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Open Access 01-04-2020 | Dystonia | Original Article

POLR3A variants with striatal involvement and extrapyramidal movement disorder

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

Published in: Neurogenetics | Issue 2/2020

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.

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Title: POLR3A variants with striatal involvement and extrapyramidal movement disorder
Authors: Inga Harting
Murtadha Al-Saady
Ingeborg Krägeloh-Mann
Annette Bley
Maja Hempel
Tatjana Bierhals
Stephanie Karch
Ute Moog
Geneviève Bernard
Richard Huntsman
Rosalina M. L. van Spaendonk
Maaike Vreeburg
Agustí Rodríguez-Palmero
Aurora Pujol
Marjo S. van der Knaap
Petra J. W. Pouwels
Nicole I. Wolf
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Keywords: Dystonia
Movement Disorder
Leukodystrophy
Published in: Neurogenetics / Issue 2/2020
Print ISSN: 1364-6745
Electronic ISSN: 1364-6753
DOI: https://doi.org/10.1007/s10048-019-00602-4

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POLR3A variants with striatal involvement and extrapyramidal movement disorder

Abstract

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Abstract

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