The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n ¼ 86) and females with MECP2 mutations (n ¼ 920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated with BFNIS and is also involved in families with a delayed age of onset. Our data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive feature of PRRT2 families, although uncommon in our series. We showed that the age of onset of seizures is significantly correlated with underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.

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SUMMARYPurpose: To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy. Methods: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The doubleblind phase was followed by an open-label follow-up. Key Findings: Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments. Significance: Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.