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We aimed to identify caregivers' opinions on the outcome measures that matter in clinical trials in individuals with Dravet syndrome (DS). We conducted a prospective European multicenter study based on an 11 closed questions survey developed by the French reference center for rare epilepsies and DS patients' advocacy groups. Items included questions on seizures and daily life outcomes that a clinical trial on a therapy for individuals with DS should target. Statistical analyses were performed to evaluate the impact of the country of residence and of the patients' age. The survey was answered by 153 caregivers (68%: France, 28%: Germany, and 24%: Italy) off individuals with DS. Individuals with DS included 86 males (mean age of 11.4 [interquartile: 7‐20.4] years). Families ranked as important almost all the items proposed. However, items related to daily life had the highest rank in all three countries compared to items about seizures (P = 0.02). Increase in individuals' age was associated with a higher age at diagnosis (ρ = 0.26, P = 0.02), and a lower impact of seizure duration (ρ = −0.25, P = 0.005) and on the need of hospital referral (ρ = −0.26, P = 0.005). These data can help tailor patient‐centered outcome measures in future clinical and real‐life trials for DS. [ABSTRACT FROM AUTHOR]

Several specific syndromes within the RASopathies spectrum lead to an increased risk of seizures up to developing refractory epileptic encephalopathy. Management remains symptomatic. Here we report two patients treated with trametinib, a MEK1-2 inhibitor, as a precision strategy for drug-resistant epilepsy. Patient 1 is a six-year-old girl with cardiofaciocutaneous syndrome (BRAF p.F595L, germline mutation), and Patient 2 is a 14-month-old boy with Schimmelpenning syndrome (KRAS p.G12D, postzygotic somatic mutation). Trametinib was initiated at a dosage of 0.025 mg/kg/day. Patient 1 had multiple seizures per day, multifocal motor to bilateral tonic-clonic. Electroencephalography (EEG) showed a dramatic reduction in EEG discharges three months after trametinib onset, while a marked clinical improvement occurred after about five months, at the same dosage, and the girl is currently seizure-free for more than six months. Patient 2 had left cerebral hemiatrophy leading to right focal motor seizures, multiple per week to multiple per day, since the age of three months. On trametinib, he experienced an early benefit, remaining seizure-free for more than three months. However, after six months we observed recurrence of seizures. After 22 months of treatment, trametinib was discontinued because of a suspected drug-induced inflammatory colitis. After discontinuation, we observed a significant clinical and EEG "rebound effect." We provide proof of concept that MEK inhibition is a promising approach for the treatment of patients with refractory epilepsy with selected germline and mosaic RASopathies. Future trials are encouraged to better investigate their potentials and limitations. [ABSTRACT FROM AUTHOR]

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N‐terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20‐related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N‐terminal acetylation. [ABSTRACT FROM AUTHOR]