Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare early-onset developmental epileptic encephalopathy resistant to anti-epileptic drugs. The most common cause for EIMFS is a gain-of-function mutation in the KCNT1 potassium channel gene, and treatment with the KCNT1 blocker quinidine has been suggested as a rational approach for seizure control in EIMFS patients. However, variable results on the clinical efficacy of quinidine have been reported. In the present study, we provide a detailed description of the clinical, genetic, in vitro, and in vivo electrophysiological profile and pharmacological responses to quinidine of 2 EIMFS unrelated patients with a heterozygous de novo KCNT1 mutation: c.2849G>A (p.R950Q) in patient 1 and c.2677G>A (p.E893K) in patient 2. When expressed heterologously in CHO cells, KCNT1 channels carrying each variant showed gain-of-function effects, and were more effectively blocked by quinidine when compared to wild-type KCNT1 channels. On the basis of these in vitro results, add-on quinidine treatment was started at 3 and 16 months of age in patients 1 and 2, respectively. The results obtained reveal that quinidine significantly reduced seizure burden (by about 90%) and improved quality of life in both patients, but failed to normalize developmental milestones, which persisted as severely delayed. Based on the present experience, early quinidine intervention associated with heart monitoring and control of blood levels is among the critical factors for therapy effectiveness in EIMFS patients with KCNT1 gain-of-function mutations. Multicenter studies are needed to establish a consensus protocol for patient recruitment, quinidine treatment modalities, and outcome evaluation, to optimize clinical efficacy and reduce risks as well as variability associated to quinidine use in such severe developmental encephalopathy.

Introduction: Glucose Transporter Type I Deficiency Syndrome ( GLUT 1 DS ) classical symptoms are seizures, involuntary movements, and cognitive impairment but so far the literature has not devoted much attention to the last. Methods: In our retrospective study involving 25 patients with established GLUT 1 DS diagnosis, we describe the cognitive impairment of these patients in detail and their response to the ketogenic diet in terms of cognitive improvement. Results: We outlined a specific cognitive profile where performance skills were more affected than verbal ones, with prominent deficiencies in visuospatial and visuomotor abilities. We demonstrated the efficacy of ketogenic diet ( KD ) on cognitive outcome, with particular improvement tin total and verbal IQ ; we found that timing of KD introduction was inversely related to IQ outcome: the later the starting of KD , the lower the IQ , more notable nonverbal scale (verbal IQ correlation coefficient −0.634, p ‐value = 0.015). We found a significant direct correlation between cognition and CSF /blood glucose ratio values: the higher the ratio, the better the cognitive improvement in response to diet (from T0–baseline evaluation to T1 on average 18 months after introduction of KD ‐: TIQ correlation coefficient 0.592, p ‐value = 0.26; VIQ correlation coefficient 0.555, p ‐value = 0.039). Finally, we demonstrated that a longer duration of treatment is necessary to find an improvement in patients with “severely low ratio.” Conclusion: Our results were consistent with the hypothesis that timing of the diet introduction is a predictive factor of cognitive outcome in these patients, confirming that earlier initiation of the diet may prevent the onset of all GLUT 1 DS symptoms: epilepsy, movement disorders, and cognitive impairment.