Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.

Ketogenic diet for infantile spasms refractory to first-line treatments: an open prospective study.

UNLABELLED: Ketogenic diet (KD) is an efficient treatment for refractory epilepsy including infantile spasms (IS). We evaluated the effect of a KD to treat IS as a third-line treatment, after vigabatrin (VGB) and steroids. We evaluated the efficacy and the tolerability of KD in IS using the rate of seizure-free patients at 1 month. METHODS: We conducted an open study using the data from a prospective database of two French child neurology departments (Amiens & Robert Debré-Paris, France) over a three-year period. All the patients followed the KD for 6 months. The addition of an antiepileptic drug was allowed after 1 month of KD in the non-seizure-free patients. RESULTS: 17 patients were treated by KD for IS. The KD was initiated at the mean age of 9.4±1.1 months. After 1 month with KD, 6/17 (35%) patients were seizure free while 11/17 (65%) were seizure-free after the third month. However, an additional antiepileptic drug (felbamate or topiramate) was given to all patients that were not seizure-free under KD. The KD was well tolerated. CONCLUSION: Our responder rate is similar to previous studies despite an early use (before 1-year-old) and the use of KD after VGB and steroids. The KD was well-tolerated in this population of young infants. Felbamate leads to an increase in the responder rate after the use of KD.