Baseline clinical characteristics classified by variant topology and biological effect of the variant in patients with pathogenic and likely pathogenic dominant variants (AD-CMT2A)
| Clinical characteristics . | Variant topology (AD-CMT2A) . | Biological effect of variants . | ||
|---|---|---|---|---|
| GTPase domain variants . | Non-GTPase domain variants . | Mitochondrial hypofusion (R94Q, T105M) . | Mitochondrial hyperfusion (L76P, R364W) . | |
| Patients, n | 104 | 75 | 11 | 17 |
| Age of symptom onset, years, mean ± SD | 11.79 ± 15.35 (range 1–81) | 11.37 ± 14.76 (range 1–70) | 5.55 ± 2.97 (range 2.5–12) | 5.71 ± 14.85 (range 1–63) |
| Disease duration, years, mean ± SD | 19.03 ± 13.99 (range 0.1–53.1) | 21.31 ± 15.96 (range 2.6–65.2) | 19.19 ± 12.67 (range 3.6–43.7) | 17.51 ± 16.68 (range 2.7–49.3) |
| Foot deformities, n | 73/93 (78%) | 54/67 (81%) | 7/8 (88%) | 11/14 (79%) |
| Ankle-foot orthoses, n | 67/96 (70%) | 37/70 (53%) | 9/10 (90%) | 14/16 (88%) |
| Walking aids, n | 24/93 (26%) | 22/68 (32%) | 4/10 (40%) | 8/16 (50%) |
| Wheelchair-dependent, n | 25/96 (26%) | 18/67 (27%) | 4/10 (40%) | 9/16 (56%) |
| Foot surgery, n | 29/95 (31%) | 13/71 (18%) | 5/10 (50%) | 2/17 (12%) |
| Dexterity difficulties, n | 68/97 (70%) | 38/69 (55%) | 8/10 (80%) | 11/15 (73%) |
| Optic nerve atrophy, n | 10/99 (10%) | 2/69 (3%) | 0/11 (0%) | 2/14 (14%) |
| Hearing loss, n | 3/90 (3%) | 8/69 (12%) | 0/10 (0%) | 2/13 (15%) |
| Scoliosis, n | 15/94 (16%) | 4/68 (6%) | 0/9 (0%) | 3/16 (19%) |
| CMTESv2 | 11.31 ± 7.06 (87) | 10.06 ± 6.68 (70) | 12.13 ± 7.02 (8) | 16.73 ± 7.81 (15) |
| CMTESv2-R | 15.15 ± 8.16 (87) | 13.19 ± 7.82 (70) | 16.25 ± 8.00 (8) | 20.07 ± 8.46 (15) |
| CMTNSv2 | 16.68 ± 10.38 (47) | 13.72 ± 8.79 (43) | 20.50 ± 16.26 (2) | 26.00 ± 8.26 (10) |
| CMTNSv2-R | 20.98 ± 11.30 (47) | 17.12 ± 9.81 (43) | 25.00 ± 16.97 (2) | 29.90 ± 8.20 (10) |
| CMTPedS | 27.88 ± 8.17 (24) | 24.96 ± 12.06 (23) | 27.00 ± 7.07 (2) | 34.78 ± 5.97 (9) |
| Clinical characteristics . | Variant topology (AD-CMT2A) . | Biological effect of variants . | ||
|---|---|---|---|---|
| GTPase domain variants . | Non-GTPase domain variants . | Mitochondrial hypofusion (R94Q, T105M) . | Mitochondrial hyperfusion (L76P, R364W) . | |
| Patients, n | 104 | 75 | 11 | 17 |
| Age of symptom onset, years, mean ± SD | 11.79 ± 15.35 (range 1–81) | 11.37 ± 14.76 (range 1–70) | 5.55 ± 2.97 (range 2.5–12) | 5.71 ± 14.85 (range 1–63) |
| Disease duration, years, mean ± SD | 19.03 ± 13.99 (range 0.1–53.1) | 21.31 ± 15.96 (range 2.6–65.2) | 19.19 ± 12.67 (range 3.6–43.7) | 17.51 ± 16.68 (range 2.7–49.3) |
| Foot deformities, n | 73/93 (78%) | 54/67 (81%) | 7/8 (88%) | 11/14 (79%) |
| Ankle-foot orthoses, n | 67/96 (70%) | 37/70 (53%) | 9/10 (90%) | 14/16 (88%) |
| Walking aids, n | 24/93 (26%) | 22/68 (32%) | 4/10 (40%) | 8/16 (50%) |
| Wheelchair-dependent, n | 25/96 (26%) | 18/67 (27%) | 4/10 (40%) | 9/16 (56%) |
| Foot surgery, n | 29/95 (31%) | 13/71 (18%) | 5/10 (50%) | 2/17 (12%) |
| Dexterity difficulties, n | 68/97 (70%) | 38/69 (55%) | 8/10 (80%) | 11/15 (73%) |
| Optic nerve atrophy, n | 10/99 (10%) | 2/69 (3%) | 0/11 (0%) | 2/14 (14%) |
| Hearing loss, n | 3/90 (3%) | 8/69 (12%) | 0/10 (0%) | 2/13 (15%) |
| Scoliosis, n | 15/94 (16%) | 4/68 (6%) | 0/9 (0%) | 3/16 (19%) |
| CMTESv2 | 11.31 ± 7.06 (87) | 10.06 ± 6.68 (70) | 12.13 ± 7.02 (8) | 16.73 ± 7.81 (15) |
| CMTESv2-R | 15.15 ± 8.16 (87) | 13.19 ± 7.82 (70) | 16.25 ± 8.00 (8) | 20.07 ± 8.46 (15) |
| CMTNSv2 | 16.68 ± 10.38 (47) | 13.72 ± 8.79 (43) | 20.50 ± 16.26 (2) | 26.00 ± 8.26 (10) |
| CMTNSv2-R | 20.98 ± 11.30 (47) | 17.12 ± 9.81 (43) | 25.00 ± 16.97 (2) | 29.90 ± 8.20 (10) |
| CMTPedS | 27.88 ± 8.17 (24) | 24.96 ± 12.06 (23) | 27.00 ± 7.07 (2) | 34.78 ± 5.97 (9) |
The amino acid positions used for the dynamin-GTPase domain are 93–342. Variants shown to cause mitochondrial hypofusion in non-human disease models are p.Arg94Gln (R94Q) and p.Thr105Met (T105M), whereas variants shown to cause mitochondrial hyperfusion are p.Leu76Pro (L76P) and p.Arg364Trp (R364W). Categorical data highlighted in bold in the variant topology group indicate a statistically significant difference (P < 0.05) between the observed values within that group. The CMTPedS was only performed in patients aged ≤20 years at the time of assessment. Data in the bottom five rows showing the clinical outcome scores represent mean ± SD (n). All percentage values are rounded to the nearest whole point.
Baseline clinical characteristics classified by variant topology and biological effect of the variant in patients with pathogenic and likely pathogenic dominant variants (AD-CMT2A)
| Clinical characteristics . | Variant topology (AD-CMT2A) . | Biological effect of variants . | ||
|---|---|---|---|---|
| GTPase domain variants . | Non-GTPase domain variants . | Mitochondrial hypofusion (R94Q, T105M) . | Mitochondrial hyperfusion (L76P, R364W) . | |
| Patients, n | 104 | 75 | 11 | 17 |
| Age of symptom onset, years, mean ± SD | 11.79 ± 15.35 (range 1–81) | 11.37 ± 14.76 (range 1–70) | 5.55 ± 2.97 (range 2.5–12) | 5.71 ± 14.85 (range 1–63) |
| Disease duration, years, mean ± SD | 19.03 ± 13.99 (range 0.1–53.1) | 21.31 ± 15.96 (range 2.6–65.2) | 19.19 ± 12.67 (range 3.6–43.7) | 17.51 ± 16.68 (range 2.7–49.3) |
| Foot deformities, n | 73/93 (78%) | 54/67 (81%) | 7/8 (88%) | 11/14 (79%) |
| Ankle-foot orthoses, n | 67/96 (70%) | 37/70 (53%) | 9/10 (90%) | 14/16 (88%) |
| Walking aids, n | 24/93 (26%) | 22/68 (32%) | 4/10 (40%) | 8/16 (50%) |
| Wheelchair-dependent, n | 25/96 (26%) | 18/67 (27%) | 4/10 (40%) | 9/16 (56%) |
| Foot surgery, n | 29/95 (31%) | 13/71 (18%) | 5/10 (50%) | 2/17 (12%) |
| Dexterity difficulties, n | 68/97 (70%) | 38/69 (55%) | 8/10 (80%) | 11/15 (73%) |
| Optic nerve atrophy, n | 10/99 (10%) | 2/69 (3%) | 0/11 (0%) | 2/14 (14%) |
| Hearing loss, n | 3/90 (3%) | 8/69 (12%) | 0/10 (0%) | 2/13 (15%) |
| Scoliosis, n | 15/94 (16%) | 4/68 (6%) | 0/9 (0%) | 3/16 (19%) |
| CMTESv2 | 11.31 ± 7.06 (87) | 10.06 ± 6.68 (70) | 12.13 ± 7.02 (8) | 16.73 ± 7.81 (15) |
| CMTESv2-R | 15.15 ± 8.16 (87) | 13.19 ± 7.82 (70) | 16.25 ± 8.00 (8) | 20.07 ± 8.46 (15) |
| CMTNSv2 | 16.68 ± 10.38 (47) | 13.72 ± 8.79 (43) | 20.50 ± 16.26 (2) | 26.00 ± 8.26 (10) |
| CMTNSv2-R | 20.98 ± 11.30 (47) | 17.12 ± 9.81 (43) | 25.00 ± 16.97 (2) | 29.90 ± 8.20 (10) |
| CMTPedS | 27.88 ± 8.17 (24) | 24.96 ± 12.06 (23) | 27.00 ± 7.07 (2) | 34.78 ± 5.97 (9) |
| Clinical characteristics . | Variant topology (AD-CMT2A) . | Biological effect of variants . | ||
|---|---|---|---|---|
| GTPase domain variants . | Non-GTPase domain variants . | Mitochondrial hypofusion (R94Q, T105M) . | Mitochondrial hyperfusion (L76P, R364W) . | |
| Patients, n | 104 | 75 | 11 | 17 |
| Age of symptom onset, years, mean ± SD | 11.79 ± 15.35 (range 1–81) | 11.37 ± 14.76 (range 1–70) | 5.55 ± 2.97 (range 2.5–12) | 5.71 ± 14.85 (range 1–63) |
| Disease duration, years, mean ± SD | 19.03 ± 13.99 (range 0.1–53.1) | 21.31 ± 15.96 (range 2.6–65.2) | 19.19 ± 12.67 (range 3.6–43.7) | 17.51 ± 16.68 (range 2.7–49.3) |
| Foot deformities, n | 73/93 (78%) | 54/67 (81%) | 7/8 (88%) | 11/14 (79%) |
| Ankle-foot orthoses, n | 67/96 (70%) | 37/70 (53%) | 9/10 (90%) | 14/16 (88%) |
| Walking aids, n | 24/93 (26%) | 22/68 (32%) | 4/10 (40%) | 8/16 (50%) |
| Wheelchair-dependent, n | 25/96 (26%) | 18/67 (27%) | 4/10 (40%) | 9/16 (56%) |
| Foot surgery, n | 29/95 (31%) | 13/71 (18%) | 5/10 (50%) | 2/17 (12%) |
| Dexterity difficulties, n | 68/97 (70%) | 38/69 (55%) | 8/10 (80%) | 11/15 (73%) |
| Optic nerve atrophy, n | 10/99 (10%) | 2/69 (3%) | 0/11 (0%) | 2/14 (14%) |
| Hearing loss, n | 3/90 (3%) | 8/69 (12%) | 0/10 (0%) | 2/13 (15%) |
| Scoliosis, n | 15/94 (16%) | 4/68 (6%) | 0/9 (0%) | 3/16 (19%) |
| CMTESv2 | 11.31 ± 7.06 (87) | 10.06 ± 6.68 (70) | 12.13 ± 7.02 (8) | 16.73 ± 7.81 (15) |
| CMTESv2-R | 15.15 ± 8.16 (87) | 13.19 ± 7.82 (70) | 16.25 ± 8.00 (8) | 20.07 ± 8.46 (15) |
| CMTNSv2 | 16.68 ± 10.38 (47) | 13.72 ± 8.79 (43) | 20.50 ± 16.26 (2) | 26.00 ± 8.26 (10) |
| CMTNSv2-R | 20.98 ± 11.30 (47) | 17.12 ± 9.81 (43) | 25.00 ± 16.97 (2) | 29.90 ± 8.20 (10) |
| CMTPedS | 27.88 ± 8.17 (24) | 24.96 ± 12.06 (23) | 27.00 ± 7.07 (2) | 34.78 ± 5.97 (9) |
The amino acid positions used for the dynamin-GTPase domain are 93–342. Variants shown to cause mitochondrial hypofusion in non-human disease models are p.Arg94Gln (R94Q) and p.Thr105Met (T105M), whereas variants shown to cause mitochondrial hyperfusion are p.Leu76Pro (L76P) and p.Arg364Trp (R364W). Categorical data highlighted in bold in the variant topology group indicate a statistically significant difference (P < 0.05) between the observed values within that group. The CMTPedS was only performed in patients aged ≤20 years at the time of assessment. Data in the bottom five rows showing the clinical outcome scores represent mean ± SD (n). All percentage values are rounded to the nearest whole point.
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