Dataset Information

Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.

ABSTRACT:

Objective

The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy.

Methods

In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons.

Results

We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures.

Significance

A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.

SUBMITTER: Pedersen S

PROVIDER: S-EPMC9796519 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.

Pedersen Sigrid S Kverneland Magnhild M Nakken Karl Otto KO Rudi Knut K Iversen Per Ole PO Gervin Kristina K Selmer Kaja Kristine KK

Epilepsia 20220710 9

<h4>Objective</h4>The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy.<h4>Methods</h4>In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium Meth ...[more]

PMID: 35762681

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Project description:ImportanceThe ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet compared with the KD are scarce.ObjectiveTo determine whether the MAD and LGIT diet are noninferior to the KD among children with drug-resistant epilepsy.Design, setting, and participantsOne hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016, and August 20, 2017, at a tertiary care referral center in India.ExposuresChildren were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs.Main outcomes and measuresPrimary outcome was percentage change in seizure frequency after 24 weeks of dietary therapy in the MAD cohort compared with the KD cohort and in the LGIT diet cohort compared with the KD cohort. The trial was powered to assess noninferiority of the MAD and LGIT diet compared with the KD with a predefined, noninferiority margin of -15 percentage points. Intention-to-treat analysis was used.ResultsOne hundred fifty-eight children completed the trial: KD (n = 52), MAD (n = 52), and LGIT diet (n = 54). Intention-to-treat analysis showed that, after 24 weeks of intervention, the median (interquartile range [IQR]) change in seizure frequency (KD: -66%; IQR, -85% to -38%; MAD: -45%; IQR, -91% to -7%; and LGIT diet: -54%; IQR, -92% to -19%) was similar among the 3 arms (P = .39). The median difference, per intention-to-treat analysis, in seizure reduction between the KD and MAD arms was -21 percentage points (95% CI, -29 to -3 percentage points) and between the KD and LGIT arms was -12 percentage points (95% CI, -21 to 7 percentage points), with both breaching the noninferiority margin of -15 percentage points. Treatment-related adverse events were similar between the KD (31 of 55 [56.4%]) and MAD (33 of 58 [56.9%]) arms but were significantly less in the LGIT diet arm (19 of 57 [33.3%]).Conclusions and relevanceNeither the MAD nor the LGIT diet met the noninferiority criteria. However, the results of this study for the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized.Trial registrationClinicalTrials.gov Identifier: NCT02708030.

Project description:BackgroundTo investigate the efficacy of the ketogenic diet (KD) and anti-epileptic drugs (AEDs) on children with refractory epilepsy (RE), and to analyze the effects of gender, therapeutic time, age, type of epilepsy syndrome, number of epileptic seizure types, and number of AEDs on the efficacy of the KD. A prospective, non-randomized, controlled cohort study was used and a total of 200 children with RE who were hospitalized in the Department of Pediatric Neurology, Children's Hospital of Chongqing Medical University from November 2015 to December 2020 were divided into a KD group and AEDs only group according to their parents' wishes.MethodsChildren in the KD group were treated with a classical KD in addition to the AEDs, while in the AEDs group, the original AEDs were continued and could be adjusted according to the clinical seizure types and other conditions. The effects of gender, therapeutic time, age, type of epilepsy syndrome, number of epileptic seizure types, and number of AEDs on the efficacy of the KD were analyzed.ResultsIn the KD group, the efficacy was 79.41%, 79.59%, 81.05%, 81.11%, 77.01%, and 78.75%, at 3, 6, 9, 12, 18, and 24 months, respectively. In the AEDs group, the efficacy was 59.18%, 60.42%, 59.78%, 59.55%, 59.30%, and 53.01% at 3, 6, 9, 12, 18, and 24 months, respectively. After 3, 6, 9, 12, 18, and 24 months of treatment, a statistically significant difference in the effective rate between the KD group and the AEDs group was seen (P<0.05). Chi-square test was used to analyze the effects of gender, therapeutic time, age, type of epilepsy syndrome, number of epileptic seizure types, and number of AEDs on the efficacy of the KD, and the results showed no statistical significance (P>0.05).ConclusionsKD therapy reduces the frequency of seizures in children with RE compared with AEDs alone. In the KD group, the gender, therapeutic time, age, type of epilepsy syndrome, number of epileptic seizure types, and number of anti-epileptic drugs had no significant effect on the efficacy of the KD diet.

Project description:ObjectiveHigh-fat and low-carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible modified Atkins diet (MAD), which is more palatable, mimicking fasting and inducing high ketone body levels. Low-carbohydrate diets may shift brain energy production, particularly impacting neuron- and astrocyte-linked metabolism.MethodsWe evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to control participants consuming a nonmodified higher carbohydrate diet (n = 6 MAD, mean age = 43.7 years, range = 21-53, diet for average 10 days; n = 10 control, mean age = 41.9 years, range = 28-64).ResultsBy metabolomics, there were 13 increased metabolites in plasma (n = 15 participants with available specimens), which included 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex (n = 16), and 11 decreased metabolites in hippocampus (n = 6), which had top associations with mitochondrial functions. Cortex and plasma 3-hydroxybutyric acid levels had a positive correlation (p = .0088, R2 = .48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p < .01, false discovery rate > 5%) in hippocampal nicotinamide adenine dinucleotide (NADH)-related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling).SignificanceShort-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to control participants, in combination with trending expression changes observed in hippocampal NADH-related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables. [Clinicaltrials.gov NCT02565966.].

Dataset Information

Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.

Objective

Methods

Results

Significance

Publications

Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study.

Similar Datasets

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