Background: Although most children with status epilepticus have a good prognosis, its effects on newborns are unclear. Objective: We compare the neurodevelopmental consequences of recurrent seizures and status epilepticus in newborns. Methods: One hundred six newborns with video-EEG–confirmed seizures, consecutively admitted to the neonatal intensive care unit of the University of Parma between January 1999 and December 2004, were enrolled in the study. Fifty-one were preterm and 55 were full-term newborns. Neonatal status epilepticus was defined as continuous seizure activity for at least 30 minutes or recurrent seizures lasting a total of >30 minutes without definite return to the baseline neurologic condition of the newborn between seizures. Neurologic outcome was assessed at 24 months of corrected age. Results: Thirty-six newborns had a normal outcome, 20 died, and 50 presented an adverse outcome. All but 1 of the 26 subjects with neonatal status epilepticus had an adverse outcome. Birth weight, severely abnormal cerebral ultrasound scans, and status epilepticus were independent predictors of abnormal outcome. Depending on gestational age (GA), neonatal status epilepticus seems to be a risk factor of adverse outcome in full-term newborns (GA ≥ 37 weeks: odds ratio [OR] 20.312, 95% CI 2.417 to 170.679, p = 0.006), and a risk factor of epilepsy in early preterm and full-term newborns (GA ≤ 29 weeks: OR 10.500, 95% CI 1.211 to 91.026, p = 0.033; GA ≥ 37 weeks: OR 6.517, 95% CI 1.321 to 32.148, p = 0.021). Conclusion: Newborns with status epilepticus are at high risk of severe neurologic disability and postneonatal epilepsy. This is particularly evident in early preterm and full-term infants.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders. We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence. Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.