Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype.

Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

Neuroscience, ethics, and national security: the state of the art.

National security organizations in the United States, including the armed services and the intelligence community, have developed a close relationship with the scientific establishment. The latest technology often fuels warfighting and counter-intelligence capacities, providing the tactical advantages thought necessary to maintain geopolitical dominance and national security. Neuroscience has emerged as a prominent focus within this milieu, annually receiving hundreds of millions of Department of Defense dollars. Its role in national security operations raises ethical issues that need to be addressed to ensure the pragmatic synthesis of ethical accountability and national security.

Kohlschütter-Tönz syndrome: mutations in ROGDI and evidence of genetic heterogeneity.

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.

Moral transhumanism: the next step.

Although transhumanism offers hope for the transcendence of human biological limitations, it generates many intrinsic and consequential ethical concerns. The latter include issues such as the exacerbation of social inequalities and the exponentially increasing technological capacity to cause harm. To mitigate these risks, many thinkers have initiated investigations into the possibility of moral enhancement that could limit the power disparities facilitated by biotechnological enhancement. The arguments often focus on whether moral enhancement is morally permissible, or even obligatory, and remain largely in the realm of the hypothetical. This paper proposes that psilocybin may represent a viable, practical option for moral enhancement and that its further research in the context of moral psychology could comprise the next step in the development of moral transhumanism.

Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10).

The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessively inherited disorders collectively considered to be one among the most common pediatric neurodegenerative lysosomal storage diseases. Four main clinical subtypes have been described based on the age at presentation: infantile, late infantile, juvenile and adult types. In addition, rare congenital cases of NCL have been reported in the literature. Previously, a homozygous mutation in the cathepsin D gene has been shown to cause congenital NCL in a patient of Pakistani origin. We report a case of a 39-week estimated gestational age female infant with severe microcephaly and hypertonia, whereas MRI showed generalized hypoplasia of the cerebral and cerebellar hemispheres. The infant died on day two after birth. Postmortem examination revealed a small, firm brain with extensive neuronal loss and gliosis. Remaining neurons, astrocytes and macrophages contained PAS-positive storage material with granular ultrastructure and immunoreactivity against sphingolipid activator protein D. A diagnosis of congenital NCL was rendered with a novel mutation, c.299C > T (p.Ser100Phe) in exon 3 of the cathepsin D gene. In the patient fibroblasts, cathepsin D activity was marginal, but the protein appeared stable and normally processed. This was confirmed in overexpression studies. Importantly, by identification of the mutation in the family, we were able to confirm the first prenatal diagnosis excluding cathepsin D deficiency in the younger sibling of the patient.

Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders.

OBJECTIVE: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). METHODS: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. RESULTS: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. CONCLUSIONS: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Febrile Infection-Related Epilepsy Syndrome (FIRES): A Literature Review and Case Study.

Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic syndrome that strikes previously healthy children aged 3-15 years and has an unknown pathogenesis and few treatments. These children experience a nonspecific febrile illness that is followed by prolonged refractory status epilepticus. Although the etiology is unknown, FIRES has a biphasic presentation, with the acute phase beginning as seizure activity lasting 1-12 weeks, then followed by the chronic phase, which is characterized by refractory seizures that cluster every 2-4 weeks, and may continue to be multifocal and independent. Treatment of FIRES is difficult, typically unresponsive to antiepileptic drugs. Some children resolve temporarily with drug-induced burst suppression comas. Other therapies such as a ketogenic diet have limited benefit. The outcome varies with the length of the acute phase and is usually poor, with up to 30% of cases ending in death and 66-100% of survivors having intellectual disability. The authors present a case of a 6-year-old child presenting with FIRES and refractory status epilepticus, which continued despite multidrug therapy. The patient underwent immunomodulatory therapy with the eventual resolution of status, but she developed a chronic, moderately severe encephalopathy, including intractable epilepsy. This case highlights the challenges of FIRES and the potential of immunomodulatory therapies for children with this disorder.

Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis.

BACKGROUND: People with epilepsy who became seizure-free while taking antiepileptic drugs might consider discontinuing their medication, with the possibility of increased quality of life because of the elimination of adverse events. The risk with this action, however, is seizure recurrence. The objectives of our study were to identify predictors of seizure recurrence and long-term seizure outcomes and to produce nomograms for estimation of individualised outcomes. METHODS: We did a systematic review and meta-analysis, and identified eligible articles and candidate predictors, using PubMed and Embase databases with a last update on Nov 6, 2014. Eligible articles had to report on cohorts of patients with epilepsy who were seizure-free and had started withdrawal of antiepileptic drugs; articles also had to contain information regarding seizure recurrences during and after withdrawal. We excluded surgical cohorts, reports with fewer than 30 patients, and reports on acute symptomatic seizures because these topics were beyond the scope of our objective. Risk of bias was assessed using the Quality in Prognosis Studies system. Data analysis was based on individual participant data. Survival curves and proportional hazards were computed. The strongest predictors were selected with backward selection. Models were converted to nomograms and a web-based tool to determine individual risks. FINDINGS: We identified 45 studies with 7082 patients; ten studies (22%) with 1769 patients (25%) were included in the meta-analysis. Median follow-up was 5·3 years (IQR 3·0-10·0, maximum 23 years). Prospective and retrospective studies and randomised controlled trials were included, covering non-selected and selected populations of both children and adults. Relapse occurred in 812 (46%) of 1769 patients; 136 (9%) of 1455 for whom data were available had seizures in their last year of follow-up, suggesting enduring seizure control was not regained by this timepoint. Independent predictors of seizure recurrence were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, age at onset of epilepsy, history of febrile seizures, number of seizures before remission, absence of a self-limiting epilepsy syndrome, developmental delay, and epileptiform abnormality on electroencephalogram (EEG) before withdrawal. Independent predictors of seizures in the last year of follow-up were epilepsy duration before remission, seizure-free interval before antiepileptic drug withdrawal, number of antiepileptic drugs before withdrawal, female sex, family history of epilepsy, number of seizures before remission, focal seizures, and epileptiform abnormality on EEG before withdrawal. Adjusted concordance statistics were 0·65 (95% CI 0·65-0·66) for predicting seizure recurrence and 0·71 (0·70-0·71) for predicting long-term seizure freedom. Validation was stable across the individual study populations. INTERPRETATION: We present evidence-based nomograms with robust performance across populations of children and adults. The nomograms facilitate prediction of outcomes following drug withdrawal for the individual patient, including both the risk of relapse and the chance of long-term freedom from seizures. The main limitations were the absence of a control group continuing antiepileptic drug treatment and a consistent definition of long-term seizure freedom. FUNDING: Epilepsiefonds.

Heart rate variability during interictal epileptiform discharges.

RATIONALE: Seizures may produce a variety of autonomic alterations. These alterations may occur due to evoked autonomic reflexes or as a direct cortical effect on autonomic control. In animal studies, lock step phenomena of interictal discharges to autonomic output have been repeatedly documented. However, the association of interictal discharges and autonomic output is not as well established in humans. METHODS: RR intervals timely locked to interictal epileptiform discharge (RR(n)) were compared to RR intervals immediately following (RR(n+1)) interictal discharges in 40 patients with focal onset epilepsy and low baseline heart beat variability. RESULTS: In 20 patients with 200 left sided interictal epileptiform discharges, RR(n) shortened in 100 and prolonged in 31 when compared to RR(n+1) intervals. While in 20 patients with 200 right sided interictal epileptiform discharges RR(n) intervals shortened in 17 and prolonged in 116 (Chi square P<0.001). No consistent differences in RR(n) intervals variability between frontal versus temporal localization of the interictal discharges from the same side was found. CONCLUSIONS: Interictal discharges, may influence autonomic control over the cardiac cycle and agree with animal studies. Further study of the relationship of interictal discharges to autonomic output is needed to delineate the potential lateralized influences over autonomic nervous system.

A novel STXBP1 mutation causes focal seizures with neonatal onset.

Mutations of the syntaxin binding protein 1 (STXBP1) have been associated with severe infantile epileptic encephalopathies (Ohtahara syndrome and West syndrome), but also with moderate to severe cognitive impairment and nonsyndromic epilepsy. We have studied a white infant who presented with focal seizures at age 2 weeks. Brain imaging was unremarkable. The electroencephalograph (EEG) demonstrated normal background frequency content but with multifocal sharp waves and no evidence of the typical patterns associated with Ohtahara or West syndrome. Therapy with levetiracetam and oxcarbazepine effectively managed the seizure episodes. Investigation of genes associated with infantile forms of epilepsy such as SCN1A, SCN1B, and ARX were negative, but we identified a novel single-nucleotide duplication mutation, c.931dupT (p.S311FfsX3), in exon 11 of the STXBP1 gene. This previously unreported STXBP1 mutation in a subject with neonatal-onset focal seizures broadens the spectrum of clinically relevant human disorders caused by STXBP1 mutations.

Successful treatment of childhood prolonged refractory status epilepticus with lacosamide.

Prolonged, refractory status epilepticus is a rare clinical syndrome that is associated with severe morbidity and mortality. Lacosamide is a newly approved medication for treatment of partial onset seizures in adults, which has a novel mechanism of action. Experimental data and recent reports suggest that lacosamide could be effective in status epilepticus. We report a child with prolonged, refractory status epilepticus that persisted for 10 weeks despite treatment with multiple anti-epileptics and anesthetics and was then aborted with lacosamide. This is the first report of the effect of lacosamide in prolonged refractory status epilepticus, and the first report of lacosamide efficacy in status epilepticus in a child.

Feasibility and acceptance of salivary monitoring of antiepileptic drugs via the US Postal Service.

Salivary and serum levels of phenobarbital, carbamazepine, and phenytoin are closely correlated. Salivary monitoring of antiepileptic drugs has a number of advantages including the potential for home collection if measured levels are unaffected by transit in the mail. Saliva was collected from 60 adult and 42 pediatric patients in the clinic. A control aliquot was immediately frozen, and a second aliquot was packaged and mailed to the laboratory. Patients were also asked to collect another sample at the same time on the following day and mail it to the laboratory. On receipt, all samples were held frozen and analyzed as a single batch by fluorescence polarization immunoassay. The effects of mailing, the duration in transit, and the season were assessed by multivariable, repeated-measures analysis of variance. One hundred two saliva samples were collected in a mean of 2.6 minutes, and the mailed aliquot was received in a mean of 6.4 days. Two children and 3 adults (4.9% of total) preferred blood collection, but the rest preferred saliva collection or had no preference. There was no significant difference between the control sample and the clinic mailed samples for any of the 3 medications. There were no significant effects of the duration in transit or the season on reliability. Transit of saliva samples in the mail does not adversely affect accuracy of antiepileptic drug measurement. Patients prefer and can successful collect saliva samples at home. Home monitoring of salivary antiepileptic drug levels is a cost-effective technique that deserves additional study.