NGLY1 Deficiency: A Prospective Natural History Study

NGLY1 deficiency is a rare genetic disorder that is characterized by: global developmental delay and/or intellectual disability, hypo- or alacrima, transient elevation of transaminases, and a hyperkinetic movement disorder. Significant phenotypic variability has been observed in the small number of affected individuals described in the medical literature.

The purpose of this study is to describe the natural history of NGLY1 deficiency in a prospective, detailed, and highly uniform manner. Study participants will be closely monitored over the course of five years in order to:

• understand the clinical spectrum and progression of NGLY1 deficiency using standardized clinical and neurodevelopmental assessments
• identify clinical and biomarker endpoints for use in therapeutic trials, and
• identify genotype-phenotype correlations

Close clinical follow-up will allow for generation of a rich dataset and detailed understanding of the natural history of NGLY1 deficiency.

Study Overview

• Status: Terminated
• Conditions: Genetic Syndrome
• Intervention / Treatment: Other: Neurodevelopmental Assessment

• Study Type: Observational
• Enrollment (Actual): 29

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University

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

Individuals of any age with NGLY1 deficiency.

Description

Inclusion Criteria:

• Parent(s)/legal representative and/or participant must be willing and able to give informed consent/assent for participation in the study
• Males or females of any age
• Suspected or confirmed diagnosis of NGLY1 deficiency with genetic variants in both NGLY1 alleles and consistent clinical characteristics
• Participant and caregiver must be willing to provide clinical data, participate in standardized assessments, and provide biological samples (if living in the United States)
• Willingness to travel to Palo Alto, CA is favored, but not required

Exclusion Criteria:

• The presence of a second, confirmed disorder, genetic or otherwise, affecting neurodevelopment or with other overlapping symptoms of NGLY1 deficiency

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Detailed phenotyping of the clinical course of NGLY1 deficiency over time	Conducted in patients with NGLY1 deficiency: detailed standardized general, neurologic, dysmorphologic, and ophthalmologic evaluations; clinical laboratory studies; electroencephalogram; nerve conduction studies; quantitative studies of autonomic function; scoring of movement disorder and NGLY1 deficiency symptom scales; and a timed 10-meter walk test. As much information as available will also be collected from existing medical records including clinical evaluations, imaging studies and neuropsychological and motor function evaluations.	5 years
Neurodevelopmental profile of NGLY1 deficiency as measured using Mullen Scales of Early Learning	Developmental assessment at baseline and longitudinally, if age and ability-appropriate.	5 years
Neurodevelopmental profile of NGLY1 deficiency as measured using Bruininks-Oseretsky Test of Motor Proficiency, Second Edition	Developmental assessment at baseline and longitudinally, if age and ability-appropriate.	5 years
Neurodevelopmental profile of NGLY1 deficiency as measured using the Peabody Scales of Motor Development	Developmental assessment at baseline and longitudinally, if age and ability-appropriate.	5 years
Neurodevelopmental profile of NGLY1 deficiency as measured using the Differential Ability Scales II	Developmental assessment at baseline and longitudinally, if age and ability-appropriate.	5 years
Neurodevelopmental profile of NGLY1 deficiency as measured using the Beery Visual Motor Integration developmental test	Developmental assessment at baseline and longitudinally, if age and ability-appropriate.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant quality of life as measured through the Pediatric Quality of Life Inventory (PedsQL)	Quality of life will be evaluated at baseline and longitudinally.	5 years
Caregiver quality of life as measured through the 36 Item Short Form Survey (SF36)	Quality of life will be evaluated at baseline and longitudinally. Caregivers will complete the survey but will not be enrolled in the study.	5 years
Biomarkers for NGLY1 deficiency identified during the course of the study	Longitudinal collection and monitoring of laboratory studies and clinical presentation as measured through standardized and quantitative assessments may identify biomarkers for NGLY1 deficiency.	5 years

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Grace Science Foundation
• Investigators: Principal Investigator: Maura Ruzhnikov, MD, Stanford University

Publications and helpful links

General Publications

• Levy RJ, Frater CH, Gallentine WB, Phillips JM, Ruzhnikov MR. Delineating the epilepsy phenotype of NGLY1 deficiency. J Inherit Metab Dis. 2022 May;45(3):571-583. doi: 10.1002/jimd.12494. Epub 2022 Mar 11.

Helpful Links

• Grace Science Foundation
• Neurogenomics at Stanford

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): November 19, 2021
• Study Completion (Actual): November 19, 2021

Study Registration Dates

• First Submitted: January 23, 2019
• First Submitted That Met QC Criteria: February 6, 2019
• First Posted (Actual): February 8, 2019

Study Record Updates

• Last Update Posted (Actual): June 8, 2022
• Last Update Submitted That Met QC Criteria: June 3, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: NGLY1 Deficiency
• Other Study ID Numbers: IRB-47335

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Researchers and clinicians with academic interest in NGLY1 deficiency may be provided access to data obtained through this study. Any data or samples shared outside of Stanford University will be done so in a coded fashion with no protected health information included and with the execution of all applicable agreements (i.e. a material transfer agreement) or ongoing collaborations as approved in eProtocol 47335.

Drug and device information, study documents

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