Genomic Profiling of Mitochondrial Disease - Imaging Analysis for Precise Mitochondrial Medicine

Genomic Profiling of Mitochondrial Disease - Imaging Analysis for Precise Mitochondrial

This study is an observational longitudinal study involving the use of MRIs and video recordings taken at home of patients completing basic tasks. Once consent is obtained, subjects will be asked to schedule an appointment with radiology to undergo the listed MRIs of the heart and/or muscle. Subjects will also be given instructions on how to use the video recording app on their personal devices, or study provided device. The subjects will be followed regularly over the course of two years, submitting video recordings of their movements and reporting to Mayo Clinic for MRIs as scheduled.

Study Overview

• Status: Recruiting
• Conditions: Mitochondrial Diseases; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Mitochondrial DNA Mutation; Chronic Progressive External Ophthalmoplegia With Myopathy

Detailed Description

Mitochondrial myopathy follows a slowly progressive disease course of gradual worsening of muscle weakness and fatigability. Progressive mitochondrial dysfunction is thought to result in structural muscle deterioration (eventually muscle fiber atrophy/necrosis) and underlie these symptoms. Therefore, the study hypothesis is that longitudinal imaging of muscle will capture mitochondrial (using muscle MRS) and structural (using muscle MRI) abnormalities to inform objectively disease progression by capturing structural and biochemical changes in muscle over time.

Conventional multivariate analysis tools such as partial least squares-discriminant analysis (PLS-DA) and principal component analysis (PCA) will be used to assess variables of importance in discrimination of 3 subgroups based on underlying molecular defect (mitochondrial DNA (mtDNA) mutations and deletions, and nuclear gene mutations (nDNA)).

This will be followed by implementation of Collaborative Laboratory Integrated Reports (CLIR) software, a multivariate pattern recognition software that generates post-analytical interpretive tools. This study proposes to quantitatively measure MRS analytes (i.e. lactate, adenosine triphosphate (ATP), etc.) and structural muscle changes by MRI (edema, fat content, etc.). The capability for interactive data analysis would be necessary because of the nature of mitochondrial myopathy (MM) progression. One of the functionalities of CLIR is the creation of post-analytical tools applicable to either diagnosis of one condition - single condition tool; or differential diagnosis between two conditions with overlapping phenotypes (mtDNA deletions, mtDNA mutations, nDNA mutations) - dual scatter plots. The advantages of CLIR are (1) integration of primary markers with all informative permutations of ratios/biomarkers. Ratios calculated between markers not directly related at the biochemical level are particularly helpful to correct for pre-analytical factors and potential analytical bias (2) adjusted for multiple covariates (age, sex) (3) generating individual plots of disease progression.

This study is an observational longitudinal study involving the use of MRIs and video recordings taken at home of patients completing basic tasks. Subjects will be approached at outpatient appointments, or via phone/mail. Once consent is obtained, subjects will be asked to schedule an appointment with radiology to undergo the listed MRIs of the heart and/or muscle. Subjects will also be given instructions on how to use the video recording app on their personal devices, or study provided device. The subjects will be followed regularly over the course of two years, submitting video recordings of their movements and reporting to Mayo Clinic for MRIs as scheduled. Patients may withdraw from the study at any time without repercussion.

• Study Type: Observational
• Enrollment (Anticipated): 90

Contacts and Locations

• Study Contact: Name: Erianna Burrel; Phone Number: 507-266-2019; Email: burrel.erianna@mayo.edu
• Study Contact Backup: Name: Alexandra Miller; Phone Number: 507-293-1139; Email: miller.alexandra@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55901
      • Recruiting
      • Mayo Clinic
      • Principal Investigator: Ralitza Gavrilova, MD
      • Contact: Kaitlin Schwartz; Phone Number: 507-293-9114; Email: Schwartz.Kaitlin@mayo.edu
      • Contact: David Kveene; Phone Number: 507-266-6917; Email: kveene.david@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All participants in the study should have genetic confirmation or muslce biopsy confirmation along with supporting clinical features of mitochondrial disease with weakness in muscle.

Description

Inclusion Criteria:

• Confirmed or suspected primary mitochondrial disorder *Suspected mitochondrial disorder would mean that the patient meets clinical criteria and has either biopsy or biochemical testing that supports the diagnosis.

Exclusion Criteria:

• Pregnant, breastfeeding
• Severe cardiac disease who are unable to undergo all the required testing
• Requiring anesthesia for MRIs
• Has severe claustrophobia
• Has implanted devices

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Observational Cohort; no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Indicators of disease severity and progression - cardiac movement	Establish the prevalence and severity of specific morbid indicators of disease severity through use of echocardiogram	2 years
Indicators of disease severity and progression - cardiac function	Establish the prevalence and severity of specific morbid indicators of disease severity through use of magnetic resonance imaging (MRI) of cardiac muscle	2 years
Indicators of disease severity and progression - skeletal muscle function	Establish the prevalence and severity of specific morbid indicators of disease severity through use of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) of skeletal muscle	2 years
Indicators of disease severity and progression - skeletal muscle movement	Establish the prevalence and severity of specific morbid indicators of disease severity through use of video scoring scale during exercise	2 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Astellas Pharma Inc; Casimir, LLC
• Investigators: Principal Investigator: Ralitza Gavrilova, MD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Anticipated): May 1, 2024
• Study Completion (Anticipated): May 1, 2024

Study Registration Dates

• First Submitted: August 12, 2021
• First Submitted That Met QC Criteria: August 12, 2021
• First Posted (Actual): August 19, 2021

Study Record Updates

• Last Update Posted (Actual): April 26, 2023
• Last Update Submitted That Met QC Criteria: April 24, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Mitochondrial DNA deletion
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Degeneration; Retinal Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Retinal Dystrophies; Cranial Nerve Diseases; Cardiomyopathies; Ocular Motility Disorders; Paralysis; Retinitis Pigmentosa; Mitochondrial Diseases; Muscular Diseases; Mitochondrial Myopathies; Ophthalmoplegia, Chronic Progressive External; Ophthalmoplegia; Kearns-Sayre Syndrome
• Other Study ID Numbers: 20-002721

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