Genome-wide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy.

OBJECTIVE: With the exception of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDTs) are unknown. We aimed to determine whether common variation across the genome influences the response to KDT for epilepsy. METHODS: We genotyped individuals who were negative for glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Genotyping was performed with the Infinium HumanOmniExpressExome Beadchip. Hospital records were used to obtain demographic and clinical data. KDT response (≥50% seizure reduction) at 3-month follow-up was used to dissect out nonresponders and responders. We then performed a genome-wide association study (GWAS) in nonresponders vs responders, using a linear mixed model and correcting for population stratification. Variants with minor allele frequency <0.05 and those that did not pass quality control filtering were excluded. RESULTS: After quality control filtering, the GWAS of 112 nonresponders vs 123 responders revealed an association locus at 6p25.1, 61 kb upstream of CDYL (rs12204701, P = 3.83 × 10-8 , odds ratio [A] = 13.5, 95% confidence interval [CI] 4.07-44.8). Although analysis of regional linkage disequilibrium around rs12204701 did not strengthen the likelihood of CDYL being the candidate gene, additional bioinformatic analyses suggest it is the most likely candidate. SIGNIFICANCE: CDYL deficiency has been shown to disrupt neuronal migration and to influence susceptibility to epilepsy in mice. Further exploration with a larger replication cohort is warranted to clarify whether CDYL is the causal gene underlying the association signal.

Ketogenic diet therapy in infants less than two years of age for medically refractory epilepsy.

PURPOSE: The Ketogenic Diet (KD) is a well-established treatment for epilepsy in children and adults. We describe our 10-year KD experience in children less than two years of age diagnosed with medically refractory epilepsy. METHODS: We conducted a retrospective case-note review of infants managed with KD at our centre between 2006 and 2016. RESULTS: Twenty-nine children between 2½ weeks and 23 months of age were identified, with mixed epilepsy aetiologies. Ninety-three percent had daily seizures and 82% were on two or more anti-epilepsy drugs (AEDs) at the time of KD commencement. KD was continued for more than four weeks in 86%. Based on a combination of parental reports, hospital observations and seizure diaries, two of 29 became seizure free, seven demonstrated >50% seizure reduction, and eight showed a decrease in seizure intensity/frequency. No adverse effects were observed in 45% patients, and dietary therapy was stopped in only two because of poor tolerability. CONCLUSION: We conclude that KD can be utilised and is generally well tolerated in infants with severe epilepsies. In addition, our experience suggests efficacy with improved seizure frequency/severity in around 50% without adverse effects on developmental outcome.

Management Strategies for CLN2 Disease.

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease.