CNKSR2 Natural History Study (CNKSR2)

Natural History Study of Infants and Children With CNKSR2-Associated Neurodevelopmental Disorders and Epilepsy

This prospective natural history study is being conducted to define the electroclinical, neurodevelopmental, and behavioral characteristics of CNKSR2 epilepsy aphasia syndrome (EAS) and intellectual disability (ID) in children aged 6 to 21 years old with CNKSR2 mutations.

The data collected from this study will serve as an external control to eventual clinical trials examining precision medicine investigational therapeutics that aim to improve the seizure burden and neurodevelopmental outcomes in patients with CNKSR2 EAS/ID.

Study Overview

• Status: Recruiting
• Conditions: Epileptic Encephalopathy, Childhood-Onset; Developmental Dysphasia; X-Linked Intellectual Disability

• Study Type: Observational
• Enrollment (Estimated): 15

Contacts and Locations

• Study Contact: Name: Alex Fay, MD, PhD; Phone Number: 415-353-7596; Email: alexander.fay@ucsf.edu
• Study Contact Backup: Name: Maya Dhar, MS; Phone Number: 415-353-9465; Email: maya.dhar@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • University of California, San Francisco (UCSF)
      • Principal Investigator: Alex Fay, MD, PhD
      • Sub-Investigator: Danilo Bernardo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Children with CNKSR2 pathogenic mutation and characteristic features of CNKSR2 neurodevelopmental disorder and/or epilepsy

Description

Inclusion Criteria:

1. Age between 6 and 21 years (inclusive) at time of consent.
2. Confirmed CNKSR2 mutation, as demonstrated by genetic testing and confirmed by the investigators.
3. Confirmed intellectual disability or developmental delays, as defined by the American Academy of Pediatrics (Moeschler, J, et al. 2014).

Exclusion Criteria:

1. Known pathogenic or clinically suspected mutation in a seizure-associated gene besides CNKSR2.
2. Confirmed mutation in a gene besides CNKSR2 that is known to increase the severity of the seizure phenotype.
3. Known central nervous system structural abnormality confirmed by imaging scan of the brain that is not consistent with the clinical phenotype of CNKSR2 EAS / ID.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in functional connectivity within the epileptiform network using resting-state functional magnetic resonance imaging (fMRI).	Functional connectivity is unitless.	Baseline, Month 12, Month 24
Change from baseline in functional connectivity within the language network using resting-state functional magnetic resonance imaging (fMRI).	Functional connectivity is unitless.	Baseline, Month 12, Month 24
Change from baseline in cortical evoked response to self-produced speech as measured by voxel-wise source reconstructed brain activation using magnetoencephalography (MEG).	Voxel-wise source reconstructed brain activation assesses localized brain function by mapping neural activity at the voxel level. It is a unitless measure.	Baseline, Month 12, Month 24
Change from baseline in cortical evoked response to altered auditory feedback during self-produced speech as measured by voxel-wise source reconstructed brain activation using magnetoencephalography (MEG).	Voxel-wise source reconstructed brain activation assesses localized brain function by mapping neural activity at the voxel level. It is a unitless measure.	Baseline, Month 12, Month 24
Change from baseline in resting state brain activity as measured by voxel-wise source reconstructed brain activation using magnetoencephalography (MEG).	Voxel-wise source reconstructed brain activation assesses localized brain function by mapping neural activity at the voxel level. It is a unitless measure.	Baseline, Month 12, Month 24
Change from baseline in resting state background brain activity during sleep as measured by phase lag index using electroencephalography (EEG).	Phase lag index ranges between 0 and 1 and is unitless. A phase lag index of zero indicates either no coupling or coupling with a phase difference centered around 0 mod π.	Baseline, Month 12, Month 24
Change from baseline in spike-wave index during sleep as measured by percentage using electroencephalography (EEG).	Spike-wave index is the sum of all spike and slow wave minutes multiplied by 100 and divided by the total non-rapid eye movement sleep minutes.	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) scaled scores.	Higher scores indicate a better outcome (minimum score: 1, maximum score: 19).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) standard scores.	Higher scores indicate a better outcome (minimum score: 45, maximum score: 155).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition (WPPSI-IV) composite scores.	Higher scores indicate a better outcome (minimum score: 40, maximum score: 160).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition (WPPSI-IV) scaled scores.	Higher scores indicate a better outcome (minimum score: 1, maximum score: 19).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by the Wechsler Abbreviated Scale of Intelligence, 2nd Edition (WASI-II) composite scores.	Higher scores indicate a better outcome (minimum score: 40, maximum score: 160).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by the Wechsler Abbreviated Scale of Intelligence, 2nd Edition (WASI-II) T-scores.	Higher scores indicate a better outcome (minimum score: 20, maximum score: 80).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by Parent Report Form of Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3) Adaptive Behavior Composite score and Domain scores.	Higher scores indicate a better outcome (minimum score: 20, maximum score: 140).	Baseline, Month 12, Month 24
Change from baseline in neurodevelopmental status as measured by Parent Report Form of Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3) V-Scale Scores.	Higher scores indicate a better outcome (minimum score: 1, maximum score: 24).	Baseline, Month 12, Month 24
Change from baseline in performance on the Receptive One-Word Picture Vocabulary Test, 4th Edition standard scores.	Higher scores indicate a better outcome (minimum score: < 55, maximum score: > 165).	Baseline, Month 12, Month 24
Change from baseline in performance on the Expressive One-Word Picture Vocabulary Test, 4th Edition standard scores.	Higher scores indicate a better outcome (minimum score: < 55, maximum score: > 165).	Baseline, Month 12, Month 24
Change from baseline in ADHD Rating Scale, 4th Edition (ADHD-RS-IV) inattention subscale raw scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 9).	Baseline, Month 6, Month 12, Month 18, Month 24
Change in hyperactivity as measured by ADHD Rating Scale, 4th Edition (ADHD-RS-IV) hyperactivity subscale raw scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 9).	Baseline, Month 6, Month 12, Month 18, Month 24
Change in physical functioning as measured by Pediatric Quality of Life Inventory (PedsQL) scale scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 100).	Baseline, Month 6, Month 12, Month 18, Month 24
Change in emotional functioning as measured by Pediatric Quality of Life Inventory (PedsQL) scale scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 100).	Baseline, Month 6, Month 12, Month 18, Month 24
Change in social functioning as measured by Pediatric Quality of Life Inventory (PedsQL) scale scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 100).	Baseline, Month 6, Month 12, Month 18, Month 24
Change in school functioning as measured by Pediatric Quality of Life Inventory (PedsQL) scale scores.	Lower scores indicate a better outcome (minimum score: 0, maximum score: 100).	Baseline, Month 6, Month 12, Month 18, Month 24

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Alex Fay, MD, PhD, alexander.fay@ucsf.edu

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 1, 2024
• First Submitted That Met QC Criteria: July 11, 2024
• First Posted (Actual): July 15, 2024

Study Record Updates

• Last Update Posted (Actual): July 15, 2024
• Last Update Submitted That Met QC Criteria: July 11, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Epilepsy; CSWS; ESES; Language Disorder; X-linked Intellectual Disability; CNKSR2
• Additional Relevant MeSH Terms: Mental Disorders; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurodevelopmental Disorders; Language Disorders; Communication Disorders; Speech Disorders; Brain Diseases; Aphasia; Intellectual Disability
• Other Study ID Numbers: 22-35959

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No