Video 1
Tremor–ataxia syndrome in a complex POLR3A-related phenotype. Patient 1 with a predominant tremor–ataxia syndrome, including head and vocal tremor, high-amplitude upper limb tremor, and upper limb ataxia. After bilateral Vim DBS tremor improved remarkably, while ataxia continued to progress.
Figure 1
The post- operatory imaging analysis (BrainLab Elements software: fusion, object management, fibertracking, stereotaxy and lead localization modules) showed the leads locations and the volume of tissue activated (VTA) generated according to the most updated stimulation parameters. a) Bilateral DBS leads (Medtronic, Activa 3389 model) and the VTAs adjacent to the DRTT at the ventral aspect of both Vim. b) Unilateral left DBS directional lead (Boston Scientific, Vercise 2202 model) and the VTA adjacent to the DRRT, at the ventral Vim. Red nuclei (red), Vim (pink), thalamus (green), DBS leads (orange), VTAs (orange spheres), dentate-rubro-thalamic tracts (DRTT) (turquoise, green and blue).
Video 2
Tremor in a POLR3A-related phenotype. Patient 2 presenting with a high-amplitude tremor of the right upper limb, significantly interfering with daily activities. Following unilateral left Vim DBS, tremor improved and remained well controlled at 4 months.
Figure 2
Case 2 brain MRI with bilateral T2/FLAIR hyperintense signal located in the superior cerebellar peduncle, around the IV ventricle, and dentate nuclei.
Table 1
Clinical phenotypes of POLR3A-related diseases.
| SPECTRUM OF POLR3A-RELATED DISEASE | |||||||
|---|---|---|---|---|---|---|---|
| CONDITION | HYPOMYELINATING LEUKODYSTROPHY TYPE 7 (HLD-7) [11] | 4H LEUKODYSTROPHY SYNDROME [26] | ATAXIA, DELAYED DENTITION, AND HYPOMYELINATION (ADDH) SYNDROME [27] | TREMOR-ATAXIA WITH CENTRAL HYPOMYELINATION (TACH) SYNDROME [28] | LEUKODYSTROPHY WITH OLIGODONTIA (LO) SYNDROME [29] | HYPOMYELINATION WITH CEREBELLAR ATROPHY AND HYPOPLASIA OF THE CORPUS CALLOSUM (HCAHC) SYNDROME [30] | WIEDEMANN-RAUTENSTRAUCH SYNDROME [32] |
| Age of onset | Infancy or childhood | Childhood, adolescence, or early adulthood | Childhood or adolescence | Infancy or early childhood | Childhood or adolescence | Adolescence or adulthood | Neonatal period |
| Neurological features | Neurodevelopmental delay Ataxia, tremor, dysarthria, spasticity, dystonia | Neurodevelopmental delay | Dysarthria, hypometric saccades, limb ataxia, dysdiadochokinesia, gait ataxia, intention tremor, pyramidal signs | Neurodevelopmental delay or cognitive decline, dysarthria, limb ataxia, gait ataxia, upper-limb tremor, dystonia, myoclonus, pyramidal signs, nystagmus | Dysarthria Mild limb ataxia Mild intention tremor Lower limb spasticity Pyramidal signs | Dysarthria, ataxia; tremor, dystonia, spasticity, intellectual disability or cognitive decline | Tremor, ataxia, hypertonia |
| Non-neurological features | Dental abnormalities (absent or delayed eruption of teeth) Endocrine abnormalities (delayed, halted, or absent puberty) Short stature Ocular abnormalities (myopia, optic atrophy, cataracts) | Dental abnormalities (hypodontia) Endocrine abnormalities (hypogonadotropic hypogonadism [delayed puberty]) | Dental abnormalities (delayed dentition, abnormal order of teeth eruption, variation in mineralization of permanent teeth, natal teeth) Short stature | Dental abnormalities (hypodontia, delayed tooth eruption, oligodontia, irregular tooth shape or placement) Endocrine abnormalities (hypogonadotropic hypogonadism [delayed puberty]) Short stature Ocular abnormalities (myopia) | Dental abnormalities (delayed dental eruption, oligodontia) Craniofacial anomalies (enophthalmia) | Not described | Obstetrical abnormalities (growth deficiency) Craniofacial anomalies (sparse scalp hair, triangular face, small mouth with thin upper vermillion, pointed chin; other anomalies include prominent scalp veins, wide cranial sutures, ears anomalies) Generalized lipodystrophy Dental abnormalities (natal teeth, hypodontia) |
| Radiological features | Diffuse hypomyelinations with variable T1 signal intensity; T2 high signal in the white matter of the brain, and relative T2 hypointense signal in the anterolateral nuclei of the thalami, dentate nucleus, globus pallidus, pyramidal tracts of the posterior limb of the internal capsule, and optic radiations; cerebellar atrophy; thinning of the corpus callosum | Diffuse hypomyelination; hypointense signal of the optic radiation, the ventrolateral thalamus, part of the posterior limb of the internal capsule, and the dentate nucleus; Cerebellar atrophy more of the vermis than of the hemispheres; Spinal cord hypomyelination | Hypomyelination of the supratentorial white matter (hyperintense signal on T2); Thin corpus callosum; Cerebellum atrophy (particular in the vermis) | Diffuse supra-tentorial hypomyelination involving periventricular and the subcortical region as well as U-fibers. Thinning of corpus callosum | Diffuse leukodystrophy of the deep white matter of both centrum semi-ovale and cortico-spinal tracts | Lack of myelin throughout the supratentorial cerebral white matter; Thin corpus callosum; cerebral atrophy; mild cerebellar atrophy | Hypomyelination; Polymicrogyria of the perisylvian cortex |