Development of a Mitochondrial Myopathy-Composite Assessment Tool
Jean Flickinger1,2, Jiaxin Fan3, Amanda Wellik1
1Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Background:
'Mitochondrial Myopathy' (MM) refers to genetically-confirmed Primary Mitochondrial Disease (PMD) that predominantly impairs skeletal muscle function. Validated outcome measures encompassing core MM domains of muscle weakness, muscle fatigue, imbalance, impaired dexterity, and exercise intolerance do not exist. The goal of this study was to validate clinically-meaningful, quantitative outcome measures specific to MM.
Methods:
This was a single centre study. Objective measures evaluated included hand-held dynamometry, balance assessments, Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), 30 second Sit to Stand (30s STS), and 6-minute walk test (6MWT). Results were assessed as z-scores, with < -2 standard deviations considered abnormal. Performance relative to the North Star Ambulatory Assessment (NSAA) of functional mobility was assessed by Pearson's correlation.
Results:
In genetically-confirmed MM participants [n = 59, mean age 21.6 ± 13.9 (range 7 - 64.6 years), 44.1% male], with nuclear gene aetiologies, n = 18/59, or mitochondrial (mtDNA) aetiologies, n = 41/59, dynamometry measurements demonstrated both proximal [dominant elbow flexion (-2.6 ± 2.1, mean z-score ± standard deviation, SD), hip flexion (-2.5 ± 2.3), and knee flexion (-2.8 ± 1.3)] and distal muscle weakness [wrist extension (-3.4 ± 1.7), palmar pinch (-2.5 ± 2.8), and ankle dorsiflexion (-2.4 ± 2.5)]. Balance [Tandem Stance (TS) Eyes Open (-3.2 ± 8.8, n = 53) and TS Eyes Closed (-2.6 ± 2.7, n = 52)] and dexterity [FDT (-5.9 ± 6.0, n = 44) and 9HPT (-8.3 ± 11.2, n = 53)] assessments also revealed impairment. Exercise intolerance was confirmed by strength-based 30s STS test (-2.0 ± 0.8, n = 38) and mobility-based 6MWT mean z-score (-2.9 ± 1.3, n = 46) with significant decline in minute distances (slope -0.9, p = 0.03, n = 46). Muscle fatigue was quantified by dynamometry repetitions with strength decrement noted between first and sixth repetitions at dominant elbow flexors (-14.7 ± 2.2%, mean ± standard error, SEM, n = 21). All assessments were incorporated in the MM-Composite Assessment Tool (MM-COAST). MM-COAST composite score for MM participants was 1.3± 0.1(n = 53) with a higher score indicating greater MM disease severity, and correlated to NSAA (r = 0.64, p < 0.0001, n = 52) to indicate clinical meaning. Test-retest reliability of MM-COAST assessments in an MM subset (n = 14) revealed an intraclass correlation coefficient (ICC) of 0.81 (95% confidence interval: 0.59-0.92) indicating good reliability.
Conclusions:
We have developed and successfully validated a MM-specific Composite Assessment Tool to quantify the key domains of MM, shown to be abnormal in a Definite MM cohort. MM-COAST may hold particular utility as a meaningful outcome measure in future MM intervention trials.
Insights
Researchers developed and validated the Mitochondrial Myopathy-Composite Assessment Tool (MM-COAST) to measure key aspects of muscle weakness and fatigue in patients with mitochondrial myopathy (MM). This tool shows promise for future clinical trials in MM.
Area of Science:
- Neurology
- Genetics
- Biomedical Engineering
Background:
- Mitochondrial Myopathy (MM) is a primary mitochondrial disease (PMD) impacting skeletal muscle.
- Validated outcome measures for MM domains like weakness, fatigue, and exercise intolerance are lacking.
- This study aimed to validate clinically meaningful, quantitative outcome measures specific to MM.
Purpose of the Study:
- To develop and validate a composite assessment tool for Mitochondrial Myopathy (MM).
- To quantify key domains of MM including muscle weakness, fatigue, imbalance, dexterity, and exercise intolerance.
- To establish a reliable and clinically meaningful outcome measure for MM research and intervention trials.
Main Methods:
- A single-center study evaluated objective measures: dynamometry, balance tests, Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), 30s Sit to Stand (30s STS), and 6-minute walk test (6MWT).
- Results were assessed as z-scores; performance was correlated with the North Star Ambulatory Assessment (NSAA).
- All assessments were combined into the MM-Composite Assessment Tool (MM-COAST).
Main Results:
- Dynamometry revealed significant proximal and distal muscle weakness in MM participants (n=59).
- Balance and dexterity assessments showed impairments; exercise intolerance was confirmed by 30s STS and 6MWT.
- MM-COAST demonstrated good test-retest reliability (ICC=0.81) and correlated with NSAA (r=0.64), indicating clinical meaning.
Conclusions:
- A MM-specific Composite Assessment Tool (MM-COAST) was successfully developed and validated.
- MM-COAST quantifies key abnormal domains in a definite MM cohort.
- MM-COAST is a potentially valuable outcome measure for future MM intervention trials.
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