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.

Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy

“…Recently, a similar MRI phenotype was described in patients with a c.1771-7C>G or c.1771-6C>G variant, in trans with a missense, nonsense, splice site, or synonymous variant. 21,22 Clinical severity varied according to the trans POLR3A variant; patients homozygous for the splicing variant typically displayed a milder phenotype, whereas those harboring a trans loss of function variant displayed severe features with early onset. [21][22][23][24] Of interest, patients homozygous or compound heterozygous for the c.1771-7C>G and/or c.1771-6C>G variants did not display white matter involvement and were described as only having the neuronal MRI features, including striatal involvement with caudate nucleus and putamen atrophy, and occasional red nuclei signal abnormalities.…”

“…21,22 Clinical severity varied according to the trans POLR3A variant; patients homozygous for the splicing variant typically displayed a milder phenotype, whereas those harboring a trans loss of function variant displayed severe features with early onset. [21][22][23][24] Of interest, patients homozygous or compound heterozygous for the c.1771-7C>G and/or c.1771-6C>G variants did not display white matter involvement and were described as only having the neuronal MRI features, including striatal involvement with caudate nucleus and putamen atrophy, and occasional red nuclei signal abnormalities. [21][22][23][24] We hypothesize that these specific splicing variants cause a cell-specific effect (i.e., basal ganglia neurons) compared with other POLR3-HLD variants.…”

“…[21][22][23][24] Of interest, patients homozygous or compound heterozygous for the c.1771-7C>G and/or c.1771-6C>G variants did not display white matter involvement and were described as only having the neuronal MRI features, including striatal involvement with caudate nucleus and putamen atrophy, and occasional red nuclei signal abnormalities. [21][22][23][24] We hypothesize that these specific splicing variants cause a cell-specific effect (i.e., basal ganglia neurons) compared with other POLR3-HLD variants. This could explain why, when this variant is combined with a loss of function allele, patients with a severe phenotype have a specific MRI pattern (i.e., more myelin than the typical phenotype, with progressive basal ganglia involvement).…”

Multimodal evaluation of an Italian family with a hereditary spastic paraplegia and POLR3A mutations

“…Another recent paper reports an extrapyramidal syndrome with dystonia. 7 Interestingly, most of the patients described so far, carried the same intronic mutation (c.1909 + 22G > A). The intronic variant c.1909 + 22G > A is present in almost all the populations included in gnomAD and it has an ultrarare allele frequency (MAF 0.001365).…”

“…4 Even more recently, Harting and coworkers described a cohort with basal ganglia involvement and extrapyramidal disorders such as parkinsonism and dystonia. 7 Our multimodal evaluation further expands the phenotypic spectrum associated with mutations in the POLR3A gene, in fact, for the first time, we describe an Italian family with a pure hereditary spastic paraplegia (SPG) and biallelic POLR3A variants. In addition, in line with previous transcranial magnetic stimulation (TMS) studies performed on SPG patients, 8 we carried out an extensive TMS battery to evaluate the function of intracortical circuits in the primary motor cortex.…”