Developmental Epileptic Encephalopathies In The Genomic-Metabolomic Era

Administrator: Hasan Tekgul

Metabolomics in DEEs.
Phillip L. Pearl

Metabolomics, the profiling of metabolites from physiologic fluids and tissues, has emerged as a pivotal tool in biomarker discovery and identifying potential targets for further mechanistic studies and interventions.  Mechanistic insights from metabolomics, along with (epi)genomics, transcriptomics, and proteomics are leading to new interventions, from silencing gene expression to altering enzymatic activity and immunomodulation. An increasing number of studies have reported alterations in the blood, brain tissue, cerebrospinal fluid and urine metabolome in patients with epilepsy and animal models of epilepsy. New therapeutic approaches are developing at a rapid pace in metabolic DEEs. Examples of metabolite discoveries using NMR profiling, biomarker development, and controllable gene restoration therapy in SSADH deficiency will be illustrated as specific examples of metabolomics in DEEs. (Lai W, Du D, Chen L. Metabolomics Provides Novel Insights into Epilepsy Diagnosis and Treatment: A Review. Neurochem Res. 2022 Apr;47(4):844-859., Eid T. Harnessing Metabolomics to Advance Epilepsy Research. Epilepsy Curr. 2022 Feb 17;22(2):123-129., Bruxel EM, Bruno DCF, do Canto AM, Geraldis JC, Godoi AB, Martin M, Lopes-Cendes I. Multi-omics in mesial temporal lobe epilepsy with hippocampal sclerosis: Clues into the underlying mechanisms leading to disease. Seizure. 2021 Aug;90:34-50)

Genetic insights into the etiology-specific diagnoses of DEEs.
Hasan Tekgül

The developmental and epileptic encephalopathies (DEEs) were once thought to be largely due to environmental insults. Recently, DEEs have been primarily attributed to genetic causes. The genetic landscape of DEEs has been largely shaped by the rise of high throughput sequencing. To date, dozens of genes convincingly linked to DEE have been identified via whole exome and genome sequencing. New genetic technologies and data-driven analyses clearly demonstrate that DEE is not an aggregate of simple Mendelian disorders. The picture is more complicated than we could have assumed. Today, clinical testing with comprehensive gene panels, exomes, or genomes are increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies, help to understand pathophysiological mechanisms of cognitive impairment and enabled precision medicine approaches. (Bayat A, Bayat M, Rubboli G, Møller RS. Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy. Genes (Basel). 2021 Jul 8;12(7):1051., Symonds JD, McTague A. Epilepsy and developmental disorders: next generation sequencing in the clinic. Eur J Paediatr Neurol 2020; 24: 15–23)

Precision Therapies for DEEs.
Nicola Specchio

The term precision medicine describes the treatment of patients with therapy targeted to the precise molecular pathogenesis of disease. In other words, precision medicine offers customized treatment for a single epileptic syndrome based on the involved gene and the specific molecular alteration. It contrasts with a “one-size-fits-all” approach.  In the last two decades, a genetic etiology has been revealed in more than half of all epilepsies.  Single gene defects in ion channels such as SCN1A, SCN2A, KCNQ2 and so on or neurotransmitter receptors have been associated with most inherited forms of epilepsy, including some focal and lesional forms as well as specific epileptic developmental encephalopathies. DEEs have a wide range of etiologies such as genetic, metabolic, and structural brain abnormalities. The seizures seen in DEE are refractory and seizure freedom rate is low. The initial treatment is almost always antiseizure drugs. The treatment of DEE is more empirical rather than aimed at targeting the underlying cause. Despite appropriate drug selection, most of the patients are not seizure-free and have cognitive disability.  As a result of advances in the genetics of DEE, precision medicine provides hope for patients with DEE. (Striano P, Vari MS, Mazzocchetti C, Verrotti A, Zara F. Management of genetic epilepsies: From empirical treatment to precision medicine. Pharmacol Res. 2016;107:426–429)