in studies incapable of detecting meaningful benefit.^18,19 Defining these measures now will shape not only the next generation of clinical trials, but also the future standard of care for adults living with genetic DEEs.

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Danielle Andrade, MD, MSc, FRCPC, CSCN (EEG), is a professor of medicine (neurology) at the University of Toronto and serves as director of the Adult Genetic Epilepsy Program and the Adult Genetic Epilepsy Fellowship Program, as well as medical director of the Epilepsy Program. She is also president of the Canadian League Against Epilepsy.