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Mutations in  POLR3A  are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G &gt; A mutation in  POLR3A . Here, we present 10 patients from 8 unrelated families with  POLR3A -related late-onset spastic ataxia, all harboring the c.1909 + 22G &gt; A variant. Most of them showed an ataxic-spastic picture, two a “pure” cerebellar phenotype, and one a “pure” spastic presentation. The non-neurological findings typically associated with  POLR3A  mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The  POLR3A  mutations present in this cohort were the c.1909 + 22G &gt; A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14–18. Interestingly, this patient had the most “complex” presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset  POLR3A -related disorders, and therefore further expand the phenotype.

POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients