Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5

Background and Objectives KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.Methods We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.Results We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.Discussion We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.</p

The feasibility of using actigraphy to characterize sleep in Rett syndrome

Abstract Background Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the MECP2 gene. Sleep problems are reported by the majority of caregivers of individuals with RTT. Methods The present study aimed to replicate and extend previous work about the feasibility of measuring sleep with an actigraph device in a sample of girls with clinically diagnosed RTT (N = 13, mean age = 9 years, 5 months). Participants wore an actigraph device day and night for seven consecutive days. Materials also included a parent-completed sleep diary to measure bedtime, duration of nighttime sleep, and daytime sleep, and the Child Sleep Habit’s Questionnaire (CSHQ). Results The means for the sample as measured by actigraphy were 492.3 min (SD = 47.3) of total night sleep (TNS), 76.0% (SD = 6.7) sleep efficiency, 86.0 min (SD = 34.2) of wake after sleep onset, and 46.1 min (50.8) of sleep when parents reported a nap occurring. Parents reported 589.7 min (SD = 53.6) of TNS, 15.9 min (SD = 12.0) of WASO, and 93.6 min (SD = 66.8) of daytime sleep according to sleep diaries, with all parents reporting at least one nap during the week. Relations were found between sleep characteristics and seizure status and CSHQ total scores. No age-related changes were observed for any sleep characteristic, regardless of collection method. Five of nine participants above the cutoff score on the CSHQ indicate the need for further evaluation for a sleep disorder. Conclusions Overall, actigraphy was feasible in this community-based sample of girls with RTT. The results replicated some aspects of previous studies of sleep in RTT (e.g., no age-related changes in total nighttime sleep or efficiency). Some participants met the American Academy of Sleep Medicine guidelines for recommended total sleep time, with others showing too much or too little sleep. Each of the three methods for describing sleep presented its own advantages and challenges. Future work should be prospectively designed, validate the use of actigraphy in this population, and include a typically developing comparison sample to improve the precision of our understanding of sleep in RTT

Transcranial Direct Current Stimulation (tDCS) Paired with Occupation-Centered Bimanual Training in Children with Unilateral Cerebral Palsy: A Preliminary Study

Objective. We investigated the preliminary efficacy of cathodal transcranial direct current stimulation (tDCS) combined with bimanual training in children and young adults with unilateral cerebral palsy based on the principle of exaggerated interhemispheric inhibition (IHI). Methods. Eight participants with corticospinal tract (CST) connectivity from the lesioned hemisphere participated in an open-label study of 10 sessions of cathodal tDCS to the nonlesioned hemisphere (20 minutes) concurrently with bimanual, goal-directed training (120 minutes). We measured the frequency of adverse events and intervention efficacy with performance (bimanual—Assisting Hand Assessment (AHA)—and unimanual—Box and Blocks), self-report (Canadian Occupational Performance Measure (COPM), ABILHAND), and neurophysiologic (motor-evoked potential amplitude, cortical silent period (CSP) duration, and motor mapping) assessments. Results. All participants completed the study with no serious adverse events. Three of 8 participants showed gains on the AHA, and 4 of 8 participants showed gains in Box and Blocks (more affected hand). Nonlesioned CSP duration decreased in 6 of 6 participants with analyzable data. Cortical representation of the first dorsal interosseous expanded in the nonlesioned hemisphere in 4 of 6 participants and decreased in the lesioned hemisphere in 3 of 4 participants with analyzable data. Conclusions. While goal achievement was observed, objective measures of hand function showed inconsistent gains. Neurophysiologic data suggests nonlinear responses to cathodal stimulation of the nonlesioned hemisphere. Future studies examining the contributions of activity-dependent competition and cortical excitability imbalances are indicated

Parental perspectives of episodic irritability in an ultra-rare genetic disorder associated with NACC1

Abstract Background A recurrent de novo variant (c.892C>T) in NACC1 causes a neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM). An unusual and consistently reported feature is episodic extreme irritability and inconsolability. We now characterize these episodes, their impact on the family, and ascertain treatments that may be effective. Parents of 14 affected individuals provided narratives describing the irritability episodes, including triggers, behavioral and physiological changes, and treatments. Simultaneously, parents of 15 children completed the Non-communicating Children’s Pain Checklist-Revised (NCCPC-R), a measure to assess pain in non-verbal children. Results The episodes of extreme irritability include a prodromal, peak, and resolving phase, with normal periods in between. The children were rated to have extreme pain-related behaviors on the NCCPC-R scale, although it is unknown whether the physiologic changes described by parents are caused by pain. Attempted treatments included various classes of medications, with psychotropic and sedative medications being most effective (7/15). Nearly all families (13/14) describe how the episodes have a profound impact on their lives. Conclusions NECFM caused by the recurrent variant c.892C>T is associated with a universal feature of incapacitating episodic irritability of unclear etiology. Further understanding of the pathophysiology can lead to more effective therapeutic strategies

Evidence of altered salivary cytokine concentrations in Rett syndrome and associations with clinical severity

Background: Immune dysregulation may play a role in the development of Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations of the MECP2 gene. Abnormal cytokine concentrations have been documented in the serum of individuals with RTT. Measurement of salivary cytokines has been investigated as a potential alternative approach to measurement in blood and serum, but it is unclear whether salivary cytokine concentrations can provide valid information about systemic immune function in neurodevelopmental disorders. The goal of this study was to evaluate the potential validity of salivary cytokines as biomarkers of immune dysregulation in RTT. Methods: Saliva samples from 16 individuals with RTT (all female; age range 2–40 years) and 16 healthy control females (age range 2–40 years) were analyzed for concentrations of 12 cytokines. Between-group differences in concentrations, and correlations with clinical severity in the RTT group were evaluated. Results: Concentrations of several salivary cytokines (IL-1β, IL-6, IL-8, IL-10, GM-CSF, TNF-α, and VEGF) were increased in RTT compared to controls. The same cytokines showed significant positive correlations with clinical severity scores. There were no differences in concentrations of IL-2, IL-4, IL-5, IL-12p70, and IFN-γ. Conclusion: The results suggest that salivary cytokines may be a possible indicator of immune dysregulation in RTT. Future research should investigate whether these results can be applied to other neurodevelopmental disorders