POLR3A variants with striatal involvement and extrapyramidal movement disorder

Area of Science:

• Genetics
• Neurology
• Radiology

Background:

• Biallelic POLR3A variants typically cause 4H leukodystrophy, marked by hypomyelination and specific neurological signs, with basal ganglia spared.
• Atypical presentations of POLR3A variants involving the striatum and red nucleus have been rarely reported.

Purpose of the Study:

• To characterize a striatal variant of POLR3A-related disease.
• To differentiate this variant from classic 4H leukodystrophy based on clinical and MRI findings.

Main Methods:

• Retrospective review of clinical and genetic data from nine patients with POLR3A variants and striatal changes.
• Analysis of 18 MRI scans to identify characteristic radiological features.

Main Results:

• All patients presented with prominent extrapyramidal involvement, including hypotonia and choreic movements in younger children.
• Characteristic MRI findings included striatal T2-hyperintensity and atrophy, with superior cerebellar peduncle involvement.
• Distinct from 4H leukodystrophy, this variant showed no frank hypomyelination but abnormal myelination of specific tracts.

Conclusions:

• The striatal variant of POLR3A-related disease is clinically and radiologically distinct from 4H leukodystrophy.
• This variant is associated with specific intronic POLR3A variants (c.1771-6C>G or c.1771-7C>G) in combination with another POLR3A variant.