Transcriptomic profile of epileptic children treated with ketogenic therapies

Abstract

Background: Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods: Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results: Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions: Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy.

Human MicroRNAs Modulated by Diet: A Scoping Review

“…Studies that investigated changes in the postprandial period are summarized in Table 1 . The remaining 18 studies studied changes in expression of miRNA in response to sustained interventions [ [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] ]. These studies are presented in Table 2 .…”

Impressive efficacy of the ketogenic diet in a KCNQ2 encephalopathy infant: a case report and exhaustive literature review

“…Epigenetic processes are known too to be related to changes in neuronal activity and epileptogenesis and, recently, the role of molecular mediators of epigenetic changes including non-coding RNAs, methylation of DNA and histone acetylation via de-acetylase inhibition and mitochondrial biogenesis have been hypothesized to be involved in KD's therapeutic effects, as well (17)(18)(19)(20); a recent transcriptional study on miRNA and mRNA's expression of eight pediatric patients affected by intractable epilepsy has demonstrated that KD induces changes at the transcriptomic level in genes encoding ion channels, neurotransmitter receptors and synapse structural proteins, resulting in down-regulation of synaptic transmission, which is the most relevant biologic pathway related to epilepsy, and subsequent decreased excitability (17). KD's use for early-onset intractable seizures has been described among pediatric patients with KCNQ2 mutations.…”

“…Others suggest that the unpredictable response to KD might be, instead, mutation-independent and related to changes induced by KD at the transcriptomic level (17).…”

“…KD is a hyperlipidic, hypoglucidic, normoprotein diet regimen inducing and maintaining a chronic state of ketosis that results in neuroprotection and improvement of seizure frequency and severity by inducing an increase in cellular mitochondrial function and biogenesis, a decrease in oxidative stress, changes in potassium channels, an increase in the brain-derived neurotrophic factor (BDNF) and in the purinergic and GABAergic neurotransmission, attenuation of neuroinflammation and even changes in gut microbiota ( 17 ).…”

“…A recent preclinical in vitro study described molecular mechanisms besides the response to KD in the first missense loss-of-function pathogenic variant described within the S4 segment of Kv7.3, suggesting that the type and location of mutation predicts the response to specific treatments ( 22 ). Others suggest that the unpredictable response to KD might be, instead, mutation-independent and related to changes induced by KD at the transcriptomic level ( 17 ). Unfortunately, data available to date only allow speculative hypothesis and further preclinical and clinical studies of combined analysis of gene and miRNAs’ expression are needed to clearly assess this issue and to allow, in the future, to use KD as a targeted-therapy.…”