A prospective study on changes in blood levels of cholecystokinin-8 and leptin in patients with refractory epilepsy treated with the ketogenic diet.

OBJECTIVE: To evaluate the changes in serum CCK-8 and leptin levels in patients with refractory epilepsy treated with the ketogenic diet (KD). METHODS: In this prospective study, patients aged between one and 40 years with refractory epilepsy were included. CCK-8 and leptin were measured in serum at baseline and after three and 12 months of treatment with the KD using an enzyme-linked Immunoabsorbant Assay. Seizure frequency and responsiveness were calculated. RESULTS: Fifty-four patients were included; 26 patients (48%) were still on the KD at 12 months. After three and 12 months, respectively, 39% and 26% were responders. CCK-8 values were statistically significantly increased at three months (p=0.005) and 12 months (p=0.012). In responders, at three months follow-up, this increase of CCK-8 was significant (p=0.020), whereas in the non-responders it was not (p=0.34). Leptin values were decreased at three and 12 months, the decrease at three months being statistically significant in post-pubertal men (p=0.028) and post-pubertal women (p=0.007). SIGNIFICANCE: In responders to the KD, serum CCK-8 increased statistically significantly during treatment at three months. Serum leptin decreased statistically significantly at three months in men and in post-pubertal women. It is plausible that the increase of CCK-8 and the decrease of leptin contribute to the anti-convulsive effect of the KD.

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.

The MCT-ketogenic diet as a treatment option in refractory childhood epilepsy: A prospective study with 2-year follow-up.

The present study assessed the long-term (i.e., 24months) efficacy of the ketogenic diet (KD) as an add-on therapy in children with refractory epilepsy, with focus on seizure frequency, seizure severity, and tolerability. Most patients were treated with the MCT-diet. At one and two years, 33% and 23%, respectively, of the 48 included patients were still on the KD. After three months, one year, and two years of treatment, 16.7% of the patients were responders. The highest responder rate (i.e., 22.9%) was seen at six and nine months of treatment. Of the fifteen patients with seizure clusters during baseline, 60% were responders after three months when looking at cluster reduction and most of them were not responders for the total seizure frequency. From three months of treatment onwards, most of the patients had a relevant decrease in seizure severity which was mainly related to the most severe seizure type. Gastrointestinal dysfunction was often reported, especially in the first six weeks of treatment. Growth deceleration was present in 30% of the patients, and weight reduction in 15%. Improved arousal was mentioned in 30% of patients. No patients developed ECG abnormalities or kidney stones. Increase in lipid profile was rare. The KD is an effective therapy for children with therapy-resistant epilepsy. Effectiveness is reflected in the reduction of seizure frequency as well as in the reduction of seizure severity. After 6months of treatment, it is obvious which patients are responders and tolerate the treatment well. Most of these patients will continue to benefit from the KD for a longer time. Long-term use of the diet was well tolerated.