Table 1.
Clinical and genetic characteristics of individuals with de novo POLR3B variants
| Subject | 1 | 2 | 3 | 4 | 5 | 6 |
|---|---|---|---|---|---|---|
| POLR3B variant (NM_018082.5) | c.1124A>T (de novo) | c.1277T>C (de novo) | c.3137G>A (de novo) | c.1094C>T (de novo) | c.1087G>A (de novo) | c. 1385C>G (de novo) |
| Predicted effect on protein | p.Asp375Val | p. Leu426Ser | p. Arg1046His | p.Ala365Val | p.Glu363Lys | p.Thr462Arg |
| Age at last review | 16 years | 4 years | 11 years | 22 years | 8 years | 14 years |
| Gender | female | male | male | male | female | female |
| Current height (centile) | 166 cm (50%) | 96 cm (1%) | 152 cm (95%) | 165 cm (5%) | 116 cm (10%) | 157 cm (30%) |
| Current weight (centile) | 74.3 kg (85%) | 13.5 kg (1%) | 51.9 kg (95%) | 95.45 kg (95%) | 19.9 kg (20%) | 55.4 kg (63%) |
| Current OFC (centile) | 51 cm (<3%) | 48 cm (5%) | 55 cm (85%) | 58 cm (~98%) | 47 cm (~3%) | 51 cm (<2%) |
| Age achieved walking | 3.5 years | 22 months | 16 months | 18 months | 2.5 years | 16 months |
| Global developmental delay/intellectual disability | severe; on formal testing verbal reasoning and adaptive skills <1% (ABAS-II, Leiter-R, PPVT-4) | language DQ 51%, visual motor DQ 51% | normal intellectual functioning; grade-level academic performance | IQ at age 21 years: FSIQ 46 (moderate ID) | IQ at age 7 years: £55 (mild to moderate ID) | severe; reading, writing, and adaptive function at kindergarten level at age 14 |
| Communication/speech | first words at 5 years, sentences at 7 years, mainly uses single words and short phrases at 16 years, dysarthria | first words at 2 years, 2–3-word phrases, dysarthria | normal speech | first word at 13 months, put 2 words together at 2.5 years, dysarthria | language development initially normal, can use simple sentences, dysarthria | significant early delay, phrases at 3 years but limited vocabulary, now short phrases, dysarthria |
| Gross motor | ambulatory, spastic gait, ataxia, occasional dystonic posturing | ambulatory, in-toeing L > R | mild gross motor delay as an infant | ambulatory, ataxia, falls monthly, spasticity and increasing unsteadiness | ambulatory, spastic gait | gross motor delay, ambulatory, spastic gait, mild ataxia |
| Fine motor | needs assistance to feed herself, dress, and bathe, can print her name | feeds self with spoon and fork | normal | can use utensils but prefers finger feeding, does not color within lines, needs assistance with most ADLs | needs assistance with all activities of daily living | cuts own food but needs help with buttons and zippers, feeds self, needs assistance to bathe and toilet |
| Appendicular hypertonia/spasticity | severe, progressive | none | none | severe, progressive, LEs≫UEs | clearly present, progressive | moderate, all 4 limbs, LE > UE |
| Deep tendon reflexes | 4+ with sustained ankle clonus, +Hoffman sign | normal and symmetric | 1+ in biceps, triceps, absent in patella and ankles bilaterally | 3+ throughout, except 1+ at the ankles | arms, 3+; legs, 4+ (crossed adductor reflex, sustained ankle clonus) | 3+ bilaterally |
| Extensor plantar responses | yes | no | no | yes | yes | yes |
| Muscle weakness | MRC grade 5/5 UEs, tibialis anterior and extensor hallucis longus 4/5 | normal strength | prominent distal leg weakness | not tested formally but grossly normal, no asymmetry | not tested formally, no obvious weakness | MRC grade 5/5 throughout |
| Sensory examination | not able to cooperate with formal exam | grossly normal | decreased vibration and proprioception in distal limbs | uncooperative for detailed exam, hypersensitivity in the feet bilaterally | detailed sensory exam not possible, light touch preserved | unable to cooperate with formal exam |
| Cerebellar testing | mirror movements, intention tremor, mild dysmetria, gait ataxia, unable to perform tandem gait | normal for age | slightly wide-based gait | slow finger to nose movements, clearly ataxic gait with bilateral circumduction, unable to perform tandem gait or stance | mild intention tremor and dysmetria, unable to balance on one foot or perform tandem gait | no overt appendicular ataxia but mild gait ataxia and unable to perform tandem gait |
| Seizures | no | onset 3 years, head and bilateral arm drop attacks, also generalized seizures | no | onset 6 months, refractory generalized epilepsy, myoclonic, rarely atonic and absence | onset 12 months, head drop attacks, refractory to medications and ketogenic diet | no |
| Brain MRI | mild cerebellar atrophy, non-specific T2 and FLAIR hyperintensities | normal | normal (except for Chiari I malformation) | non-specific white matter signal abnormalities, stable over time | normal (age 5 years) | initially delayed myelination that normalized by 14 years |
| EMG/NCS (age when performed) | length-dependent primary axonal neuropathy with secondary demyelination, markedly decreased velocities in motor fibers of tibial and deep peroneal nerves (13 years) | normal (4 years) | severe demyelinating sensory motor polyneuropathy, normal amplitudes, mild-moderate prolonged distal latencies, significant slowing of conduction velocities (10 years) | predominantly demyelinating sensory motor neuropathy, slow motor conduction velocities, markedly decreased amplitudes in tibial nerve, absent sural responses (12 years) | combined axonal and demyelinating polyneuropathy of both motor and sensory nerves (7 years) | predominantly demyelinating polyneuropathy with slow conduction velocities (6 and 8 years) |
Abbreviations are as follows: OFC, occipitofrontal circumference; DQ, development quotient; ID, intellectual disability; L, left; R, right; ADLs, activities of daily living; LE, lower extremity; UE, upper extremity; MRC, Medical Research Council