1. and Myotonia Correlates Directly with CTG Repeat Size of the DM1 Gene
Computerized Hand Grip Myometry Reliably Measures Myotonia and Strength in Myotonic Dystrophy (DM1)
and Myotonia Correlates Directly with CTG Repeat Size of the DM1 Gene
RT Moxley III MD1, WB Martens BA1, EL Logigian MD1, CL Blood BS1, N Dilek MS1, CA Barbieri RN1, AW Wiegner PhD2, RT Moxley IV BS1, CA Thornton1 MD
From the Department of Neurology, University of Rochester, Rochester, NY (1); and Harvard Medical School, Boston, MA (2)
Poster P02.158
OBJECTIVE
To develop a reliable, sensitive, quantitative measure of grip myotonia and strength in DM1 using an electronic isometric grip myometer; and to compare such a measure with leukocyte CTG repeat size of the DM1 gene and with whole body muscle strength and function.
Clinical Aspects
Normals
DM1 Patients
p-value N 17 29 NS
Age: Mean (Range)
40.9 (21-62)
45.9 (23-62)
Sex: F (%)
8 (47%)
11 (38%)
Hand Temperature: Mean (Range)
29.2 (25-33)
30.6 (27-33)
Symptom Duration: Mean (Range)
21 (5-41)
CTG Repeat Length: Mean (Range)
586 ( )
Strength
mean:
range
mean: range
Peak Average Force (kg)
42.5:
10.4:
<.0001
Global QMA Strength (z score)
-4.81: (-1.88)
Global MMT Score (0-5 scale) 
3.9:   
Relaxation Times
Relaxation Time (sec)
mean+2.5SD
# >mean+2.5SD
90% to 75%
.10:
.30
.24:
9 (31%)
<.01
90% to 50%
.19:
.39
.46:
12 (41%)
<.001
90% to 10%
.33:
.57
1.77:
23 (79%)
90% to 5%
.37:
.61
2.42:
25 (86%)
50% to 5%
.18:
.29
1.96:
28 (97%)
RESULTS
DM1 patients were significantly weaker than normal controls and had significantly longer relaxation times at all relaxation intervals (see Table). The DM1 average RTs were approximately twice those of normals in the early phases of relaxation (90%-75% and 90%-50%), about 6 times those of normals in the later phases (90%010% and 90%-5%), and more than 10 times that of normals at the terminal phase (50%-5%). This methodology detected grip myotonia in the majority of the DM1 population (as high as 97% exceeded the normal mean SDs at 50%-5%).
The variability for the DM1 group between the three trials of the day 1 early testing session was low. The average standard deviation was 1.04 for PF, .12 for RT 90%-75%, .18 for 90%-50%, .57 for 90%-10%, .79 for 90%-5%, and .78 for 50%-5%.
Peak average forces and relaxation times for each patient were consistent on consecutive days, displaying a high degree of correlation (r=.96, p<.0001 for PF, r=.54, p<.01 for 90%-75%, r=.65, p<.001 for 90%-50%, r=.85, p<.0001 for 90%-10%, r=.77, p<.0001 for 90%-5%, and r=.76, p<.0001 for 50%-5%)(see Figures 4-6) (see Figures 5-8).
Decreases in grip strength (r=-.42, p<.03) and increases in myotonia (r=.52, p<.01 at 90%-5%) correlated directly with increasing CTG repeat size of the DM1 gene, as did whole body muscle weakness (r=-.37, p<.05 for manual testing of 34 muscles and r=-.42, p<.03 for quantitative myometry of 12 muscle groups).
BACKGROUND
DM1 is a multisystem, dominantly inherited disease caused by an unstable CTG repeat expansion in the 3’ non-translated region of DM1 gene on chromosome 19. Myotonia, weakness of facial and distal limb muscles, and cataracts are core clinical findings. Methods to quantitate grip myotonia and strength are needed to assess the natural history of these manifestations and to evaluate potential treatments.
METHODS
Study Participants:
29 DM1 patients had clinical myotonia (including a minimum of 3 seconds myotonia upon percussion of the thenar eminence) and an abnormal expansion of the CTG repeat in the myotonic dystrophy gene (DMPK). 17 normal volunteers were asymptomatic staff members and free from acute medical problems. In the patients, measurements of myotonia took place on 2 consecutive mornings following an overnight fast. Normals had one morning session following an overnight fast.
Hand Grip Myotonia:
Subjects were seated in a specially constructed chair with calibrated adjustable arm rests (see Photo). The right arm of each subject was placed on a support with labeled peg positions, from elbow to wrist, to permit standardized, reproducible positioning of the hand.
Three sets of measurements (trials) were performed with a 10 minute rest period between each (see Figures 1-3). Each trial consisted of six 3 second maximum voluntary isometric contractions on the hand myometer spaced 10 seconds apart. For the present analysis only the initial contraction will be used. A subsequent paper will explore the so called ‘warm-up effect’-the tendency of DM1 patients to display less myotonia with repeated exercise of the hand.
Relaxation times (RTs) and peak force values (PFs) were determined by an automated computer program. For each contraction curve the program calculated average PF as the mean of the force generated at the maximum positive and negative slope points. The program then identifies the points on the declining, relaxation phase of the force curve corresponding to 90%, 75%, 50%, 10%, and 5% of peak average force. RTs (in seconds) were then calculated between these designated points (see Figure 4).
Upper limits for the various RTs in the normal group were defined as mean SD. Student’s t test was used to compare normal and patient PF and RT. Correlation analysis was performed using SAS statistical software to assess the relationship between RT and PF with CTG repeat length, age, gender, and whole body strength as measured by MMT and QMA. All p-values were 2-tailed.
CONCLUSIONS
Myotonia and hand grip strength can be quantitated reliably in patients with DM1 using an automated analysis of repeated hand grip squeezes on a computerized myometer.
Hand grip peak force is significantly lower in DM1 patients than normals.
Relaxation times are prolonged in the majority of DM1 patients, and on average are significantly longer than in normals.
Muscle relaxation is most slowed in the terminal rather than the initial phase of relaxation.
Relaxation time is positively correlated with CTG repeat length in DM1 patients.
Hand grip strength and relaxation times may serve as a surrogate for whole body strength in DM1 patients.
Figure 4: Analysis Program
Figure 3: DM1-3 Trials
Figure 1: Normal Volunteer
Figure 2: DM1 Patient
ACKNOWLEDGEMENTS
This study was supported in part by the Food and Drug Administration (FD-R ), and by a General Clinical Research Center grant (5 MO1 RR00044) from the National Center for Research Resources, NIH.