Adaptive functioning and neurodevelopment in patients with Dravet syndrome: 12-month interim analysis of the BUTTERFLY observational study.

OBJECTIVE: The BUTTERFLY observational study aims to elucidate the natural trajectory of Dravet syndrome (DS) and associated comorbidities in order to establish a baseline for clinical therapies. We present the 12-month interim analysis of the study. MATERIALS AND METHODS: Patients with a genetically confirmed diagnosis of DS were enrolled in the study. Adaptive functioning and neurodevelopmental status were measured using the Vineland Adaptive Behavior Scale, Third Edition (Vineland-III), Bayley Scales of Infant Development, Third Edition (BSID-III), and Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Executive function, ambulatory function and locomotor activities, and overall clinical status were measured using the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P) scale, Gillette Functional Assessment Questionnaire (Gillette FAQ), and Clinician or Caregiver Global Impression of Change scales (CGI-C or CaGI-C) respectively. RESULTS: Overall, 36 patients were enrolled across three age groups, with 35 patients completing at least part or all of one post-baseline visit through Month 12. Significant improvements in receptive communication, as assessed by Vineland-III and BSID-III raw scores, and in verbal comprehension subtests, as assessed by WPPSI-IV raw scores, were observed in BUTTERFLY patients for the all-patient group. Many patients performed on the impaired end of the BRIEF-P Global Executive Composite scale at baseline suggesting difficulties in executive function, and no significant change was observed in BRIEF-P scores for the all-patient group. Most patients performed in the dynamic range of the Gillette FAQ at baseline, and no significant change was observed in Gillette FAQ scores for the all-patient group. Lastly, there was significant improvement observed in the CaGI-C scores for the all-patient group. SIGNIFICANCE: This BUTTERFLY interim analysis shows small improvements in communication skills along with stability in other developmental abilities across patients with DS enrolled in the study from baseline to Month 12.

Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment.

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n â€‹= â€‹1) or G239S variant (n â€‹= â€‹2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 â€‹mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.