Table 1.
Clinical characteristics of POLR3A patients
| Study ID | F1-3 | F1-5 | F1-7 | F1-8 | F2-1 | F3-1 | F4-1 | F5-1 | F6-1 | F7-1 | F8-1 | F9-1 | F10-1 | F11-1 | F12-1 | F13-1 | F14-1 | F15-1 | F16-1 | F16-2 | F17-1 | F18-1 | F19-1 | F20-1 | F21-3 | F22-6 | F22-7 | F23-3 | F23-5 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| c.1909 + 22G>A | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Het | Hom | − | − | − | − | − | − |
| Second mutation | Q31* | Q31* | Q31* | Q31* | D372N | F431 Sfs*26 | E12 61K | L454F | S825 Qfs*18 | G904* | A515V | G854 Afs*5 | splice | Q511* | V1315fs*7 | K71 3Kfs*3 | C109S | G350 Gfs*27 | R873* | R873* | M85 2fs*7 | L356P | − | V1033A (hom) | c.1771-7C>G (hom) | ||||
| Mode of inheritance | AR | AR | AR | AR | AR | S | S | S | S | AR | S | S | S | S | S | S | S | AR | AR | AR | S | S | S | ARa | S | AR | AR | AR | AR |
| Gender | F | M | F | M | F | M | M | M | M | F | M | M | F | M | M | F | F | F | F | F | M | M | F | M | M | F | F | M | F |
| Race | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU | CAU |
| Origin | GER | GER | GER | GER | GER | GER | GER | GER | GER | USA | UK | GER | GER | GER | GER | GER | GER | GER | UK | UK | UK | UK | USA | BEL | GER | TR | TR | IL | IL |
| Age at onset (y) | 51 | 15 | 20 | 14 | 20 | 15 | 20 | 28 | 13 | 17 | 18 | 12 | 26 | 12 | 18 | 6 | 12 | 31 | 21 | 23 | 12 | 20 | 11 | 2 | 16 | 0b | 0b | 2 | 2 |
| Age at exam (y) | 57 | 53 | 50 | 48 | 47 | 68 | 56 | 38 | 27 | 30 | 31 | 42 | 56 | 66 | 41 | 50 | 45 | 45 | 30 | 35 | 25 | 42 | 18 | 20 | 55 | 29 | 21c | 12 | 19 |
| Loss of independent walkingd | N/A | 23 | 8 | 18 | 26 | 29 | 27 | N/A | N/A | N/A | 13 | 27 | 29 | 26 | N/A | 37 | 31 | N/A | 7 | 7 | 8 | 10 | 12 | 32 | N/A | 14 | 0e | N/A | 16 |
| Cognitive deficits | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − | +f | − | − | + | + | + |
| Depression | + | + | + | + | − | − | − | + | − | − | − | − | + | − | − | + | + | − | − | − | − | + | − | + | − | + | + | − | − |
| Pyramidal and peripheral motor system | |||||||||||||||||||||||||||||
| UL/LL spasticity | −/− | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | +/+ | −/− | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/− | −/− | −/+ | −/+ | −/+ | −/+ | −/+ | −/− | −/− | −/+ | −/− | −/− | −/− | −/− |
| UL/LL tendon reflexes | ↓/↓ | ⌋/⌋ | ⌋/↑ | −/⌋ | ↓/↓ | −/− | ⌋/↓ | ⌋/↓ | ⌋/↓ | ⌋/↑ | −/↓ | ⌋/↑ | ↑/⌋ | ↑/↑ | ⌋/↓ | −/⌋ | −/↓ | ⌋/⌋ | −/− | −/− | −/⌋ | −/⌋ | −/− | ⌋/⌋ | ⌋/⌋ | ⌋/↓ | ⌋/↓ | ⌋/⌋ | ⌋/⌋ |
| Extensor plantar response | − | + | + | + | + | − | + | + | + | + | + | + | − | + | + | + | + | + | − | − | − | − | − | − | − | − | − | + | + |
| UL/LL weakness | −/− | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/− | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | −/+ | +/+ | +/+ | −/+ | −/− | −/+ | −/+ | −/+ | −/− | −/+ |
| Muscle atrophy | − | LL | − | − | − | − | − | − | LL | − | − | − | − | UL/LL | UL/LL | − | − | − | − | − | LL | UL/LL | − | − | LL | n.d. | LL | − | − |
| Cerebellar system | |||||||||||||||||||||||||||||
| Sacc. pursuit | + | + | − | + | − | + | + | + | − | + | − | − | − | + | − | + | + | − | + | + | + | + | − | + | + | + | + | + | + |
| Dysarthria/dysphagia | −/− | +/− | +/+ | +/− | +/− | +/− | −/− | −/− | −/− | −/− | −/− | −/− | −/− | +/+ | −/− | −/− | +/− | −/− | +/− | +/− | −/− | +/− | −/− | +/− | +/− | +/+ | +/+ | +/+ | +/+ |
| UL/LL intention tremor | +/− | +/− | −/− | +/− | +/− | +/− | +/− | −/− | −/− | −/− | −/− | −/− | −/− | +/− | −/+ | +/− | +/− | −/+ | +/− | −/− | +/+ | −/− | −/− | +/+ | +/+ | −/− | −/− | −/− | −/− |
| Ataxia | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + |
| Vibration/surface sens. (LL) | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/↓ | ↓/⌋ | ↓/↓ | ↓/⌋ | ↓/⌋ | ↓/⌋ | ↓/↓ | ↓/↓ | ↓/⌋ | ↓/⌋ | ↓/↓ | n.d. | ↓/↓ | n.d. | ↓/⌋ | ⌋/⌋ | ↓/⌋ | ↓/⌋ | ↓/↓ | n.d. | n.d. |
| Urinary/faecal urgency | −/− | +/− | +/− | +/− | −/− | −/− | +/+ | +/− | −/− | +/− | −/− | +/− | +/n.d | +/− | +/− | +/− | +/− | −/− | −/+ | −/+ | −/− | −/− | −/− | −/− | +/− | −/− | +/+ | −/− | −/− |
| Dentition abnormalities | + | + | + | + | + | + | + | n.d. | + | n.d. | n.d. | + | n.d. | − | − | + | + | n.d. | − | − | − | − | n.d. | n.d. | n.d. | n.d. | − | − | − |
| Others | RLS, sleep disturbance | Facial hemispasm, sleep disturbance | Sleep disturbance | RLS, sleep disturbance | Sleep disturbance | RLS, sleep disturbance | − | Aggressive behaviour | − | Tremor (head, voice, UL) | − | − | Tremor (head, voice) | Severe dystonic tremor (head, voice) | Mild dystonic tremor (head) | Tremor (head), RLS, vitiligo | Pes cavus | − | − | − | − | − | Pes cavus | Autism | Rigor | Pes cavus | Infantile seizures dystonia | Rigor, hypokinesia | Rigor, hypokinesia |
| Neurophysiology | |||||||||||||||||||||||||||||
| Abnormal nerve conduction studies | − | + | − | + | − | + | − | − | − | n.d. | − | − | − | + | + | − | − | − | n.d. | n.d. | n.d. | n.d. | + | − | n.d. | n.d. | − | n.d. | n.d. |
| Abnormal MEPs | + | + | + | + | + | + | + | + | + | n.d. | n.d. | + | + | n.d. | + | + | + | + | n.d. | n.d. | n.d. | n.d. | n.d. | + | n.d. | n.d. | n.d. | n.d. | n.d. |
| Abnormal SEPs | + | + | + | + | + | + | + | + | n.d. | n.d. | + | + | + | n.d. | n.d. | + | + | + | n.d. | n.d. | n.d. | n.d. | n.d. | + | n.d. | n.d. | n.d. | n.d. | n.d. |
| Abnormal VEPs | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | + | + | n.d. | n.d. | n.d. | n.d. | + | n.d. | n.d. | n.d. | n.d. | − | n.d. | n.d. | n.d. | n.d. | n.d. | + | n.d. | n.d. | n.d. | n.d. | n.d. |
| MRI | |||||||||||||||||||||||||||||
| Spinal cord atrophy | + | + | + | + | + | n.d. | + | + | n.d. | n.d. | + | n.d. | + | + | + | + | + | + | n.d. | n.d. | n.d. | n.d. | n.d. | n.d.g | n.d. | n.d. | − | n.d. | n.d. |
| Cerebellar atrophy | − | − | − | − | − | n.d. | − | − | − | n.d. | − | n.d. | − | − | − | − | − | − | − | − | − | − | n.d. | + | n.d. | n.d. | − | − | n.d. |
| TCC | + | + | + | + | + | n.d. | − | − | − | N/E | − | n.d. | N/E | − | − | + | − | N/E | N/E | N/E | N/E | N/E | N/E | + | n.d. | n.d. | − | − | n.d. |
| SCP hyperintensity (FLAIR) | + | + | + | + | + | n.d. | + | + | + | N/E | − | n.d. | N/E | + | n.d. | + | + | N/E | N/E | N/E | N/E | N/E | N/E | N/E | n.d. | n.d. | − | − | n.d. |
| Hypomyelinaton | − | − | − | − | − | n.d. | − | − | − | n.d. | − | n.d. | − | − | n.d. | − | − | − | − | − | − | − | n.d. | n.d. | n.d. | n.d. | − | − | n.d. |
AR = autosomal recessive; BEL = Belgium; CAU = Caucasian; F = female; gen = generalized; GER = Germany; IL = Israel; LL = lower limb; M = male; MEP = motor evoked potential; n.d. = not done; N/E = not evaluated; RLS = restless legs syndrome; S = sporadic; SCP = superior cerebellar peduncle; SEP = cortical latencies of somatosensory evoked potentials; TCC = thin corpus callosum; TR = Turkey; UL = upper limb; VEP = cortical latencies of visual evoked potentials. + = clinical sign is present; − = clinical sign is absent; ↑ = increase of clinical sign; ↓ = decrease of clinical sign; ↔ = normal/unchanged findings.
aChild from incestuous relationship between brother and sister.
bStart at ∼2 months of age.
cDeath at age 24 years.
dIn years after disease onset.
eNever able to walk independently.
fSevere cognitive decline at the age of 39 years.
gAtrophy of brainstem and pons.