Epileptic Encephalopathies: New Genes and New Pathways

Abstract

Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist.In this review we provide a summary of the key features of several early-and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.

Early and effective treatment of KCNQ2 encephalopathy

“…Early infantile epileptic encephalopathies (EIEEs) are a heterogeneous group of severe epilepsies with multiple seizure types beginning in infancy with a poor motor and cognitive prognosis …”

Regulation of KCNQ/Kv7 family voltage-gated K + channels by lipids

“…M-channels are variable in terms of tetramer subunit composition [118, 119], which also can involve contributions from Kv7.5 [120]. Mutations in Kv7.2 or Kv7.3 can result in a form of epilepsy known as benign familial neonatal convulsions (BFNC) [121–123], as well as more severe epileptic encephalopathy [124]. Kv7.4 is expressed in the neurons of the auditory pathway and in the inner ear; loss-of-function mutations are associated with progressive hearing loss [121, 123, 125].…”

Comprehensive overview: efficacy, tolerability, and cost-effectiveness of clobazam in Lennox–Gastaut syndrome

“…It is estimated that between 1% and 10% of childhood epilepsies are a result of this syndrome 6. Previous data have suggested that only approximately 10% of LGS patients have seizures that are fully controlled with medication therapy 7.…”