Volume 34, Issue 3

Knowledge of underlying genetic causes of developmental and epileptic encephalopathies (DEE) in adults is still limited when compared to the routine diagnostic approach in similarly affected children. A well-documented longitudinal study of adults with DEE is of utmost importance to understand the natural history of the respective entity. This information is of great value especially for genetic counselling of newly diagnosed children with identical genetic diagnoses and may impact treatment and management of affected individuals. In our meta-analysis we provide an overview of the most recurrent genetic findings across an adult DEE cohort ( n = 1 , 020n=1,020). The gene mostly associated with a pathogenic or likely pathogenic variant in adult DEE is SCN1A , followed by MECP2 and CHD2 . Studies employing exome sequencing and calling of both single nucleotide variants and copy number variants are associated with diagnostic yields of almost 50 %. Finally, we highlight three remarkable cases, each representing the oldest individual ever published with their genetic diagnosis, i. e., Angelman syndrome, Miller–Dieker syndrome, and CAMK2A -related disorder, and describe lessons learned from each of these adults.

Developmental and epileptic encephalopathies comprise a heterogeneous group of monogenic neurodevelopmental disorders characterized by early-onset seizures, marked epileptic activity and abnormal neurocognitive development. The identification of an increasing number of underlying genetic alterations and their pathophysiological roles in cellular signaling drives the way toward novel precision therapies. The implementation of novel treatments that target the underlying mechanisms gives hope for disease modification that will improve not only the seizure burden but also the neurodevelopmental outcome of affected children. So far, beneficial effects are mostly reported in individual trials and small numbers of patients. There is a need for international collaborative studies to define the natural history and relevant outcome measures and to test novel pharmacological approaches.

An epilepsy diagnosis has large consequences for an individual but is often difficult to make in clinical practice. Novel biomarkers are thus greatly needed. Here, we give an overview of how thousands of common genetic factors that increase the risk for epilepsy can be summarized as epilepsy polygenic risk scores (PRS). We discuss the current state of research on how epilepsy PRS can serve as a biomarker for the risk for epilepsy. The high heritability of common forms of epilepsy, particularly genetic generalized epilepsy, indicates a promising potential for epilepsy PRS in diagnosis and risk prediction. Small sample sizes and low ancestral diversity of current epilepsy genome-wide association studies show, however, a need for larger and more diverse studies before epilepsy PRS could be properly implemented in the clinic.

Zusammenfassung In diesem Beitrag beschreiben und analysieren wir auf der Basis von gedruckten Quellen und Oral History Interviews die Frage der Nicht-Direktivität in der humangenetischen Beratung in Deutschland im Zeitraum von 1970 bis 2010. Dabei steht insbesondere die Frage im Fokus, inwieweit die fachwissenschaftlichen und gesellschaftlichen Diskurse zu ethischen Fragen in der genetischen Beratung von Fachkundigen wahrgenommen und inwieweit Aspekte der nicht-direktiven Beratung diskutiert wurden. Wie die Ergebnisse zeigen, maßen Fachkundige nicht nur rückblickend der Autonomie von Ratsuchenden einen hohen Stellenwert bei und lehnten „direktive“ Beratungen zumindest in öffentlichen Positionierungen ab. Ethische Begründungsansätze betrachteten sie hier als zentral.