Objective: To expand on the phenotypic spectrum of POLR3A c.1909+22G>A splice variant and report two patients’ tremor response to deep brain stimulation.

Background: Polymerase III is an enzyme responsible for essential RNA processing and translation; POLR3A is one of its largest subunits, and forms the enzyme’s catalytic complex. Whilst biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent-onset spastic ataxia without leukodystrophy. Recent reports also demonstrate extrapyramidal features with one patient responding to pallidal deep brain stimulation.

Method: We identified individuals with biallelic POLR3A, one of which must be c.1909+22G>A, from PathWest diagnostic genomics laboratory Perth Australia and neurogenetics laboratory National Hospital for Neurology and Neurosurgery London United Kingdom. We performed detailed clinic-radiological phenotyping and a systemic literature review.

Results: We report eight new cases of POLR3A-related disorder, presenting predominantly as movement disorders. Six patients manifested as spastic ataxia; one of whom developed severe segmental dystonic tremor in his neck and arms. Another patient developed late childhood onset pure dystonic tremor of arms while her sister remains asymptomatic except for hypodontia. Subtle neuroimaging findings of white matter changes such as superior cerebellar peduncle T2 hyperintensity were often missed. Both patients with severe dystonic tremor of arms responded to thalamic deep brain stimulation. Dystonia and upper limb tremor were seen in a quarter of patients with POLR3A-related disorder based on 160 cases although these clinical features were probably under-reported.

Conclusion: Biallelic POLR3A-related disorder with the c.1909+22G>A variant present predominantly with late-childhood to adulthood onset spastic ataxia. However, patients can manifest with pure dystonia or remain minimally symptomatic. Patients with severe dystonic tremor may respond to deep brain stimulation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/polr3a-related-disorders-and-response-to-deep-brain-stimulation/