Development of a Mitochondrial Myopathy-Composite Assessment Tool

Abstract

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.

Keywords: Composite measure; Exercise intolerance; Mitochondrial myopathy; Muscle fatigue; Muscle weakness; Outcome measures.

Figure 1

Mitochondrial Myopathy objective measures. Assessments in each of five domains tested and order of assessments is displayed. Measurement of muscle strength using dynamometry was the initial assessment performed, followed by dynamometry repetitions, balance assessments, 30 second Sit to Stand (30s STS), Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), and the 6-Minute Walk Test (6MWT). ^aMuscle group assessed only in adults per protocol. ^bMuscle group assessed only in children per protocol.

Figure 2

Dynamometry assessments revealed both proximal and distal weakness in Definite MM participants. Data are presented as mean z-scores ± standard deviation (SD) on dominant (Dom) and non-dominant (ND) sides. Z-scores < −2 is considered abnormal. Shaded area indicates normal z-score (0 to −2). (A–C) Dynamometry-measured muscle strength in the upper extremities in the Definite MM group (n = 59). (B) Dynamometry measurements in child MM (n = 35) indicate muscle weakness in elbow flexion (−2.3 ± 1.1, Dom, −2.4 ± 1.4, ND), wrist extension (−2.6 ± 1.4, Dom, −2.8 ± 1.5, ND), grasp (−2.2 ± 1.2, Dom, −2.2 ± 1.3, ND) and pinch strength (−2.6 ± 3.0, Dom, −3.2 ± 1.4, ND). (C) Dynamometry measurements in adult MM (n = 24) indicate muscle weakness in elbow flexion (−3.2 ± 3.0, Dom, −2.3 ± 2.6, ND) and wrist extension (−4.6 ± 1.4, Dom, −4.8 ± 1.8, ND). (D–F) Dynamometry-measured muscle strength in MM lower extremities (n = 59). (E) Dynamometry measurements in child MM (n = 35) indicate muscle weakness in hip flexion (−3.0 ± 1.4, Dom, −3.0 ± 1.5, ND) and knee flexion (−2.8 ± 1.3, Dom, −2.8 ± 1.3, ND). (F) Dynamometry measurements in adult MM (n = 24), indicate muscle weakness in ankle dorsiflexion (−3.8 ± 2.6, Dom, −3.2 ± 2.5, ND).

Figure 3

Balance and dexterity assessments revealed deficits in Definite MM compared to Unlikely participants and in child MM vs. adult MM. Data are presented as mean z-score ± standard deviation (S.D.). (A) Balance testing was significantly impaired (< −2 S.D.) on Tandem Stance (TS) Eyes Open (*p=0.02, n = 53) and Eyes Closed (****p < 0.0001, n = 52) in Definite MM compared to the Unlikely MM (n = 32) participants. (B) In child MM participants, TS Eyes Closed (−3.2 ± 3.4, n = 24) was impaired. (C) In adult MM participants, TS Eyes Open (−5.8 ± 11.6, n = 28) was abnormal. (D) FDT (*p = 0.033, n = 44) and 9HPT (**p = 0.006, n = 53) was significantly more impaired in the Definite MM cohort compared to the Unlikely group (n = 25 and n = 26, respectively). (E–F) FDT and 9HPT were impaired in child (E) and adult MM (F). There was no significant difference on t-test comparison between the FDT and 9HPT z-scores in either age group.

Figure 4

Exercise intolerance, muscle fatigue, and functional assessments revealed deficits in Definite MM participants. (A) 30s STS presented as mean z-score ± SD was abnormal (< −2 S.D.) in adult Definite MM (−2.1 ± 0.7, n = 16) and borderline abnormal in child Definite MM (−2.0 ± 0.8, n = 22). (B) Dynamometry repetitions in Definite MM reveals the mean negative % decrement (mean ± SEM) between the sixth to the first repetition on the non-dominant (ND) and dominant sides at elbow and hip flexion. (C) T-test comparison of the z-scores ± S.D. between the first and the sixth repetitions, ND (***p = 0.0002) and Dom (****p < 0.0001) sides at elbow flexion, and ND (p = 0.13) and Dom (*p = 0.02) sides at hip flexion. (D) The North Star Ambulatory Assessment (NSAA) mean total score was significantly lower (**p = 0.006) in the Definite MM participants (n = 58) compared to the Unlikely participants (n = 31). (E) Mixed-effects analysis revealed a significant decline in minute distance (m) in Definite MM (slope = −0.9, p = 0.03). (F) The mean MM-COAST Composite Score in the Definite MM participants (n = 53) was significantly higher than in the Unlikely participants (n = 29), ***p = 0.0005.

Figure 5

Mitochondrial Myopathy-Composite Assessment Tool (MM-COAST). Assessments selected from study objective measures to be included in the final MM-COAST in each of five domains tested and order of assessments is displayed. Muscle strength assessment of only four muscle groups with dynamometry was the initial assessment performed, followed by dynamometry repetitions of elbow flexion, balance assessments, 30 second Sit to Stand (30s STS), Nine Hole Peg Test (9HPT), Functional Dexterity Test (FDT), and the 6-Minute Walk Test (6MWT).

Figure 6

MM-COAST Composite Score. Approach to scoring the MM-COAST for a composite score is shown. Test scores are assigned for each domain assessment raw score, based on z-score (chart A) or % decrement for muscle fatigue only (chart B), summed and averaged to achieve a domain score. The mean domain score is presented as the MM-COAST Composite Score. *For participants with a normative SD of 0, use Table S5–A for Tandem Stance Eyes Open assigned score.