The developmental and epileptic encephalopathies

Subtitle:from genotype-phenotype correlations to disease modeling in zebrafish

The epilepsies are a heterogeneous group of disorders characterized by an enduring predisposition to epileptic seizures. Epilepsy is ranked fifth of all neurological disorders in terms of global burden of disease, underscoring the critical socio-economic impact of the disorder. The developmental and/or epileptic encephalopathies (DEEs) are a group of rare epilepsy syndromes that are distinguished by their early onset therapy-resistant seizures and development delay that often leads to severe cognitive impairment. It is hypothesized that genetic factors play a role in up to 70 % of epilepsies, both as a causal factor or as a risk or modifier allele. Based on current knowledge, DEEs with a genetic aetiology are regarded as monogenic disorders mainly, and the culprit gene mutation is identified in 30-40 % of patients. The general purpose of this PhD thesis was to obtain a better understanding of the genetic architecture of rare epilepsy syndromes, with special focus on the DEEs. This was done through [1] the identification of novel molecular genetic causes of epilepsy, both on a structural and single gene level, with the identification of the valyl-tRNA synthestase gene, VARS, as a novel epilepsy gene; [2] the delineation of the phenotypic spectrum and description of genotype-phenotype correlations of two known epilepsy genes, STXBP1 and NEXMIF; and [3] generation and characterization of a vars knock-out zebrafish model. The research presented in this thesis can aid clinicians and geneticists in formulating a genetic diagnosis and in counseling parents about prognosis, comorbidities and recurrence risk of the DEEs covered. Furthermore, the research brings more insight into the complexities of the underlying neurobiology of DEEs, highlighting the role of tRNA synthetase encoding genes. In time, a better understanding of the genetic architecture of DEEs and the underlying neurobiology may accelerate the development of novel precision medicine approaches to treat this severe group of disorders.

Publication year:2019

Keywords:Doctoral thesis

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