Introduction
Materials and methods
Results
Genomic analyses
Family | Family 1 | Family 2 | Family 3 | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Patient | IV:1 | IV:2 | III:4 | III:6 | III:8 | IV:1 | III:7 | III:8 | III:9 | III:10 | III:18 |
Age at onset | < 1.5 yr | < 1.5 yr | < 1 yr | 1.5 yr | < 1 yr | < 1.5 yr | < 1.5 yr | < 1.5 yr | < 1.5 yr | < 1.5 yr | < 1.5 yr |
Age at last exam | 5 yr | 2 yr | 26 yr | 17 yr | 13 yr | 7 yr | 48 yr | 46 yr | 45 yr | 42 yr | 38 yr |
Gender | M | F | F | F | F | F | M | F | M | F | F |
Growth | N | N | N | N | N | N | Abn† | Abn† | Abn† | Abn† | Abn† |
Regression | + | + | + | + | + | + | + | + | + | + | + |
GDD | + | + | + | + | + | + | + | + | + | + | + |
Cognition* | N | N | N | N | N | N | N | N | N | N | N |
Age at sitting | 6 mo | 6 mo | NS | 6 mo | NS | 9 mo | 9 mo | 9 mo | 9 mo | 9 mo | NS |
Age at walking | NW | NW | NW | 1 yr | NW | NW | NW | NW | NW | NW | NW |
Wheelchair bound | 4 yr | − | 6 yr | 6 yr | 6 yr | + | +‡ | +‡ | +‡ | +‡ | +‡ |
Age at talking | 1.5 yr | 1.5 yr | NT | NA | NT | 1.5 yr | 1.5 yr | 1.5 yr | 1.5 yr | 1.5 yr | 3 yr |
Dysarthria | + | + | NT | 7 yr | NT | 6 yr | + | + | + | + | + |
Anarthria | − | − | NT | 8 yr | NT | 7 yr | + | + | + | + | 5 yr |
Dysphagia/drooling | −/− | −/− | 7 yr/− | 8 yr/− | < 2 yr/− | 6 yr/− | 5–7 yr/+ | 5–7 yr/+ | 5–7 yr/+ | 5–7 yr/+ | 6–7 yr/+ |
Ocular movements | N | N | N | N | N | N | N | N | N | N | N |
Facial muscle spasticity/Trismus | −/− | −/− | −/+ | −/+ | −/+ | ± | +/+ | +/+ | +/+ | +/− | ± |
Facial dystonia | − | − | + | + | + | − | − | − | − | − | − |
Generalized dystonia | − | − | + | + | + | − | − | − | − | − | − |
Opisthotonus | − | − | 7 yr | 8 yr | < 2 yr | − | − | − | − | − | − |
Fasciculations | − | − | − | − | − | − | − | − | − | − | − |
Muscle atrophy | + | − | − | − | − | + | + | + | + | + | + |
Spastic paraparesis | + | + | + | + | + | + | + | + | + | + | + |
Spastic tetraparesis | + | + | + | + | + | + | + | + | + | + | + |
Hyperreflexia | + | + | + | + | + | + | + | + | + | + | + |
Clonus | + | + | − | − | − | + | + | + | + | + | + |
Extensor plantar responses | + | + | + | + | + | + | + | + | + | + | + |
Incontinence | − | − | − | − | − | − | + | + | + | + | + |
Emotional lability¶ | − | − | + | + | + | + | + | + | + | + | + |
Cerebellar signs | NA | NA | − | − | − | − | NA | NA | NA | NA | NA |
Scoliosis | − | − | − | − | − | + | + | + | + | + | |
Brain MRI | N | NA | NA | NA | N | N | Abn§ | NA | NA | NA | NA |
NCS | N | N | N | N | N | N | NA | NA | NA | NA | NA |
Family 1
Family 2
Family 3
Discussion
Family/origin† | Pt | Age at exam | Mutation‡ | Age at onset | Loss of ambulation | Upper limb involvement | Dysphagia/drooling | Dysarthria/anarthria | Ocular movements | Wheelchair bound | Cognition | EMG | MEP/SSEP | Brain imaging |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 1 | 14 yr | c.1425_1426delAG p.E476Gfs*71 | 14 mo | 2 yr | + | NA/NA | 3–7 yr/14 yr | N | NA§ | N | N | NA/NA | Abn |
2 | 6 yr | 11 mo | NW | + | NA/NA | 5–6 yr/− | N | − | N | NA | NA/NA | Abn | ||
3 | 2.5 yr | 9 mo | NW | + | NA/NA | +/− | N | − | N | NA | NA/NA | NA | ||
2 | 4 | 36 yr | c.3619delA p.M1207* | 1 yr | NW | < 7 yr | +/NA | 13 yr/+ | N | + | N | N | Abn/Abn | Abn |
5 | 31 yr | 1 yr | NW | < 7 yr | +/NA | 13 yr/+ | N | + | N | N | Abn/NA | NA | ||
6 | 24 yr | 1 yr | NW | < 7 yr | +/NA | 13 yr/+ | N | + | N | NA | Abn/NA | NA | ||
3 | 7 | 18 yr | c.1472_1481del p.V491Gfs*3 | 1.5 yr | 4 yr | 6 yr | 13 yr/NA | 4 yr/12 yr | Abn | +§ | N | N | Abn/N | Abn |
4 | 8 | 23 yr | c.2537_2538delAT p.N846Ifs*13 | 16 mo | 5 yr | 10 yr | 18 yr/NA | 10 yr/16 yr | Abn | + | N | N | Abn/Abn | Abn |
5 | 9 | 20 yr | c.1007_1008delTA p.I336Tfs*5 | 1.5 yr | 4 yr | 9 yr | +/NA | 9 yr/11 yr | Abn | + | N | N | Abn/Abn | Abn |
6 Pakistan [14] | 10 | 12 yr | c.4721delT p.V1574Afs*44 | 1.5 yr | + | + | NA/NA | +/+ | NA | + | NA | NA | NA | NA |
7 Buchari Jewish [15] | 11 | 9 yr | c.2992C > T p.R998* | 1 yr | NW | 2 yr | NA/+ | 3 yr/− | NA | − | NA | NA | NA/NA | NA |
12 | 6 yr | 14 mo | NW | 6 yr | NA/NA | 3 yr/− | NA | − | N | N | NA/NA | N | ||
8 Turkey [16] | 13 | 22 yr | c.470G > A p.C157Y | < 1 yr | NW | 12 yr | -/NA | +/NA | NA | 12 yr | N | NA | NA/NA | NA |
14 | 20 yr | < 1 yr | NW | 10 yr | +/NA | +/NA | NA | 10 yr | NA | N | Abn/NA | Abn | ||
9 The Netherlands [17] | 15 | 13 yr | c.2143C > T p.Q715* | 8 mo | NW | < 4 yr | 5 yr/+ | 5 yr/13 yr | NA | 13 yr | N | N | Abn/NA | N |
16 | 8 yr | 1.5 yr | NW | + | 4 yr/NA | 4 yr/− | NA | − | N | N | Abn/NA | N | ||
10 Hungary [18] | 17 | 11 yr | [c.1821_1825dup]; [c.3529G > T] [p.E609Afs*9]; [p.G1177*] | 10 mo | NW | 2 yr | 5 yr/5 yr | 5 yr/− | NA | 11 yr | N | N | Abn/N | N |
18 | 6 yr | < 1 yr | NW | − | -/NA | 5 yr/− | NA | 6 yr | NA | NA | NA/NA | N | ||
11 Germany [19] | 19 | 7 yr | c.1999-2A > T p.E724fs*32 | 1.5 yr | NW | < 7 yr | NA/NA | < 7 yr/− | N | NA | Abn¶ | NA | NA/NA | Abn |
12 Italy [20] | 20 | 17 yr | c.3836 + 1G > T p.K1234 fs*3 | 1 yr | NW | 8 yr | 8 yr/NA | 8 yr/11 yr | N | 8 yr§ | N | Abn◊ | NA/Abn | Abn |
13 Portugal [21] | 21 | 16 yr | [c.1425_1428del]; [c.145G > A] [p.G477Afs*19]; [p.G49R] | 3 yr | NW | 6 yr | 14 yr/+ | 8 yr/13 yr | Abn | 8 yr | N | N | NA/NA | N |
14 Saudi Arabia [11] | 22 | 8 yr | c.2761C > T p.R921* | 1–2 yr | 4 yr | + | < 4 yr/NA | +/8 yr | NA | NA | N | N | NA/NA | Abn |
23 | 4 yr | 2 yr | 4 yr | NA | 4 yr/NA | 4 yr/NA | NA | NA | N | N | NA/NA | NA | ||
15 Turkey [22] | 24 | 19 yr | c.2351 + 2C > A | 2 yr | + | + | +/NA | +/8 yr | NA | 8 yr | NA | NA | NA/NA | NA |
25 | 12 yr | 6 mo | NW | + | +/NA | NT | NA | + | NA | NA | NA/NA | NA | ||
26 | 6 yr | 1 yr | NW | + | +/NA | +/− | N | NA | N | NA | NA/NA | Abn | ||
27 | 4.5 yr | 1.5 yr | NW | + | +/NA | +/− | N | NA | N | NA | NA/NA | Abn | ||
16 China [23] | 28 | 13 yr | [c.2351_2351 + 17del]; [c.1310_1313del] [p.G437Vfs*9]; [p.E724Gfs*26] | 13 mo | NW | 4 yr | 5 yr/5 yr | 5 yr/− | NA | 5 yr | NA | N | NA/NA | N |
29 | 4 yr | < 1 yr | NW | + | +/+ | +/− | NA | NA | NA | NA | NA/NA | NA | ||
17 Pakistan [24] | 30 | 15 yr | c.2998delA p.I1000* | 1–2 yr | NW | + | NA/NA | +/− | NA | 10 yr | Abn¶ | Abn◊ | Abn/NA | NA |
31 | 13 yr | 1–2 yr | NW | + | NA/NA | +/− | NA | 8 yr | Abn¶ | Abn◊ | Abn/NA | NA | ||
32 | 16 yr | 1–2 yr | NW | + | NA/NA | +/− | NA | 10 yr | Abn¶ | Abn◊ | Abn/NA | N | ||
33 | 7 yr | 1–2 yr | NW | + | NA/NA | +/− | NA | 12 yr | Abn¶ | Abn◊ | Abn/NA | NA | ||
34 | 18 yr | 1–2 yr | NW | + | NA/NA | +/− | NA | 10 yr | Abn¶ | Abn◊ | Abn/NA | NA | ||
35 | 6 yr | 1–2 yr | NW | + | NA/NA | +/− | NA | 6 yr | Abn¶ | Abn◊ | Abn/NA | NA | ||
18 Pakistan [24] | 36 | NA | c.194 T > C p.F65S | 1–2 yr | NW | + | 5 yr/NA | 5 yr/+ | N | + | N | NA | NA/NA | NA |
37 | 13 yr | 1–2 yr | NW | + | 5 yr/NA | 5 yr/+ | N | 10 yr | N | NA | NA/NA | NA | ||
38 | NA | 1–2 yr | NW | + | 5 yr/NA | 5 yr/+ | N | + | N | NA | NA/NA | NA | ||
39 | 22 yr | 1–2 yr | NW | + | 5 yr/NA | 5 yr/+ | N | 12 yr | N | NA | NA/NA | N | ||
40 | 26 yr | 1–2 yr | NW | + | 5 yr/NA | 5 yr/+ | N | 9 yr | N | NA | NA/NA | NA | ||
19 Pakistan [25] | 41 | 7 yr | c.1918C > T p.R640* | 1–2 yr | NW | − | −/+ | ± | N | − | N | N | NA/NA | N |
42 | 6 yr | 1–2 yr | NW | − | −/− | +/− | N | − | N | NA | NA/NA | NA |