A quantitative measure of handgrip myotonia in non-dystrophic myotonia

Abstract

Introduction: Non-dystrophic myotonia (NDM) is characterized by myotonia without muscle wasting. A standardized quantitative myotonia assessment (QMA) is important for clinical trials.

Methods: Myotonia was assessed in 91 individuals enrolled in a natural history study using a commercially available computerized handgrip myometer and automated software. Average peak force and 90% to 5% relaxation times were compared with historical normal controls studied with identical methods.

Results: Thirty subjects had chloride channel mutations, 31 had sodium channel mutations, 6 had DM2 mutations, and 24 had no identified mutation. Chloride channel mutations were associated with prolonged first handgrip relaxation times and warm-up on subsequent handgrips. Sodium channel mutations were associated with prolonged first handgrip relaxation times and paradoxical myotonia or warm-up, depending on underlying mutations. DM2 subjects had normal relaxation times but decreased peak force. Sample size estimates are provided for clinical trial planning.

Conclusion: QMA is an automated, non-invasive technique for evaluating myotonia in NDM.

Figure 1

Quantitative myotonia assessment apparatus and sample trials. A. Patient is seated in a modified chair with forearm secured in neutral position on a pegboard, fingers gripped lightly around force transducer. B. Automated software identifies peak force onset and offset by positive and negative changes in slope, then peak force is averaged between arrows. The software automatically identifies 90% and 5% of average peak force during the relaxation phase. C. Sample trial for subject with chloride channel mutation. D. Sample trial for subject with sodium channel mutation.

Figure 2

90% to 5% relaxation times over sequential handgrips 1–6 for different mutation types. A. Subjects with dominant chloride channel mutations (n=11) show an increased 1^st handgrip relaxation times with a pattern of warm-up of myotonia in subsequent handgrips. B. Recessive chloride channel subjects (n=10) show increased relaxations times compared to dominant, there is a pattern of warm-up in successive handgrips. C. Sodium subjects with the T1313M mutation (n=11) show paradoxical myotonia in successive handgrips. D. Subjects with R1448H mutations (n=5), on the other hand have essentially normal QMA relaxation times. E. No clear myotonia was demonstrated in subjects with G1306A mutations (n=5). F. Although there were no clear abnormalities on QMA for DM2 (n=6), in the group there is a subtle trend towards warm-up.

Figure 3

Average peak force (kg) over sequential handgrips 1 to 6 for different mutation types. A. Dominant chloride channel subjects (n=11) have increased 1^st handgrip peak force compared to recessive subjects which decreases in subsequent handgrips. B. Recessive chloride channel subjects (n=10) show an increase in force in successive handgrips. C. Sodium channel subjects with the T1313M mutation (n=11) show the largest drop in force over subsequent handgrips compared to D. R1448H subjects (n=5). E. G1306A subjects (n=5) show an increase in force in subsequent handgrips. F. DM2 subjects (n=6) show an essentially flat peak force versus handgrip profile.

Figure 4

Power curve versus effect size for cross-over trial. 50 subjects would have 80% power to detect a reduction in 90% to 5% relaxation time of just over 30% with a level of significance of 0.05. Y axis = statistical power. X axis = percent reduction in 90% to 5% relaxation time. Alpha = 0.05.