POLR3A variants with striatal involvement and extrapyramidal movement disorder

Inga Harting,Petra J W Pouwels,Murtadha Al-Saady,Stephanie Karch,Annette Bley,Maja Hempel,Aurora Pujol,Richard Huntsman,Nicole I Wolf,Maaike Vreeburg,Agustí Rodríguez-Palmero,Marjo S Van Der Knaap,Tatjana Bierhals,Ingeborg Krägeloh-Mann,Rosalina M L Van Spaendonk,Ute Moog,Geneviève Bernard

doi:10.1007/s10048-019-00602-4

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.

Highlights

RNA polymerase III (POLR3) transcribes genes encoding small, non-coding RNAs including tRNAs, 5S RNA, 7SK RNA, and U6 small nuclear RNA, which are involved in the regulation of transcription, RNA processing, and translation [1].Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the articleDisease-causing variants in genes coding for POLR3 subunits were first discovered in patients with hypomyelinating leukodystrophy
Clinical manifestations and hypomyelination in 4H leukodystrophy are more severe in patients with variants in POLR3A and POLR1C than in patients with variants in POLR3B [7, 8]; hypomyelination, is not obligatory, and manifestation without hypomyelination occurs in patients with variants in POLR3A or POLR3B [9]
We present nine patients with biallelic variants in POLR3A carrying at least one of two intronic variants (c.1771-6C > G or c.1771-7C > G), with predominantly extrapyramidal manifestations and characteristic MR changes of striatum, superior, and, often, inferior cerebellar peduncle

Summary

Introduction

MCP were T2-hyperintense in 29, decussation of SCP in two, and ICP was not involved in any of the 36 patients with classic 4H leukodystrophy re-reviewed for comparison. Signal of supratentorial white matter on T2w and T1w images was normal in three of the four older patients examined between 4 and 29 years (patients 6–9), while mild T2hyperintensity of pyramidal tract in the centrum semiovale and subcortical white matter was present in patient 9.

Results

Conclusion