POLR3A variants with striatal involvement and extrapyramidal movement disorder

Abstract

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant.

Keywords: Basal ganglia; Brainstem; Hypomyelination; Inferior cerebellar peduncle; MRI; POLR3A; Striatum; Superior cerebellar peduncle.

Fig. 1

Localisation of variants and conservation in POLR3A. This figure shows the localization of intronic variants (in blue) and exonic variants (in red) in POLR3A. a Two missense variants are both located in the discontinuous cleft domain, one in the pore domain. b denotes conservation of mutated amino acids across different species. c Motifs of primary sequence conservation surrounding the c.3387C base pair based on alignment of 61 species using WebLogo, demonstrating the high conservation of the c.3387C base pair. The observed variant (c.3387C > A) does not lead to an amino acid change but is predicted to activate an exonic cryptic acceptor site in exon 26

Fig. 2

Characteristic MRI pattern of striatal variant of POLR3A-related disease. MRI in patient 1 at 1.5 years demonstrates the characteristic combination of atrophic, T2-hyperintense striatum ,and T2-hyperintense SCP (A-E: T2w; F: ADC-map; insets: 1 = ICP, 2 = peridentate white matter, 3 = SCP). a T2-hyperintensity of ICP (1) and peridentate white matter (2) are additional findings. b Further additional findings are T2-hyperintensity of tegmentum and intraparenchymal course of trigeminal nerve. T2-hyperintensity of SCP (3, insets in B-D) is seen along its course from the cerebellum (b), dorsal mesencephalon (c) to the decussation in the anterior mesencephalon (d). e, f: Homogeneous, mild, and symmetric T2-hyperintensity of the striatum with volume loss and increased diffusion. NB the lateral medullary lamina between pallidum and putamen is commonly seen at this age due to its relative T2-hyperintensity compared with pallidum and putamen; increased conspicuity is due to T2-hyperintensity of putamen (e)

Fig. 3

Small striatum and infratentorial changes at first MRI of patient 4. At 20 months, the striatum is small (e, age-matched control image in (f) for comparison), but its signal does not exceed that of the cortex and is normal. Note involvement of ICP (a), dentate nuclei, hila, and peridentate white matter (b), and of SCP including the decussation (b–d)

Fig. 4

Evolution of brainstem and striatal changes in patients 1 (A, B) and 5 (C, D). A, In patient 1 at 0.5 years, the decussation of SCP mildly hyperintense (A₄; inset: normal finding in age-matched control) and the striatum is normal (A₅). B At 2 years ICP (B₁), hila of dentate nuclei and peridentate white matter (B_1,2) are newly hyperintense, and SCP is now clearly hyperintense along its mesencephalic course (B₃) and in the decussation (B₄). The striatum is homogeneously T2-hyperintense and atrophic (B₅). C Patient 5 also has a normal striatum at 2 years (C₅). ICP (C₁), hila of dentate nuclei, peridentate white matter (C₂) and SCP (C₃), along to the red nucleus (C₄) are T2-hyperintense. At 4.8 years (D), infratentorial changes (D_1–4) are regressing whereas the striatum is newly T2-hyperintense and atrophic (D₅)

Fig. 5

Striatal injury, regressing infratentorial changes, and normal supratentorial white matter in patient 7 at 13.6 and 18.5 years. T2-hyperintensity of inferior cerebellar peduncle (a, arrows in inset) and outlining the mesencephalic course of superior cerebellar peduncles (b, c; NB wide perivascular spaces in anterior mesencephalon) including their decussation (d) at 13.6 years (a–f). This has resolved by 18.5 years (g–l). The striatum is shrunken and T2-hyperintense (k), supratentorial white matter normal (including ADC, not depicted).