Background and ObjectivesClinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.MethodsRetrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.ResultsForty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.DiscussionThe disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

ObjectiveEarly identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations.MethodsPatients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.ResultsWe included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.ConclusionsWe highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

No abstract

Background Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies. Methods This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age. Results The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects. Conclusions Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.

No abstract

No abstract

Background: Despite the wide availability of novel anti-seizure medications (ASMs), 30% of patients with epilepsy retain persistent seizures with a significant burden in comorbidity and an increased risk of premature death. This review aims to discuss the therapeutic strategies, both pharmacological and non-, which are currently in the pipeline.Methods: PubMed, Scopus, and EMBASE databases were screened for experimental and clinical studies, meta-analysis, and structured reviews published between January 2018 and September 2021. The terms “epilepsy,” “treatment” or “therapy,” and “novel” were used to filter the results.Conclusions: The common feature linking all the novel therapeutic approaches is the spasmodic rush toward precision medicine, aiming at holistically evaluating patients, and treating them accordingly as a whole. Toward this goal, different forms of intervention may be embraced, starting from the choice of the most suitable drug according to the type of epilepsy of an individual or expected adverse effects, to the outstanding field of gene therapy. Moreover, innovative insights come from in-vitro and in-vivo studies on the role of inflammation and stem cells in the brain. Further studies on both efficacy and safety are needed, with the challenge to mature evidence into reliable assets, ameliorating the symptoms of patients, and answering the challenges of this disease.

Mutations in the DHDDS gene (MIM: 617836), encoding a subunit of dehydrodolichyl diphosphate synthase complex, have been recently implicated in very rare neurodevelopmental diseases. In total, five individuals carrying two de novo mutations in DHDDS have been reported so far, but genotype–phenotype correlations remain elusive. We reported a boy with a de novo mutation in DHDDS (NM_205861.3: c.G632A; p.Arg211Gln) featuring a complex neurological phenotype, including mild intellectual disability, impaired speech, complex hyperkinetic movements, and refractory epilepsy. We defined the electroclinical and movement disorder phenotype associated with the monoallelic form of the DHDDS-related neurodevelopmental disease and possible underlying dominant-negative mechanisms.