GNAO1 Natural History Study (GNAO1)

Natural History of GNAO1-associated Neurodevelopmental Disorder

The purpose of the GNAO1 Natural History Study is to establish the clinical phenotype of GNAO1 associated neurologic disease, its association with genotype, and areas of clinical importance within the disease.

Study Overview

• Status: Enrolling by invitation
• Conditions: GNAO1

Detailed Description

GNAO1 associated neurologic disease is a rare autosomal dominant neurodevelopmental disorder characterized genetically by heterozygous de novo mutations in GNAO1 gene which encodes Gαo, the α subunit of Go, a G protein signal transducer. Phenotypically, it is characterized by developmental delay, epilepsy and/or movement disorder. Medical therapy is symptomatic and often ineffective for many patients. While there are basic and translational studies underway to develop more mechanistic treatments aimed at developing disease modifying treatments, our general knowledge of the natural history of GNAO1 associated neurologicis is extremely limited, making it difficult to select the best measures for identifying changes over time. Without this information,it will be difficult to detect any potential therapeutic efficacy in future trials of novel therapies. To address this critical void in our understanding, we propose to retrospectively and prospectively examine symptom progression(short-and long-term)and developmental outcomes in patients with GNAO1 associated neurologic disease. Retrospective data will be collected on a cohort of 50 patients. Standardized historical clinical information will be received from the physicians and care-givers of these patients, in collaboration with the Bow Foundation Registry. These data will provide an overview of the onset and severity of symptoms over development. In addition, prospective data will be acquired during in-person clinical evaluations of a cohort of 15-20 patients who are not receiving any experimental interventions. In combination, these two approaches will provide critical information about the natural history of GNAO1 associated neurologic disease in children, identify metrics that track change most reliably over time, and collect pilot data for larger future studies.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Minors and adults who have a confirmed pathogenic mutation in GNAO1 or a variant of unknown significance and clinical symptoms likely to be consistent with GNAO1 (e.g. global developmental delay, movement disorder, seizures) as determined by study physicians.

Description

Inclusion Criteria:

• Enrollment in the Bow Foundation GNAO1 registry.
• Evidence of a known pathogenic mutation in GNAO1 or a variant of unknown significance and clinical symptoms likely to be consistent with GNAO1 as determined by study physicians.

Exclusion Criteria:

• Inability to obtain informed consent from parents or adult subjects.
• Inability to obtain medical records.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chorea	The Abnormal Involuntary Movement Scale (AIMS) assesses the severity of dyskinesias, as well as the overall severity, incapacitation, and the subject's level of awareness of the movements, and distress associated with them.	March 2019; May-Oct 2020
Dystonia	The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) assesses the severity of dystonia in nine body regions. The scale takes into account the severity and frequency of the dystonic movements.	March 2019; May-Oct 2020
Gross motor development, mobility	The Gross Motor Function Measure (GMFM-88) is a standardized observational instrument designed and validated to measure changes in gross motor function over time in children with cerebral palsy.	March 2019; May-Oct 2020
Spasticity	The Modified Ashworth Scale (MAS) is a muscle tone assessment scale used to assess the resistance experienced during passive range of motion. The MAS is the current standard for clinical assessment of extremity spasticity.	March 2019
Fine motor development	The Peabody Developmental Motor Scales 2nd Edition (PDMS-2) is an early childhood motor development program that provides both in-depth assessment and training or remediation of gross and fine motor skills. The assessment is composed of six subtests that measure interrelated motor abilities that develop early in life. We are mainly interested in two subtests: Grasping and Visual-Motor Integration.	March 2019
Quality of Life and Caregiver Burden	The Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire attempts to understand and quantitate the quality of life of patients and caregiver burden.	March 2019; May-Oct 2020

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: The Bow Foundation
• Investigators: Principal Investigator: Amy Viehoever, MD, Ph.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Narayanan UG, Fehlings D, Weir S, Knights S, Kiran S, Campbell K. Initial development and validation of the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Dev Med Child Neurol. 2006 Oct;48(10):804-12. doi: 10.1017/S0012162206001745.
• Ananth AL, Robichaux-Viehoever A, Kim YM, Hanson-Kahn A, Cox R, Enns GM, Strober J, Willing M, Schlaggar BL, Wu YW, Bernstein JA. Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder. Pediatr Neurol. 2016 Jun;59:81-4. doi: 10.1016/j.pediatrneurol.2016.02.018. Epub 2016 Mar 17.
• Feng H, Sjogren B, Karaj B, Shaw V, Gezer A, Neubig RR. Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. Neurology. 2017 Aug 22;89(8):762-770. doi: 10.1212/WNL.0000000000004262. Epub 2017 Jul 26.
• Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N. Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay. Eur J Hum Genet. 2016 Jan;24(1):129-34. doi: 10.1038/ejhg.2015.92. Epub 2015 May 13.

Helpful Links

• The Bow Foundation website

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2019
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 25, 2021
• First Submitted That Met QC Criteria: June 25, 2021
• First Posted (Actual): July 6, 2021

Study Record Updates

• Last Update Posted (Actual): July 6, 2021
• Last Update Submitted That Met QC Criteria: June 25, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: pediatric; epilepsy; neurology; Natural History Study; movement disorder; GNAO1
• Other Study ID Numbers: 201901128

Drug and device information, study documents

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