Developmental and epileptic encephalopathies - therapeutic consequences of genetic testing

Abstract

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.

Keywords: children; developmental and epileptic encephalopathy; monogenic etiology; precision treatment.

Figure 1

The current classification for monogenic developmental and epileptic encephalopathies (DEE, formerly EIEE; listed in the Online Mendelian Inheritance in Man database) comprises 102 genes, with the number doubling in the last 5 years. The genes are assigned in the timeline to the year of first description. In addition to this increasing list, many genes are not yet included and a recent study calculated that up to 1,000 more genes for developmental disorders can be identified [29]. Mode of inheritance: black: autosomal-dominant; red: autosomal-recessive; green: X-linked.

Figure 2

Diagnostic yield from different molecular genetic techniques. Chromosomal analyses and array CGH analyses have been conducted to detect causative genetic alterations in up to 10 % (e. g., microdeletions: del2211.2, Angelman syndrome, del1p36). With new exome-wide genetic analyses (next-generation sequencing), causative monogenic etiologies were identified in up to 40 % of children with early epileptic encephalopathies (West syndrome, epilepsy with migrating seizures of infancy, Dravet syndrome) and in more than 20 % of late epileptic encephalopathies (e. g., continuous spikes and waves during sleep [CSWS]). Modified after [25], [30], [43].

Figure 3

Number of publications in PubMed for search terms “epilepsy and gene” (blue) and “precision medicine and epilepsy” (green). The number of publications on precision medicine (green) has rapidly increased during the last 5 years, following the increase in identified genetic causes (blue) (source: www.pubmed.gov). Modified after [30].

Figure 4

Genotype–phenotype correlation of genes associated with developmental and epileptic encephalopathies (DEE) and age-related electroclinical epileptic encephalopathies (EE), personally curated by the author from the Online Mendelian Inheritance in Man database, reviews and genotype–phenotype studies, not scaled (neonatal: early myoclonic encephalopathy [EME], Ohtahara syndrome; infantile: epilepsy with migrating seizures in infancy [EIMFS], West syndrome, Dravet syndrome; childhood: Lennox–Gastaut syndrome, myoclonic-atonic epilepsy, epilepsy-aphasia spectrum [continuous spikes and waves during sleep, Landau–Kleffner syndrome]). Single encephalopathies such as EIMFS (KCNT1) or Dravet syndrome (SCN1A) have a high genotype–phenotype correlation (red lines). By contrast, West syndrome has a low genotype–phenotype correlation and a high number of different genetic alterations have been identified [1], [7], [9], [15], [30], [33], [43].