Neurometabolic Profile of Individuals With Primary Mitochondrial Disease

Primary Mitochondrial Disease (PMD) is a genetic neurometabolic disorder, leading to central nervous system degeneration and increased risk of early mortality. There is a strong link between the pathophysiology of mitochondrial disease and biomarkers related to the biochemistry of redox imbalance, involving the levels of glutathione. Investigators will use Magnetic Resonance Imaging and Spectroscopy to non-invasively measure glutathione and other chemicals in the brain to identify redox imbalance in patients with PMD.

Study Overview

• Status: Recruiting
• Conditions: Primary Mitochondrial Disease

Detailed Description

Primary Mitochondrial Disease (PMD) is a genetic neurometabolic disorder, leading to the degeneration of the central nervous system (CNS) and increased risk of early mortality. PMD can be caused by mutations in several genes in the mitochondrial DNA as well as nuclear DNA. Although a rare disease, PMD can significantly impact quality of life, increasing healthcare costs and caregiver burden. There is a lack of non-invasive, validated, and objective markers of mitochondrial function. However, there is a strong link between the pathophysiology of mitochondrial disease and biomarkers related to the biochemistry of redox imbalance, involving the levels of glutathione (GSH). Redox imbalance can also result in the overgeneration of radicals, causing neuronal damage. With the advancement in magnetic resonance techniques, the investigators can measure the levels of GSH and other neurochemicals non-invasively in the brain. Investigators in this proposal will use Magnetic Resonance Spectroscopy and Imaging (MRS and MRI) to measure brain chemicals, structure, and function.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Zarazuela Zolkipli-Cunningham; Phone Number: (267) 426-4961; Email: mmfpclinicalresearch@chop.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Contact: Zarazuela Zolkipli-Cunningham; Phone Number: 267-426-4961; Email: mmfpclinicalresearch@chop.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This is an observational study among two study population groups: genetically confirmed PMD patients and healthy volunteers.

Description

Inclusion Criteria:

• Must be between 8 and 75 years, inclusive
• Genetically confirmed primary mitochondrial disease
• Receiving standard-of-care treatment including mitochondrial supplements that may include N-acetylcysteine (NAC), a precursor of glutathione

Inclusion Criteria for Healthy Controls:

• Must be between 8 and 75 years, inclusive

Exclusion Criteria:

• MRI contraindications
• In the investigator's opinion, inability to fully comply with research procedures
• Active self-reported alcohol and/or substance abuse, including tobacco-use
• A pacemaker; any metal-based medical or non-medical devices/implants; any non-removable metal-based object (e.g., body piercings, jewelry, etc.) that cannot be cleared through radiologic evaluation
• Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation
• Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation
• Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite)
• At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study
• Any female participant with childbearing potential who is knowingly pregnant or suspects that she is pregnant will be removed from the study. (Although there are no known risks of MRI on pregnant females or fetuses, there is a possibility of yet undiscovered pregnancy-related risks. Since there is no direct benefit from participating in this protocol for pregnant females, they will be excluded to ensure their long-term safety and that of their unborn fetus.)
• To note, for this protocol, participants are instructed to lie still in the MRI scanner; there is no contrast or sedation. Participants who do not possess the cognitive and / or physical abilities to perform these procedures will not be included.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Genetically Confirmed Primary Mitochondrial Disease; Individuals with Genetically Confirmed Primary Mitochondrial Disease
Healthy Controls; Individuals who have no history of Primary Mitochondrial Disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess group differences in brain chemical levels in Genetically Confirmed Primary Mitochondrial Disease (GC-PMD) compared to healthy controls (HC)	Metabolite concentrations from H Magnetic Resonance Spectroscopy (MRS) will be processed in Osprey followed by linear combination modelling of MRS spectra. Water-scaled metabolite estimates will be calculated and corrected for tissue composition and relaxation effects to generate metabolite concentrations.	Approximately 1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma glutathione levels in Genetically Confirmed Primary Mitochondrial Disease (GC-PMD) compared to healthy controls (HC)	Analyze and report plasma glutathione levels (µM) in affected cases versus healthy controls. Glutathione is an antioxidant that protects cells from oxidative stress and detoxification. Differences between the two groups is anticipated.	Approximately 1 day
Change in Corticol Thickness in Genetically Confirmed Primary Mitochondrial Disease (GC-PMD) compared to healthy controls (HC)	Morphometric analyses and reporting of cortical thickness, surface area, and volume in affected cases versus healthy controls. Reporting cortical thickness involves using structural magnetic resonance imaging (MRI) to measure the width of the gray matter of the cortex, typically in millimeters, and analyzing regional variations to asses brain structure and function.	Approximately 1 day
Change in Cerebral Blood Flow in Genetically Confirmed Primary Mitochondrial Disease (GC-PMD) compared to healthy controls (HC)	Cerebral blood flow imaging (using spin labeling or similar), analyses, and reporting in affected cases versus healthy controls. Studying blood flow in the brain can assess for cerebrovascular disease.	Approximately 1 day

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: February 19, 2025
• First Submitted That Met QC Criteria: March 17, 2025
• First Posted (Actual): March 24, 2025

Study Record Updates

• Last Update Posted (Actual): February 5, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Mitochondrial Diseases
• Other Study ID Numbers: 24-022407

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