Genetic aetiologies in relation to response to the ketogenic diet in 226 children with epilepsy

Abstract

A ketogenic diet is used in children with drug-resistant epilepsy but predictors for efficacy are largely lacking. Our aim was to evaluate if causative genetic variants could predict seizure response to the ketogenic diet. A cohort study of 226 children with refractory epilepsy and classic ketogenic diet treatment for at least 3 months (76.9% of the 294 who started) was performed. The median age at diet start was 5.1 years (range 0.1-17.8), 118 were girls and 108 boys. They had previous trials of a median of 6.0 anti-seizure medications (range 0-12) and intellectual disability was found in 87%. Seizure response (≥50% reduction) was found in 138/226 patients (61.1%) at 3 months, 121 (53.5%) at 6 months, 107 (47.3%) at 1 year and in 80 (37.0%) at 2 years follow-up of ketogenic diet. Age of epilepsy onset was lower and combined epilepsy type less common in responders compared to non-responders but no differences were found for specific seizure types, ketogenic ratio or beta-hydroxybutyric acid blood levels. A causative pathogenic/likely pathogenic variant was detected in 107/153 = 69.9% in 48 different genes. Next generation sequencing was used in 91/226 (40%) cases with a diagnostic yield of 58.2% (53/91). In comparison with cases without a revealed genetic aetiology, patients with a causative genetic variant had less atonic seizures and epileptic spasms and a better seizure response with 17.3% seizure free and 25% with >90% seizure reduction at 2-year follow-up. Causative variants in SLC2A1, SCN1A, STXBP1 and PAFAH1B1 showed significant diet response (P < 0.05) and good efficacy was also associated with DEPDC5, GLDC, KCNT1, PDHA1, SLC25A12 and TSC1. Causative variants in COL4A1 and DYNC1H1 were among genes linked to a lack of response. To our knowledge not described previously, we report a good ketogenic diet response related to causative variants in CSNK2A1, FARS2, GABRB3, GRIN1, KCNA2, KCTD3, STX1B and SLC16A2 but a lack of response for causative variants in CLN5, GLI3, MACF1, MAGEL2, NANS, NEMO/IKBKG, RORB, SLC17A5 and UFSP2. After grouping of genes into functional groups, causative variants in transporter genes had the best response (P = 0.009) and variants in other membrane-related proteins (ion channels and neurotransmitter receptors) also showed good efficacy. However, the gene group related to cell structural integrity and/or homeostasis had the worst diet response (P = 0.00006). In conclusion, our results support that causative genetic variants may be used as prognostic markers of ketogenic diet response, constituting an example in the expanding area of precision medicine.

Keywords: WGS; epilepsy; genetic causative variants; ketogenic diet; seizures.

Graphical Abstract

Figure 1

Flowchart showing seizure response for the total cohort of children with epilepsy (n = 294) starting on the classic KD at our centre. 226 children completed 3 months on diet and constitute the study cohort. Data on seizure response at follow-up after 3 and 6 months and 1 and 2 years on diet are shown. Those with seizure reduction ≥50% are considered responders (R) and <50% reduction as non-responders (N). Discontinuation of KD was due to inefficacy, side effects and/or noncompliance. *10 patients shorter follow-up than 2 years since the start of KD.