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.

Cortical Visual Impairment Across a Range of Neurodevelopmental Disorders: Clinical Characterization, Diagnostic Tool Evaluation, and Association with Developmental Outcomes.

Cortical visual impairment is particularly relevant in children with neurodevelopmental disorders yet remains underdiagnosed. This study assessed the prevalence and severity of cortical visual impairment in 4 neurogenetic conditions: STXBP1, SLC6A1, Ring 14, and 8p-related disorders. We also evaluated the -Clinical Severity Assessment-Clinician vision subdomain as a diagnostic tool and examined the association between cortical visual impairment and developmental outcomes.

Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia.

Introduction: DENND2B is a DENN (differentially expressed in normal and neoplastic cells) domain-containing protein that has important roles in regulating the cell cycle, cell division and ciliogenesis, but to date has not been associated with any human disease.

Methods: Here we report on 11 individuals with monoallelic variants in DENND2B with a shared constellation of features and perform in silico and in vivo zebrafish modelling of the DENND2B variants identified in these patients.

Results: Features shared among these patients include developmental delay, intellectual disability and psychiatric/behavioral concerns, and episodes of psychosis and/or catatonia.

The natural history of CDKL5 deficiency disorder into adulthood.

Knowledge of the natural history of deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood.

A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases.

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials.

Prevalence of cerebral visual impairment in developmental and Epileptic Encephalopathies: a systematic review protocol.

Background: Developmental and Epileptic Encephalopathies (DEEs) are defined by drug-resistant seizures and neurodevelopmental disorders. Over 50% of patients have a genetic cause. Studies have shown that patients with DEEs, regardless of genetic diagnosis, experience a central visual function disorder known as Cerebral (cortical) Visual Impairment (CVI).

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.

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.

Communication of individuals with CDKL5 deficiency disorder as observed by caregivers: A descriptive qualitative study.

CDKL5 deficiency disorder (CDD) is a genetically caused developmental epileptic encephalopathy that causes severe communication impairments. Communication of individuals with CDD is not well understood in the literature and currently available measures are not well validated in this population. Accurate and sensitive measurement of the communication of individuals with CDD is important for understanding this condition, clinical practice, and upcoming interventional trials.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

Objective: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold.

Methods: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE.

CDKL5 deficiency disorder and other infantile-onset genetic epilepsies.

Aim: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile-onset epilepsies.

Method: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile-onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features.

The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder.

Background: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity.

Epilepsy panels in clinical practice: Yield, variants of uncertain significance, and treatment implications.

Objective: There has been increasing utilization of genetic testing for pediatric epilepsy in recent years. Little systematic data is available examining how practice changes have impacted testing yields, diagnostic pace, incidence of variants of uncertain significance (VUSs), or therapeutic management.

Methods: A retrospective chart review was performed at Children's Hospital Colorado from February 2016 through February 2020.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

Objective: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies.

Methods: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses.

Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE).

Objective: Chromosome 15q duplication (Dup15q) syndrome and cyclin‑dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275).

Methods: ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline.

Patterns of developmental regression and associated clinical characteristics in SLC6A1-related disorder.

Introduction: SLC6A1-related disorder is a genetic neurodevelopmental disorder that is caused by loss of function variants in the gene. Solute Carrier Family 6 Member 1 () gene encodes for gamma-aminobutyric acid (GABA) transporter type 1 (GAT1), which is responsible for reuptake of GABA from the synaptic cleft. Tight regulation of GABA levels plays an important role in brain development by balancing inhibitory and excitatory neuronal signaling.

Analysis of electrocardiograms in individuals with CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an epileptic encephalopathy associated with medically refractory epilepsy. We sought to determine whether prolonged corrected QT interval (QTc) or other cardiac conduction abnormalities were seen in CDD in a clinical cohort. A cohort of individuals with CDD was evaluated in the Children's Hospital Colorado's International Foundation for CDKL5 Research designated Center of Excellence clinic with routine electrocardiograms obtained as part of routine clinical care.