Content Validation of the Communication Inventory Disability-Observer Reported (CID-OR).

CDKL5 deficiency disorder is a rare and severe developmental and epileptic encephalopathy that has profound effects on communication. It is essential that communication be measured accurately for upcoming gene therapy trials. The Communication Inventory Disability-Observer Reported (CID-OR) was developed from a framework of communication derived from parent/caregiver interview data (n = 23), in consultation with disability and communication experts, and after reviewing concepts in existing measures.

Symptom Onset in Classic Rett Syndrome: Analysis of Initial Clinical Severity Scale Entries.

Objective: To assess clinical features of Rett Syndrome (RTT) at registration into the NIH-sponsored Natural History (NH) study using the Clinical Severity Scale (CSS).

Introduction: The CSS was established in 2000 to assess characteristics of individuals with RTT and related disorders. We analyzed the CSS at enrollment into the NH study of all individuals with classic RTT.

Natural history of epilepsy in FOXG1 Syndrome.

Background: FOXG1 syndrome is rare neurodevelopmental disorder with microcephaly, brain malformations, epilepsy, and cognitive and motor disabilities as major features. Knowledge of the clinical features is primarily from case series and a foundation sponsored registry. We expand insight into epilepsy in FOXG1 syndrome by examining longitudinal data from 94 individuals from a multi-site natural history study and local cohorts.

Altered oscillatory coupling reflects possible inhibitory interneuron dysfunction in Rett syndrome.

Background: Rett syndrome is a rare neurodevelopmental disorder caused primarily by pathogenic variants in the gene, leading to lifelong cognitive impairments. To understand the broad neural disruptions in Rett syndrome, it is essential to examine large-scale brain dynamics at the level of neural oscillations. Phase-amplitude coupling-a form of cross-frequency interaction that supports information integration across temporal and spatial scales-is a promising candidate measure for capturing such widespread neural dysfunction.

Considerations and procedures for acquiring EEG as part of multi-site studies for Rett syndrome and other genetic neurodevelopmental disorders.

There is increasing interest in the utility of electrophysiological measures such as resting EEG and evoked potential (EPs) to serve as biomarkers to facilitate therapeutic development for rare genetic neurodevelopmental disorders (NDDs). Research on this topic thus far has been encouraging, but has also revealed the necessity for unique methods when acquiring EEG and EPs in children with genetic NDDs. Details of these methods are typically beyond the scope of research publications, yet are crucial to the quality and ultimately, usability of the data.

Interictal spikes and evoked cortical potentials share common spatiotemporal constraints in human epilepsy.

Interictal epileptiform discharges (IEDs) are pathologic hallmarks of epilepsy which frequently arise and spread through networks of functionally-connected brain regions. Recent studies demonstrate that the sequential recruitment of brain regions by propagating IEDs is highly conserved across repeated discharges, suggesting that IED propagation is spatiotemporally constrained by features of the underlying epileptic network. Understanding how repetitive IED sequences relate to the spatiotemporal organization of the epileptic network may reveal key insights into the pathophysiological role of IEDs during epileptogenesis.

Medical Biases and Misconceptions Impact Diagnoses in Males With Loss of Function MECP2 Variants.

Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. These variants were historically believed to be incompatible with life in males; however, recent advances in genetic testing have revealed significant clinical heterogeneity. The current study aimed to improve our understanding of diagnostic experiences in males with confirmed pathogenic alteration of MECP2.

The genetic and phenotypic spectrum of GABRB1-related disorders.

Pathogenic variants in GABAA receptor subunits genes (GABR*) are important contributors to rare and common genetic epilepsies. Here, we present a comprehensive analysis of variants in GABRB1, which encodes the GABAA receptor β1 subunit, by revealing their functional implications, establishing genotype-phenotype correlations, and evaluating treatment response. Clinical information on individuals carrying a GABRB1 variant was obtained through an international collaboration and literature review.

Autosomal dominant -related neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA): An emerging mitochondrial disorder.

Purpose: Hexokinase 1 () encodes a ubiquitously expressed hexokinase, which is responsible for the first step of glycolysis, phosphorylation of glucose to glucose-6-phosphate. Both autosomal recessive and dominant variants in this gene have previously been shown to cause human disease, and presently, there are clinical data available for 27 individuals with the monoallelic neurodevelopmental disorder with visual defects and brain anomalies. Delineation of the entire phenotypic spectrum and genotype-phenotype relations will aid in management and counseling decisions.

Co-activation of interictal epileptiform discharges localizes seizure onset zone and fluctuates with brain state.

Seizures are increasingly understood as emergent phenomena of complex, pathophysiologic networks. Interictal spikes are ubiquitous markers of paroxysmal synchronization in the epileptic brain and have been shown to co-activate between brain regions with millisecond-scale latencies, suggesting that they can spread through distributed networks of functionally inter-connected neuronal populations. In this study, we examined the relationship between interictal spike co-activation, seizure localization and resting-state EEG activity in children with medically refractory epilepsy.

Multiple subpial transections with concomitant responsive neurostimulation of the insula: illustrative case.

Background: Focal epilepsy arising from the eloquent cortex can be treated with palliative surgical interventions such as multiple subpial transection (MST) or responsive neurostimulation (RNS). These techniques can be performed to reduce the burden of disabling seizures while avoiding disability associated with resection of the eloquent brain.

Observations: A 17-year-old girl with a history of complex, refractory multifocal epilepsy and previous right anterior temporal lobectomy and left temporal neocortical RNS presented with refractory status epilepticus.

Mapping the Epileptogenic Brain Using Low-Frequency Stimulation: Two Decades of Advances and Uncertainties.

Cortical stimulation is the process of delivering brief pulses of electrical current and visualizing the distributed pattern of evoked responses across the brain. Compared to high-frequency stimulation, which has long been used for seizure provocation and functional mapping, low-frequency stimulation (<1-2 Hz) is rarely incorporated into the epilepsy surgery evaluation. Increasingly, researchers have demonstrated that various cortico-cortical evoked potential (CCEP) features, including early and delayed responses, evoked high-frequency oscillations, and derived network metrics, may be useful biomarkers of tissue excitability and abnormal connectivity.

Results from the phase 2/3 DAFFODIL study of trofinetide in girls aged 2-4 years with Rett syndrome.

Background: Trofinetide is the first available treatment for Rett syndrome (RTT) and is approved in the United States in adults and pediatric patients aged ≥2 years. The DAFFODIL study was conducted in girls aged 2-4 years with RTT to examine the safety, tolerability, and efficacy of trofinetide and to validate that the recommended dosage, according to body weight, achieved target exposure.

Methods: DAFFODIL was a phase 2/3, open-label study of trofinetide consisting of two treatment periods (12 weeks [period A] and ∼21 months [period B]).

Functional Characterization of Parallel Fiber-Purkinje Cell Synapses in Two Friedreich's Ataxia Mouse Models.

Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by GAA expansions in the FXN gene, which codes for the protein frataxin (FXN). These mutations reduce FXN expression, leading to mitochondrial dysfunction and multisystemic disease. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, may drive the neurological phenotypes of FRDA, but the mechanisms underlying such neurological phenotypes remain unclear.

A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome.

Background: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.

Design: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.

Methods: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment.

International workshop: what is needed to ensure outcome measures for Rett syndrome are fit-for-purpose for clinical trials? June 7, 2023, Nashville, USA.

Introduction: The clinical, research and advocacy communities for Rett syndrome are striving to achieve clinical trial readiness, including having fit-for-purpose clinical outcome assessments. This study aimed to (1) describe psychometric properties of clinical outcome assessment for Rett syndrome and (2) identify what is needed to ensure that fit-for-purpose clinical outcome assessments are available for clinical trials.

Methods: Clinical outcome assessments for the top 10 priority domains identified in the Voice of the Patient Report for Rett syndrome were compiled and available psychometric data were extracted.

Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder.

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR.

Clinical Features and Disease Progression in Older Individuals with Rett Syndrome.

Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old).

Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder.

Objective: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability.

Parent-reported outcome measures evaluating communication in individuals with rare neurodevelopmental disorders: A systematic review.

Background: Communication impairments are a leading concern for parent caregivers of individuals with rare neurodevelopmental disorders (RNDDs). Clinical trials of disease modifying therapies require valid and responsive outcome measures that are relevant to individuals with RNDDs. Identifying and evaluating current psychometric properties for communication measures is a critical step towards the selection and use of appropriate instruments.

Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

Study Objectives: Sleep difficulties are common in CDKL5 deficiency disorder, a developmental and epileptic encephalopathy. This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Somnolence (DOES), and Sleep Breathing Disorders domains of the Sleep Disturbance Scale for Children for CDKL5 deficiency disorder.

Methods: A cross-sectional psychometric study design was used.