Mazurkiewicz‐Bełdzińska, Maria

Abstract Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30 ‐associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9‐year‐old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9‐year‐old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30 ‐associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

Abstract Objective: The risk of premature deaths in patients with epilepsy (approx. 50 mln. patients worldwide) is about 2–3 times higher as compared to general population. This phenomenon is mainly explained by cardiovascular causes as well as sudden unexpected deaths in epilepsy (SUDEP). Epilepsy is associated with sympathetic overdrive and renin-angiotensin-system abnormalities all of which may be implicated in organ damage (both directly and indirectly via high blood pressure; BP). In our study, we aimed at the evaluation of several cardiovascular risk factors and organ damage in patients with epilepsy; its’ relation to disease control and comorbid hypertension. Design and method: A total of 48 patients and matched controls were included in the study. Anthropometry, biochemical assessment, office and ambulatory blood pressure, structural and/ or functional vascular changes were recorded. One-way ANOVA and ANCOVA were employed (mean ± SE). Results: Patients were comparable in terms of age and BMI. Hypertensives were aware of high BP in 50% of cases. Study subgroups were comparable in terms of heart rate, serum uric acid, triglicerides, HDL, glucose, serum creatinine and eGFR, serum potassium (P = NS for all comparisons). Total cholesterol was the lowest in well-controlled epileptic patients which was followed by refractory disease and epilepsy with comorbid hypertension (167.6 ± 6.7 vs. 196.9 ± 7.4 vs. 223.5 ± 8.9; respectively). Patients with refractory epilepsy had comparable serum LDL and PWV to hypertensive well-controlled epileptics; both contrasted with values recorded in patients with well-controlled epilepsy who were free of hypertension (LDL: 121.7 ± 6.8 vs. 140.9 ± 8.2 vs. 99.2 ± 6.1; respectively, and PWV: 6.4 ± 0.24 vs. 6.8 ± 0.30 vs. 5.5 ± 0.22; respectively). Reported differences were valid after adjustment for age and BMI. Conclusions: Except for BP values, patients with refractory epilepsy who are free of hypertension have similar CV risk profile to patients with high BP. These findings along with underdiagnosed hypertension may explain higher CV mortality and morbidity documented in epilepsy.

AbstractObjectiveTo estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo‐controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox–Gastaut syndrome.MethodsPatients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.ResultsOverall, 235 patients received CBD (CBD10 [GWPCARE3 only],n = 67; CBD20 [pooled GWPCARE3&4],n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6–48.0). Patients had previously discontinued a median (range) of six (0–28) antiepileptic drugs (AEDs) and were currently taking a median of three (0–5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients.SignificanceTreatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week period.