Updates on the diagnostic evaluation, genotype-phenotype correlation, and treatments of genetic epilepsies.

PURPOSE OF REVIEW: This article reviews the latest publications in genetic epilepsies, with an eye on publications that have had a translational impact. This review is both timely and relevant as translational discoveries in genetic epilepsies are becoming so frequent that it is difficult for the general pediatrician and even the general child neurologist to keep up. RECENT FINDINGS: We divide these publications from 2021 and 2022 into three categories: diagnostic testing, genotype-phenotype correlation, and therapies. We also summarize ongoing and upcoming clinical trials. SUMMARY: Two meta-analyses and systematic reviews suggest that exome and genome sequencing offer higher diagnostic yield than gene panels. Genotype-phenotype correlation studies continue to increase our knowledge of the clinical evolution of genetic epilepsy syndromes, particularly with regards to sudden death, auditory dysfunction, neonatal presentation, and magnetoencephalographic manifestations. Pyridoxine supplementation may be helpful in seizure management for various genetic epilepsies. There has been interest in using the neurosteroid ganaxolone for various genetic epilepsy syndromes, with clear efficacy in certain trials. Triheptanoin for epilepsy secondary to glucose transporter 1 ( GLUT1 ) deficiency syndrome is not clearly effective but further studies will be needed.

Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation.

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

Cox regression model with randomly censored covariates.

This paper deals with a Cox proportional hazards regression model, where some covariates of interest are randomly right-censored. While methods for censored outcomes have become ubiquitous in the literature, methods for censored covariates have thus far received little attention and, for the most part, dealt with the issue of limit-of-detection. For randomly censored covariates, an often-used method is the inefficient complete-case analysis (CCA) which consists in deleting censored observations in the data analysis. When censoring is not completely independent, the CCA leads to biased and spurious results. Methods for missing covariate data, including type I and type II covariate censoring as well as limit-of-detection do not readily apply due to the fundamentally different nature of randomly censored covariates. We develop a novel method for censored covariates using a conditional mean imputation based on either Kaplan-Meier estimates or a Cox proportional hazards model to estimate the effects of these covariates on a time-to-event outcome. We evaluate the performance of the proposed method through simulation studies and show that it provides good bias reduction and statistical efficiency. Finally, we illustrate the method using data from the Framingham Heart Study to assess the relationship between offspring and parental age of onset of cardiovascular events.

Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances.

The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.

A Review of Targeted Therapies for Monogenic Epilepsy Syndromes.

Genetic sequencing technologies have led to an increase in the identification and characterization of monogenic epilepsy syndromes. This increase has, in turn, generated strong interest in developing "precision therapies" based on the unique molecular genetics of a given monogenic epilepsy syndrome. These therapies include diets, vitamins, cell-signaling regulators, ion channel modulators, repurposed medications, molecular chaperones, and gene therapies. In this review, we evaluate these therapies from the perspective of their clinical validity and discuss the future of these therapies for individual syndromes.

Abnormal Genetic Testing in Males With Concomitant Neurodevelopmental Disabilities and Genital Malformation.

BACKGROUND: Neurodevelopmental disorders (NDDs) affect 1:6 children in the United States and are often linked to genetic disorders. Because many genes are enriched in brain and testicular tissue, genital malformations identified early may be a predictor of genetic disorders in children with NDDs. However, few studies have evaluated the specific effects of genital malformations. This study assesses the association between genital malformations and abnormal genetic testing among male patients with NDD. METHODS: A retrospective chart review was performed of 447 male patients seen at Children's Health Dallas (2009 to 2019) with concomitant genital malformations and NDDs. We assessed the strength of factors associated with obtaining a genetic test and having abnormal results. RESULTS: We identified 447 patients with concomitant genital malformations and NDD. Fifty-six percent (251 of 447) received genetic testing, of which 68.5% (172 of 251) had abnormal results. Patients with mixed genitourinary malformations, global developmental delay (GDD), intellectual delay, or autism spectrum disorder were more likely to have a genetic test. Patients with bilateral testicular involvement, GDD, severe language delay, wheelchair dependence, or abnormal magnetic resonance imaging findings were more likely to have abnormal results. CONCLUSION: The diagnostic yield of 68.5% in our cohort of male patients with genital malformations was higher than previous reports of 5% to 35% in NDD populations. More severe phenotypic features may be associated with increased yield. Identification of genital malformations during infancy may guide clinical surveillance, and copresentations with NDDs may support genetic testing.

Autologous hematopoietic stem cell transplantation in a pediatric patient with aquaporin-4 neuromyelitis optica spectrum disorder.

We report on a child with an early and severe manifestation of an Aquaporin-4 (AQP-4) positive Neuromyelitis Optica Spectrum Disorder (NMOSD) who had a refractory disease course despite aggressive immunotherapy and underwent autologous hematopoietic stem cell transplant (AHSCT).

Why Brain Criticality Is Clinically Relevant: A Scoping Review.

The past 25 years have seen a strong increase in the number of publications related to criticality in different areas of neuroscience. The potential of criticality to explain various brain properties, including optimal information processing, has made it an increasingly exciting area of investigation for neuroscientists. Recent reviews on this topic, sometimes termed brain criticality, make brief mention of clinical applications of these findings to several neurological disorders such as epilepsy, neurodegenerative disease, and neonatal hypoxia. Other clinicallyrelevant domains - including anesthesia, sleep medicine, developmental-behavioral pediatrics, and psychiatry - are seldom discussed in review papers of brain criticality. Thorough assessments of these application areas and their relevance for clinicians have also yet to be published. In this scoping review, studies of brain criticality involving human data of all ages are evaluated for their current and future clinical relevance. To make the results of these studies understandable to a more clinical audience, a review of the key concepts behind criticality (e.g., phase transitions, long-range temporal correlation, self-organized criticality, power laws, branching processes) precedes the discussion of human clinical studies. Open questions and forthcoming areas of investigation are also considered.

Status Epilepticus in Children.

For various reasons, status epilepticus in children is different than in adults. Pediatric specificities include status epilepticus epidemiology, underlying etiologies, pathophysiological mechanisms, and treatment options. Relevant data from the literature are presented for each of them, and questions remaining open for future studies on status epilepticus in childhood are listed.