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The genetic basis for response to the Ketogenic diet in drug-resistant epilepsy

Schoeler, NE; (2014) The genetic basis for response to the Ketogenic diet in drug-resistant epilepsy. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The Ketogenic diet (KD) is an alternative treatment option for people with drug-resistant epilepsy. It can reduce seizure frequency, but it is resource-intensive and may cause adverse side effects. Predictors of response – which, in the absence of specific metabolic disorders, are unknown – would improve patient selection and may enhance understanding of how the KD exerts its antiseizure effect. This project is concerned with identifying possible genetic markers of response to the KD. DNA was extracted from capillary blood taken from individuals who were following the KD for their epilepsy, or who had done so in the past. Individuals were classed as responders if they achieved ≥50 seizure reduction. Response was classified at various follow-up points, as well as a summary of response over time. Association studies were conducted using candidate gene (KCNJ11 and BAD) sequencing, genome-wide single nucleotide polymorphism array, and whole exome sequencing data to determine whether there was an over-representation of specific gene variants in KD responders, compared to non-responders. Common variation in KCNJ11 and BAD was not significantly associated with KD response. rs12204701 reached significance in the array-based genome-wide association study including common variants, with 3-month diet response as the phenotype. No significant results were obtained when summary diet response was taken as the phenotype. Using the gene-based c-alpha test with the exome sequencing data, including all exonic and splicing variants, ANKRD36C reached significance; using a pathway-based count of case-unique alleles test, the ‘ERBB1 Internalisation’ pathway reached significance. No further significant results were obtained from the exome sequencing data when using other gene- and pathway-based tests or when variants were further filtered according to predicted functional consequence. Other genes with large differences in responder/non-responder minor or alternative allele counts are also of interest. It is unknown how these may contribute to variability in KD response. Some common themes were identified amongst the genes and pathways of significance and suggestive significance: cell cycling, apoptosis, glucose homeostasis, neurological processes and triglyceride biosynthesis. It is biologically plausible that these processes influence KD response, although it is likely that many genes play a role. A larger sample size is needed in order to improve power to detect genotypic-phenotypic associations and increase confidence in the importance of the genes of interest.

Type: Thesis (Doctoral)
Title: The genetic basis for response to the Ketogenic diet in drug-resistant epilepsy
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1435546
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