General characteristics at study entry
Patient characteristics are summarized in Table 1. A total of 33 Japanese GNE myopathy patients (12 males and 22 females) participated in this study. Two female patients were siblings, and all other patients were unrelated to each other. Mean age at the time of data collection was 43.2 ± 13.4 years (mean ± SD), and mean age at disease onset was 26.6 ± 11.3 years. Thirty percent (11/33) of patients were ambulant and completed the 6MWT without assistance, 18.2% (6/33) required assistance (e.g., cane and/or brace), and 60.6% (20/33) had lost ambulation. Mean age at loss of ambulation was 34.1 ± 11.7 years.
GNE mutations (Supplementary Table 1, 2)
Of the 33 patients included in this study, 27% (9/33) harbored the p.V603L homozygous mutation, while 73% (24/33) harbored a compound heterozygous mutation. Of these heterozygotes, 12% (4/33) had the p.D207V/p.V603L genotype. Frequent alleles were V603L (39%, 26/66), D207V (18%, 12/66), and C44S (3%, 2/66).
Patient characteristics during and at end of follow-up period (Table 2)
Table 2
Results of initial and annual evaluations.
| pre | 1 year | 2 year | 3 year | 4 year | 5 year |
| n | | n | | n | | n | | n | | n |
physical evaluation | summed MMT | 38.6 +/- 22.5 | 33 | 36.5 +/- 21.7** | 29 | 34.7 +/- 20.3** | 23 | 31.7 +/- 21.4** | 21 | 29.7 +/- 19.0** | 13 | 32.3 +/- 22.1** | 21 |
| GMFM (%) | 50.4 +/- 38.4 | 29 | 46.3 +/- 38.7 | 26 | 42.6 +/- 39.0* | 22 | 41.0 +/- 39.9* | 19 | 28.6 +/- 37.1 | 11 | 33.9 +/- 37.1** | 18 |
| 6MWT | 350.5 +/- 144.4 | 12 | 307.5 +/- 134.1 | 11 | 307.0 +/- 147.8 | 8 | 265.5 +/- 102.9 | 8 | 222.0 +/- 130.1** | 4 | 270.8 +/- 112.2 | 4 |
| HHD (N) | 163.1 +/- 113.0 | 23 | 152.0 +/- 145.6 | 21 | 132.0 +/- 97.0 | 15 | 144.4 +/- 137.1 | 13 | 116.3 +/- 161.4 | 8 | 130.9 +/- 146.1 | 12 |
| Grip power (kg) | 9.1 +/- 8.1 | 23 | 6.3 +/- 6.4 | 20 | 6.4 +/- 7.6 | 18 | 7.2 +/- 7.5 | 15 | 4.6 +/- 5.6* | 10 | 6.1 +/- 8.2* | 16 |
| Pinch power (N) | 26.5 +/- 22.2 | 27 | 20.6 +/- 20.3 | 24 | 19.7 +/- 21.4** | 22 | 15.0 +/- 15.0** | 18 | 12.1 +/- 12.9* | 12 | 16.3 +/- 20.2** | 19 |
respitaroy function | FVC (%) | 87.0 +/- 25.0 | 33 | 84.3 +/- 27.6 | 30 | 87.4 +/- 25.0* | 23 | 81.2 +/- 26.8** | 22 | 75.0 +/- 24.0** | 12 | 75.8 +/- 31.2** | 23 |
VC (%) | 86.9 +/- 24.2 | 33 | 85.5 +/- 27.3 | 30 | 88.9 +/- 23.4 | 23 | 83.3 +/- 24.8* | 22 | 76.5 +/- 21.5** | 12 | 77.9 +/- 29.7** | 23 |
DEXA | Whole-body lean body mass (kg) | 31.1 +/- 7.1 | 32 | 30.6 +/- 7.2 | 29 | 30.3 +/- 7.3 | 23 | 30.0 +/- 6.5 | 22 | 27.7 +/- 5.8 | 14 | 28.7 +/- 6.2 | 20 |
Arm lean body mass (kg) | 2.7 +/- 1.1 | 32 | 2.7 +/- 1.1 | 29 | 2.6 +/- 0.9 | 23 | 2.7 +/- 1.0 | 22 | 2.5 +/- 0.8 | 14 | 2.6 +/- 0.9 | 21 |
Leg lean body mass (kg) | 8.6 +/- 2.6 | 32 | 8.5 +/- 2.5 | 29 | 8.5 +/- 2.6 | 23 | 8.3 +/- 2.2 | 22 | 7.3 +/- 1.7 | 14 | 7.7 +/- 2.1 | 21 |
CK (IU/L) | 268.3 +/- 290.8 | 33 | 270.1 +/- 336.9 | 29 | 203.0 +/- 228.5 | 24 | 186.0 +/- 227.8* | 21 | 177.3 +/- 208.4* | 13 | 151.5 +/- 172.6* | 23 |
ADL score | Barthel index | 54.8 +/- 39.6 | 33 | 50.4 +/- 38.9 | 28 | 54.5 +/- 39.0 | 21 | 64.6 +/- 44.2 | 13 | 38.8 +/- 33.8 | 12 | 42.9 +/- 36.8 | 21 |
mRS | 3.6 +/- 1.2 | 33 | 3.5 +/- 1.1 | 28 | 3.6 +/- 1.1 | 22 | 3.3 +/- 1.2 | 15 | 3.9 +/- 0.7 | 12 | 3.8 +/- 1.1 | 22 |
QOL score | SF36 | Pyshical functioning | 0.0 +/- 19.3 | 33 | -4.9 +/- 15.4 | 27 | 1.2 +/- 21.3 | 16 | 0.8 +/- 16.3* | 14 | -2.5 +/- 13.9* | 14 | -5.1 +/- 16.8* | 21 |
Role physichal | 35.4 +/- 19.1 | 33 | 30.7 +/- 17.9 | 27 | 30.6 +/- 20.5 | 16 | 31.8 +/- 16.0 | 14 | 25.1 +/- 18.2 | 14 | 27.1 +/- 18.8 | 21 |
Bodily pain | 45.1 +/- 11.3 | 33 | 42.0 +/- 9.7 | 27 | 47.6 +/- 9.7 | 16 | 42.5 +/- 11.1 | 14 | 43.4 +/- 10.7 | 14 | 41.5 +/- 11.7 | 21 |
Social functioning | 38.1 +/- 13.9 | 33 | 38.6 +/- 15.0 | 27 | 35.7 +/- 15.0 | 16 | 30.3 +/- 9.4 | 14 | 31.7 +/- 19.1 | 14 | 34.9 +/- 17.3 | 21 |
General health perceptions | 40.0 +/- 9.3 | 33 | 39.2 +/- 9.1 | 27 | 40.8 +/- 6.8 | 16 | 37.0 +/- 7.1 | 14 | 35.8 +/- 9.7 | 14 | 37.1 +/- 9.0 | 21 |
Vitality | 44.5 +/- 10.8 | 33 | 42.0 +/- 10.2 | 27 | 43.8 +/- 10.5 | 16 | 41.4 +/- 8.7 | 14 | 39.5 +/- 11.1 | 14 | 39.6 +/- 14.8 | 21 |
Role emotinoal | 41.8 +/- 16.6 | 33 | 40.4 +/- 18.0 | 27 | 41.3 +/- 18.9 | 16 | 46.3 +/- 8.9 | 14 | 38.2 +/- 18.9 | 14 | 34.3 +/- 19.9 | 21 |
Mental health | 46.0 +/- 11.2 | 33 | 47.2 +/- 8.9 | 27 | 47.5 +/- 10.2 | 16 | 46.7 +/- 7.8 | 14 | 43.6 +/- 10.3 | 14 | 43.0 +/- 12.6 | 21 |
P-values are calculated relative to baseline data. *: p<0.05, **: p<0.01 |
Follow-up was disrupted for 5 ambulant patients due to their participation in Phase II/III clinical trials of SA, and 9 patients due to personal reasons (mainly difficulty visiting the hospital due to disease progression). The remaining 22 patients were followed for 5 years, although 9 of these patients missed some of the annual visits. For patients unable to attend all annual visits, we requested that they prioritize attending the 1st year and 5th year evaluations. Of patients who completed the 5th year evaluation, only 4 were able to complete the 6MWT. Two patients lost ambulation, and one patient newly developed multiple sclerosis and nephrotic syndrome, during the follow-up period.
Annual changes in physical status and measurements (Table 2)
Measurement results are shown in Table 2. A total of 30 patients participated in the 1st year follow-up visit. For physical evaluation, 2, 21, 10, 10, and 5 patients were unable to complete the GMFM, 6MWT, HHD, grip power, and pinch power tests at baseline and thus were excluded from the analysis. For 6MWT, HHD, grip power, and pinch power tests, 1, 2, 2, and 6 patients, respectively, scored 0 for these measurements during the 5-year follow-up period. Summed MMT score, 6MWT, GMFM, %FVC, %VC, and grip power significantly differed at the 1st year evaluation compared to baseline.
At the 5th year evaluation, significant reductions in summed MMT (p=0.003), GMFM (p=0.007), grip power (p=0.038), pinch power (p<0.001), %FVC (p=0.001), and %VC (p=0.002) were observed compared to baseline (Table 2, Figure 1). Two patients received non-invasive positive pressure ventilation (NPPV) due to severe nocturnal respiratory failure.
Among the muscle parameters assessed, shoulder extension, shoulder flexion, shoulder abduction, elbow extension, hip flexion, and knee extension showed significant changes at the 5th year evaluation compared to baseline.
Annual changes in parameters among non-ambulant patients (supplementary table3, Figure 2)
We also analyzed the data of non-ambulant participants. At the 5th year evaluation, significant reductions in summed MMT (p=0.006), GMFM (p=0.047), pinch power (p=0.026), %FVC (p=0.001), and %VC (p=0.005) compared to baseline were observed among 20 non-ambulant patients. On the other hand, no significant change in grip power (p=0.185) was observed in comparison with the baseline evaluation, which were significantly reduced among entire population. No significant changes were detected of SF-36 (Supplementary table 3).
ADL and QOL scores (Table 2, Table 3)
Table 3
Correlations between SF-36 and other parameters at initial visit.
| n | physical functioning | Role physical | Bodily Pain | General Health | Vitality | Social Functioning | Role emotional | Mental Health |
mean+/- SD | 33 | -0.039 | 35.39 | 45.10 | 38.07 | 45.97 | 39.97 | 41.827 | 45.97 |
SD | 19.26 | 19.13 | 11.34 | 13.94 | 11.21 | 9.32 | 16.57 | 11.21 |
significance to national standard scores (p) | <0.001** | <0.001** | 0.019* | <0.001** | 0.047* | <0.001** | 0.008** | 0.041** |
correlation (ρ) | Summed MMT | 33 | 0.898** | 0.100 | 0.313 | -0.279 | 0.003 | 0.089 | 0.07 | -0.013 |
GMFM | 29 | 0.928** | 0.182 | 0.459* | -0.195 | 0.075 | 0.077 | 0.054 | 0.051 |
6MWT | 12 | 0.731** | 0.396 | 0.102 | -0.173 | -0.289 | 0.363 | -0.107 | -0.301 |
HHD | 23 | 0.592** | -0.019 | 0.003 | -0.346 | 0.015 | -0.014 | -0.106 | -0.206 |
Grip power | 23 | 0.738** | -0.159 | -0.248 | -0.409 | -0.439 | -0.122 | -0.369 | −0.427* |
Pinch power | 27 | 0.637** | 0.310 | 0.205 | -0.022 | 0.199 | -0.011 | 0.199 | -0.011 |
%FVC | 33 | 0.638** | 0.105 | 0.422* | −0.488** | 0.004 | 0.14 | 0.144 | 0.038 |
%VC | 33 | 0.674** | 0.091 | 0.386* | −0.465** | 0.011 | 0.122 | 0.163 | 0.067 |
CK (IU/L) | 33 | 0.583** | 0.060 | 0.301 | −0.377* | 0.059 | 0.219 | -0.001 | 0.049 |
DEXA whole body | 32 | 0.434* | -0.191 | -0.010 | -0.464** | -0.113 | -0.116 | -0.26 | -0.229 |
DEXA arm | 32 | 0.315 | -0.207 | -0.159 | -0.393* | -0.161 | -0.124 | -0.305 | -0.319 |
DEXA legs | 32 | 0.524** | -0.144 | -0.024 | -0.416** | -0.063 | -0.079 | -0.180 | -0.162 |
BI | 33 | -0.742** | -0.119 | -0.285 | 0.214 | 0.009 | -0.157 | -0.13 | -0.016 |
mRS | 33 | 0.902** | 0.199 | 0.342 | -0.226 | 0.086 | 0.147 | 0.146 | 0.109 |
*: p<0.05, **: p<0.01. All assessed subscales had significantly lower scores than the national standard index (score=50). Motor function measures, respiratory function, whole body and leg lean body mass, and ADL scores were significantly correlated with the Physical Functioning subscale. |
No significant changes were observed in mRS and BI during the 5-year follow-up period. Among the subscales of SF-36, only scores for Physical Functioning were significantly reduced at the 3rd, 4th, and 5th year evaluations compared to baseline (Table 2).
National standard scores for SF-36 were used to evaluate QOL. All assessed subscales had significantly lower scores than the national standard index (score=50). Motor function measures (summed MMT, GMFM, 6MWT, grip power, and pinch power), respiratory function (%VC and FVC), whole body and leg lean body mass, and ADL scores (BI and mRS) were significantly correlated with the Physical Functioning subscale (Table 3).
Correlation between quantitative items and simplified items, DEXA, and CK (Supplementary table 4)
Summed MMT and GMFM were well correlated with pinch power, grip power, %VC or %FVC, CK, and DEXA (legs). These items were also correlated with certain muscle MMT scores (e.g., elbow flexion and knee extension).