The Efficacy of Ketogenic Diet for Specific Genetic Mutation in Developmental and Epileptic Encephalopathy.

Joon S Lee,Se H Kim,Seung T Lee,Jong R Choi,Ara Ko,Heung D Kim,Hoon-Chul Kang,Da E Jung

doi:10.3389/fneur.2018.00530

Abstract

Objectives: Pathogenic mutations in developmental and epileptic encephalopathy (DEE) are increasingly being discovered. However, little has been known about effective targeted treatments for this rare disorder. Here, we assessed the efficacy of ketogenic diet (KD) according to the genes responsible for DEE.Methods: We retrospectively evaluated the data from 333 patients who underwent a targeted next-generation sequencing panel for DEE, 155 of whom had tried KD. Patients showing ≥90% seizure reduction from baseline were considered responders. The KD efficacy was examined at 3, 6, and 12 months after initiation. Patients were divided into those with an identified pathogenic mutation (n = 73) and those without (n = 82). The KD efficacy in patients with each identified pathogenic mutation was compared with that in patients without identified genetic mutations.Results: The responder rate to KD in the patients with identified pathogenic mutations (n = 73) was 52.1, 49.3, and 43.8% at 3, 6, and 12 months after initiation, respectively. Patients with mutations in SCN1A (n = 18, responder rate = 77.8%, p = 0.001), KCNQ2 (n = 6, responder rate = 83.3%, p = 0.022), STXBP1 (n = 4, responder rate = 100.0%, p = 0.015), and SCN2A (n = 3, responder rate = 100.0%, p = 0.041) showed significantly better responses to KD than patients without identified genetic mutations. Patients with CDKL5 encephalopathy (n = 10, responder rate = 0.0%, p = 0.031) showed significantly less-favorable responses to KD.Conclusions: The responder rate to KD remained consistent after KD in DEE patients with specific pathogenic mutations. KD is effective in patients with DEE with genetic etiology, especially in patients with SCN1A, KCNQ2, STXBP1, and SCN2A mutations, but is less effective in patients with CDKL5 mutations. Therefore, identifying the causative gene can help predict the efficacy of KD in patients with DEE.

Highlights

Epileptic encephalopathy refers to a group of epileptic disorders that epileptic activities per se cause adverse impacts to the patient’s development [1]
Inclusion criteria were as follows: [1] patients with epilepsy and cognitive and behavioral impairments who were diagnosed with Developmental and epileptic encephalopathy (DEE); [2] patients whose seizures or developmental delays were noticed before the age of 3 years; [3] patients who underwent a targeted next-generation sequencing (NGS) gene panel for DEE between January 2016 and March 2017; [4] patients who failed to achieve seizure freedom with adequate trials of two or more antiepileptic drugs (AEDs); and [5] patients who started ketogenic diet (KD) therapy between January 2006 and June 2016
The variables we evaluated with respect to their possible predictive value for a responder were as follows: age at seizure onset, sex, number of AEDs being taken at the time of KD initiation, lead time from seizure onset to KD initiation, the total duration of KD implementation, epilepsy syndrome, and pathogenic mutation

Summary

Introduction

Epileptic encephalopathy refers to a group of epileptic disorders that epileptic activities per se cause adverse impacts to the patient’s development [1]. Developmental and epileptic encephalopathy (DEE) is a recently introduced concept with the advances in genetic diagnosis, as genetic etiologies can cause developmental delay irrespective of epileptic activities [2]. The causes of DEE can be various including structural and metabolic etiologies. Owing to advances in genetic testing technologies, such as next-generation sequencing (NGS), research has revealed that diverse genetic mutations, especially de novo monogenic mutations, constitute a significant portion of the etiologies of DEE [3]. The discovery of causative genes for DEE has amplified the efforts to improve our understanding of the pathophysiology of each genetic mutation, with the ultimate objective of precision medicine. Ketogenic diet (KD), mechanistic target of rapamycin (mTOR)-inhibitors, and retigabine are effective targeted treatments for glucose transporter type 1 deficiency, mTORopathies, and KCNQ2 encephalopathy, respectively [4,5,6]

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