STXBP1 and SYNGAP1 Related Disorders Natural History Study

STXBP1 and SYNGAP1 Related Disorders (RD) Natural History Study

The purpose of this study is to find out more about STXBP1 and SYNGAP1 related disorders. The information gathered by this study will be used to prepare for clinical treatment trials. The primary objective of the study is to better define and outline the clinical spectrum of STXBP1 and SYNGAP1 through detailed developmental, seizure, and quality of life assessments as an extension of routine clinical care.

Study Overview

• Status: Recruiting
• Conditions: Genetic Disease; STXBP1 Encephalopathy With Epilepsy; SYNGAP1-Related Intellectual Disability
• Intervention / Treatment: Other: Non-interventional study

Detailed Description

STXBP1 and SYNGAP1 related disorders are genetic disorders that cause differences in the synaptic transmission of the brain. Disease-causing variants in these genes lead to a spectrum of developmental delay that is most often severe, epileptic encephalopathies, and complex behavioral and psychiatric disorders. As there are multiple targeted therapies in development for these conditions, there is an urgent need to push forward a prospective natural history study in order to define specific disease outcomes in these genetic conditions.

Participation may last up to five years and will involve up to 10 study visits. Detailed questions about health and medical history, physical exams, electrographic encephalogram (EEG) or quantitative EEG (qEEG) and some age-appropriate assessments of neurodevelopmental and behavioral function are some of the study procedures. Study procedures will occur during regularly scheduled clinic visits. Participants will undergo assessments at baseline visit and semi-annually (every 6 months for 2-5 years).

The primary objective of the study is to better define and outline the clinical spectrum of STXBP1 and SYNGAP1 through detailed developmental, seizure, and quality of life assessments as an extension of routine clinical care.

The secondary objectives of the study are listed below:

• To evaluate changes in neurodevelopmental and behavioral parameters as assessed by instruments appropriate to the study population.
• To assess the burden of disease by quality-of-life instruments appropriate to the study population.
• To assess the burden of performing multiple outcome measures and scales on the caregiver, participant, and clinical personnel.
• To assess health care resource utilization

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Joeylynn Nolan, RRT NPS AE-C; Phone Number: 2674411813; Email: COYNEJ@chop.edu
• Study Contact Backup: Name: Victoria Chisari, BA, NS; Email: ChisariV@chop.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford Medicine Children's Health
      • Contact: Swetapadma Patnaik; Email: sweta@stanford.edu
      • Principal Investigator: Juliet Knowles, MD
  • Colorado
    • Aurora, Colorado, United States, 80011
      • Recruiting
      • Children's Hospital Colorado
      • Contact: Megan Stringfellow; Email: Megan.Stringfellow@childrenscolorado.org
      • Principal Investigator: Andrea Miele, PhD
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine
      • Contact: Millie Stone; Email: aks4017@med.cornell.edu
      • Principal Investigator: Zachary Grinspan, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19403
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Contact: Joeylynn Nolan; Email: coynej@chop.edu
      • Principal Investigator: Ingo Helbig, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Principal Investigator: Hsiao-Tuan Chao, MD, PhD
      • Contact: Ekaterina Sanchez Romero; Email: chao-lab@bcm.edu

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Participating individuals must have a confirmed genetic diagnosis of STXBP1 or SYNGAP1 related disorders. Participants can be any age and present with any disease severity

Description

Inclusion Criteria:

• Male or female of any age.
• Presence of a STXBP1 or SYNGAP1 gene mutation. The variant in STXBP1 or SYNGAP1 must be classified as causative based on clinical and variant classification criteria. Historical documentation is sufficient to support eligibility for the study. Confirmatory testing will be obtained, if necessary, at baseline and performed by a CLIA certified laboratory.

Exclusion Criteria:

• The presence of a confirmed mutation in a gene other than STXBP1 or SYNGAP1 that is known to contribute to a neurodevelopmental disability. This includes full gene deletions of STXBP1 or SYNGAP1 that include other genes beyond STXBP1 or SYNGAP1.
• The presence of a significant non-STXBP1-RD or non-SYNGAP1-RD related central nervous impairment/behavioral disturbance that would confound the scientific rigor or interpretation of results of the study.
• History of intraventricular hemorrhage, structural brain deficit or congenital heart disease
• The presence of a clinical comorbidity deemed by the investigator to potentially confound the typical presentation of STXBP1-RD or SYNGAP1-RD.
• Pregnant women or females of age of menarche who are found to be pregnant upon urine pregnancy testing.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
STXBP1 cohort	Other: Non-interventional study; There is no planned intervention in this study
SYNGAP1 cohort	Other: Non-interventional study; There is no planned intervention in this study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in percentiles recorded on clinical assessments over time	The primary analysis will include all subjects meeting all inclusion and exclusion criteria and completing Visit 1. For each subject, the percentage of items performed correctly on the clinical assessments will be recorded. Changes in percentiles over time will be analyzed using a linear mixed effects model, to account for repeated measures for each patient.	Every 6 months upto 5 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: STXBP1 Foundation
• Investigators: Principal Investigator: Ingo Helbig, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Xian J, Parthasarathy S, Ruggiero SM, Balagura G, Fitch E, Helbig K, Gan J, Ganesan S, Kaufman MC, Ellis CA, Lewis-Smith D, Galer P, Cunningham K, O'Brien M, Cosico M, Baker K, Darling A, Veiga de Goes F, El Achkar CM, Doering JH, Furia F, Garcia-Cazorla A, Gardella E, Geertjens L, Klein C, Kolesnik-Taylor A, Lammertse H, Lee J, Mackie A, Misra-Isrie M, Olson H, Sexton E, Sheidley B, Smith L, Sotero L, Stamberger H, Syrbe S, Thalwitzer KM, van Berkel A, van Haelst M, Yuskaitis C, Weckhuysen S, Prosser B, Son Rigby C, Demarest S, Pierce S, Zhang Y, Moller RS, Bruining H, Poduri A, Zara F, Verhage M, Striano P, Helbig I. Assessing the landscape of STXBP1-related disorders in 534 individuals. Brain. 2022 Jun 3;145(5):1668-1683. doi: 10.1093/brain/awab327.
• Yang P, Broadbent R, Prasad C, Levin S, Goobie S, Knoll JH, Prasad AN. De novo STXBP1 Mutations in Two Patients With Developmental Delay With or Without Epileptic Seizures. Front Neurol. 2021 Dec 24;12:804078. doi: 10.3389/fneur.2021.804078. eCollection 2021.
• Wang HH, Liao HF, Hsieh CL. Reliability, sensitivity to change, and responsiveness of the peabody developmental motor scales-second edition for children with cerebral palsy. Phys Ther. 2006 Oct;86(10):1351-9. doi: 10.2522/ptj.20050259.
• Demarest S, Pestana-Knight EM, Olson HE, Downs J, Marsh ED, Kaufmann WE, Partridge CA, Leonard H, Gwadry-Sridhar F, Frame KE, Cross JH, Chin RFM, Parikh S, Panzer A, Weisenberg J, Utley K, Jaksha A, Amin S, Khwaja O, Devinsky O, Neul JL, Percy AK, Benke TA. Severity Assessment in CDKL5 Deficiency Disorder. Pediatr Neurol. 2019 Aug;97:38-42. doi: 10.1016/j.pediatrneurol.2019.03.017. Epub 2019 Mar 27.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2023
• Primary Completion (Estimated): August 30, 2028
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: August 13, 2024
• First Submitted That Met QC Criteria: August 13, 2024
• First Posted (Actual): August 15, 2024

Study Record Updates

• Last Update Posted (Estimated): October 29, 2025
• Last Update Submitted That Met QC Criteria: October 28, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Natural History; Clinical Research; SYNGAP1; STXBP1
• Additional Relevant MeSH Terms: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Epileptic Encephalopathy, Early Infantile, 4
• Other Study ID Numbers: 23-021140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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