[POS-1] The genetic landscape of the developmental and epileptic encephalopathies
The ‘developmental and epileptic encephalopathies’ are severe epilepsies that typically begin in infancy or childhood, and carry significant co-morbidities and increased mortality risk. An epileptic encephalopathy is defined by frequent epileptiform activity that contributes to developmental impairment, associated with developmental slowing and regression. In many instances, the underlying aetiology may cause developmental slowing, in addition to the impact of the epileptiform activity, as inferred by the term ‘developmental encephalopathy’ which can be used with the term ‘epileptic’ where appropriate.
A genetic basis for these disorders has been increasingly recognised, with marked genetic heterogeneity. While initial discoveries implicated ion channel genes, non-ion channel genes have been recognized as causative highlighting a range of mechanisms that lead to these devastating disorders. Many patients have de novo dominant mutations, although some diseases follow X-linked, recessive or mitochondrial inheritance. The critical role of mosaicism at many levels is reframing genetic concepts and includes somatic, germline in the affected individual or inherited from a mosaic unaffected parent. These molecular insights have major implications for reproductive counseling.
With the discovery of each new gene, a phenotypic spectrum emerges. Understanding the phenotypic spectrum is key to tailoring therapy. The promise of gene discovery is precision medicine where treatment is tailored to the underlying mechanism. This may involve the use of known drugs, repurposing old drugs or developing novel targeted therapies. The revolution in genomic medicine is altering the way we approach these severe diseases and directing us to new management strategies that promise to improve outcomes.
A genetic basis for these disorders has been increasingly recognised, with marked genetic heterogeneity. While initial discoveries implicated ion channel genes, non-ion channel genes have been recognized as causative highlighting a range of mechanisms that lead to these devastating disorders. Many patients have de novo dominant mutations, although some diseases follow X-linked, recessive or mitochondrial inheritance. The critical role of mosaicism at many levels is reframing genetic concepts and includes somatic, germline in the affected individual or inherited from a mosaic unaffected parent. These molecular insights have major implications for reproductive counseling.
With the discovery of each new gene, a phenotypic spectrum emerges. Understanding the phenotypic spectrum is key to tailoring therapy. The promise of gene discovery is precision medicine where treatment is tailored to the underlying mechanism. This may involve the use of known drugs, repurposing old drugs or developing novel targeted therapies. The revolution in genomic medicine is altering the way we approach these severe diseases and directing us to new management strategies that promise to improve outcomes.