A Retrospective Survey-based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-dyskinesia Syndromes

The Epilepsy-Dyskinesia Study aims to advance the understanding of the clinical and molecular spectrum of epilepsy-dyskinesia syndromes, monogenic diseases that cause both movement disorders and epilepsy. Addressing challenges in rare disease research -such as small, geographically dispersed patient populations and a lack of standardized protocols- the study employs a multinational retrospective survey endorsed by the International Parkinson and Movement Disorder Society. This survey seeks to collect comprehensive data on clinical features, disease progression, age of onset, genetic variants, and concurrent neurological conditions, standardizing data collection across countries to provide a unified understanding of these conditions. Through retrospective review and molecular data analysis, the study aims to identify patterns and correlations between movement and seizure disorders, uncovering genotype-phenotype relationships. The initiative's goals are to enhance understanding of epilepsy-dyskinesia syndromes, inform precision medicine approaches, and foster international collaboration.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Movement Disorders; Dyskinesias; Ataxia; Neurologic Disorder; Chorea; Myoclonus; Dystonia Disorder; Epilepsy in Children; Movement Disorders in Children

Detailed Description

Overview: The Epilepsy-Dyskinesia Study aims to advance the understanding of the clinical and molecular spectrum of epilepsy-dyskinesia syndromes, which are monogenic diseases causing both movement disorders and epilepsy.

Design: Multinational Retrospective Survey:

Survey Details: Endorsed by the International Parkinson and Movement Disorder Society, this multinational retrospective survey seeks to gather comprehensive data on:

• Clinical Features and Progression: Examining developmental history and treatment responses.
• Disease Aspects: Including the age of onset for movement disorders and seizures, genetic variants, and concurrent neurological conditions.

Data Harmonization: By standardizing data collection across countries, the survey aims to overcome barriers in rare disease research and provide a unified understanding of these conditions.

Study Aims: This study seeks to broaden our understanding of the spectrum and association of movement and seizure disorders through a retrospective review. By analyzing clinical data, the study aims to identify patterns and correlations between these conditions while investigating molecular data to uncover underlying genetic and biochemical mechanisms. The ultimate goal is to enhance knowledge of how these disorders interact and progress over time, offering new insights at both clinical and molecular levels.

Overarching Goals:

1. Enhance understanding of movement disorders and epilepsy.
2. Inform precision medicine approaches.
3. Foster international collaboration for rare disease research.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Darius Ebrahimi-Fakhari, MD, PhD.; Phone Number: 617-355-0097; Email: movementdisorders@childrens.harvard.edu
• Study Contact Backup: Name: Vicente Quiroz, MD; Email: movementdisorders@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Principal Investigator: Darius Ebrahimi-Fakhari, MD, PhD
      • Contact: Darius Ebrahimi-Fakhari, MD, PhD; Phone Number: 617-355-0097; Email: movementdisorders@childrens.harvard.edu
      • Sub-Investigator: Vicente Quiroz, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll individuals diagnosed with a movement disorder due to pathogenic or likely pathogenic variants in the genes listed below. We plan to enroll at least 350 individuals over a 24-month period.

AARS2 ALG13 AP3B2 AP4B1 AP4E1 AP4M1 AP4S1 ARX ATP1A3 CACNA1A CACNA1E CACNA2D2 CDKL5 CSTB DARS2 DLAT DLD DNM1 EARS2 EPG5 FARS2 FOXG1 FRRS1L GABRA1 GABRA2 GABRB2 GABRB3 GABRG2 GRIA2 GRIA4 GRIN1 GRIN2A GRIN2B GRIN2D GNAO1 HARS2 HNRNPU IQSEC2 KCNA2 KCNB1 KCNC1 KCNMA1 KCNQ2 KCNQ3 KCNT1 LARS2 MECP2 MEF2C MTND5 MTTL1 MTTK NARS2 NHLRC1 PDE10A PDE2 PCDH12 PCDH19 PDK3 PIGP PIGQ PIGS PIGN POLG PDHA1 PDHB PDHX PRRT2 PURA RHOBTB2 SCN1A SCN1B SCN2A SCN8A SCN9A SLC13A5 SLC1A2 SLC2A1 SLC25A22 SMCA1 SNP14 ST3GAL3 STXBP1 SPTAN1 SYNGAP1 TBC1D24 TBL1WL1 TARS2 UBA5 UBE3A VAMP2 VARS2 WARS2 WDOX WDR45 YIF1B YWHAG

Description

Inclusion Criteria:

• Children between 0 - 18 years of age with a movement disorder and a pathogenic or likely pathogenic variant in one of the genes of interest:

AARS2 ALG13 AP3B2 AP4B1 AP4E1 AP4M1 AP4S1 ARX ATP1A3 CACNA1A CACNA1E CACNA2D2 CDKL5 CSTB DARS2 DLAT DLD DNM1 EARS2 EPG5 FARS2 FOXG1 FRRS1L GABRA1 GABRA2 GABRB2 GABRB3 GABRG2 GRIA2 GRIA4 GRIN1 GRIN2A GRIN2B GRIN2D GNAO1 HARS2 HNRNPU IQSEC2 KCNA2 KCNB1 KCNC1 KCNMA1 KCNQ2 KCNQ3 KCNT1 LARS2 MECP2 MEF2C MTND5 MTTL1 MTTK NARS2 NHLRC1 PDE10A PDE2 PCDH12 PCDH19 PDK3 PIGP PIGQ PIGS PIGN POLG PDHA1 PDHB PDHX PRRT2 PURA RHOBTB2 SCN1A SCN1B SCN2A SCN8A SCN9A SLC13A5 SLC1A2 SLC2A1 SLC25A22 SMCA1 SNP14 ST3GAL3 STXBP1 SPTAN1 SYNGAP1 TBC1D24 TBL1WL1 TARS2 UBA5 UBE3A VAMP2 VARS2 WARS2 WDOX WDR45 YIF1B YWHAG

Exclusion Criteria:

• Not having such diagnosis and/or not presenting a movement disorder.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Creation of a Shared Clinical Database	The primary endpoint of this multi-center study will be the creation of the Epilepsy-Dyskinesia Study and the enrollment of 350 individuals in a shared database.	1 year
Understanding of Disease Spectrum	To comprehensively understand the spectrum and association of movement and seizure disorders on both clinical and molecular levels.	1 year
Assess the Impact of Movement Disorders on Health-Related Quality of Life	To assess the impact of movement disorders on health-related quality of life specifically within the context of epilepsy-dyskinesia syndromes.	1 year
Investigate the Efficacy of Symptomatic Treatments	Investigate the efficacy of symptomatic treatments in addressing both seizure and movement disorders, aiming to identify shared therapeutic strategies.	1 year

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: International Parkinson and Movement Disorder Society

Publications and helpful links

General Publications

• de Gusmao CM, Garcia L, Mikati MA, Su S, Silveira-Moriyama L. Paroxysmal Genetic Movement Disorders and Epilepsy. Front Neurol. 2021 Mar 23;12:648031. doi: 10.3389/fneur.2021.648031. eCollection 2021.
• Mastrangelo M, Galosi S, Cesario S, Renzi A, Campea L, Leuzzi V. Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study. Front Neurol. 2022 Jun 20;13:855134. doi: 10.3389/fneur.2022.855134. eCollection 2022.
• Papandreou A, Danti FR, Spaull R, Leuzzi V, Mctague A, Kurian MA. The expanding spectrum of movement disorders in genetic epilepsies. Dev Med Child Neurol. 2020 Feb;62(2):178-191. doi: 10.1111/dmcn.14407. Epub 2019 Nov 29.
• Saenz-Farret M, Tijssen MAJ, Eliashiv D, Fisher RS, Sethi K, Fasano A. Antiseizure Drugs and Movement Disorders. CNS Drugs. 2022 Aug;36(8):859-876. doi: 10.1007/s40263-022-00937-x. Epub 2022 Jul 21. Erratum In: CNS Drugs. 2022 Sep;36(9):1017-1018. doi: 10.1007/s40263-022-00947-9.
• Spagnoli C, Fusco C, Percesepe A, Leuzzi V, Pisani F. Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review. Int J Mol Sci. 2021 Apr 18;22(8):4202. doi: 10.3390/ijms22084202.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: September 3, 2024
• First Submitted That Met QC Criteria: September 3, 2024
• First Posted (Actual): September 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: dyskinesia; movement disorders; dystonia; CDKL5; neurogenetics; MECP2; SCN1A; STXBP1; epileptic encephalopathy; GNAO1; epilepsy-dyskinesia syndrome; PRRT2; ATP1A3; CACNA1A; FOXG1; SCN8A; SLC2A1; UBA5
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Dyskinesias; Movement Disorders; Epilepsy; Nervous System Diseases; Ataxia; Dystonia; Dystonic Disorders; Myoclonus; Chorea; Dystonia 12
• Other Study ID Numbers: IRB-P00044666

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
• product manufactured in and exported from the U.S.: No