Table 1.
Clinical course of the patients with biallelic variants in POLR1A
| Patients | Patient 1 | Patient 2 | II-3 (in Kara et al.5) | II-4 (in Kara et al.5) |
|---|---|---|---|---|
| Age (sex) | Died at 16.5 y (male) | 2 y 10 m (female) | 24 y (male) | Died at 19 y (male) |
| Genetic findings | ||||
| Homozygous POLR1A variant | T642N (rs750690447) | T642N (rs750690447) | S934L | S934L |
| CADD Phred | 26.6 | 26.6 | 25.1 | 25.1 |
| Total allele frequency gnomAD v.2.1.1 | 0.00006 (15/249528) | 0.00006 (15/249528) | Not reported | Not reported |
| Development | ||||
| Perinatal | Apgar scores 2–6 at 1 and 5 min, adducted thumbs, irritability, intra- and extra-cerebral haemorrhages | Normal | NA | NA |
| Infancy | Hyperreflexia, suspected CP | Hypotonia, delayed smiling | Hyperreflexia | Hyperreflexia, no head control |
| Childhood and adolescence | Spasticity, dystonia, seizures, neurological regression | Motor delay, little contact, swallowing difficulty, spasticity | Motor delay, spasticity, seizures, neurological regression | Seizures, spasticity, non-ambulatory, no words |
| Clinical findings | ||||
| Age | 16.5 y | 2 y 10 m | 11 y | 6.5 y |
| Cognitive functioning | Profound ID | Global delay | Severe ID | Severe ID |
| Cerebellar dysfunction | Ataxia | Ataxia | Ataxia, head titubation | Ataxia, head titubation |
| Extrapyramidal signs | Severe dystonia, neurogenic scoliosis | Dystonic patterning | Not reported | Not reported |
| Growth anomalies | Not present | Brachycephaly, short stature | Low birth weight | Low birth weight, short stature |
| Ophthalmological findings | Strabismus, cataract, vertical nystagmus | Nystagmus | Optical atrophy, gaze palsy | Optical atrophy, gaze palsy |
| Brain imaging | ||||
| Cerebellum and brainstem | Cerebellar and brainstem atrophy, prominent cisterns | Cerebellar atrophy, prominent cisterns | Cerebellar atrophy | Cerebellar atrophy, enlarged fourth ventricle |
| Corpus callosum | Thinning | Thinning (subtle) | Thinning | Thinning |
| Basal ganglia | Small volume/T2 hypointensity of globi pallidi | Normal | Normal | Normal |
| Cerebral cortex | Enlarged subarachnoid spaces | Normal | Enlarged subarachnoid spaces | Enlarged subarachnoid spaces |
| Lateral ventricles | Enlarged (moderate) | Normal | Enlarged | Enlarged |
| White matter abnormality | Diffuse signal changes, hypomyelinating leukodystrophy | Diffuse signal changes, hypomyelinating leukodystrophy | Diffuse signal changes, demyelinating leukodystrophy | Diffuse signal changes, demyelinating leukodystrophy |
CADD = Combined annotation dependent depletion; CP = cerebral palsy; ID = intellectual disability; m = months; NA = not available; y = years.