Objective: To report the clinical, molecular and magnetic resonance imaging features of eight patients with POLR3A-realted spastic ataxia.

Background: POLR3-related disorders comprise a number of clinically overlapping disease entities caused by recessive mutations in POLR3A and POLR3B genes. The best recognized phenotypes consist of an early-childhood-onset hypomyelinating leukodystrophy manifesting with variable combinations of cerebellar ataxia, tremor, spasticity, mental retardation, oligodontia and hypogonadotropic hypogonadism. Recently, a novel and milder phenotype consisting in adolescent-onset spastic ataxia has been proposed to be specific of an intronic mutation (c.1909+22G4A) in the POLR3A gene. In these subjects the typical signs of hypomyelinating leukodystrophy on MRI would be absent and a characteristic hyperintensity along the superior cerebellar peduncle in T2 and FLAIR sequences would be observed instead. Whether or not the reported intronic mutation is specific for this clinical and MRI phenotype is still a matter of debate.

Method: Patients belonged to five pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin in which a multigenic diagnostic panel was administered. Clinical examination and MRI studies were done at a single centre.

Results: All affected subjects were compound heterozygous carriers of c.1909+22G>A in combination with a different novel mutation in each of the pedigrees. Bioinformatics predicted pathogenicity of the novel mutations all segregating with the phenotype. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and intention tremor. Non-neurological manifestations commonly associated with POLR3A-related disorders such as hypodontia, hypogonadism, myopia or mental impairment were absent. A characteristic hyperintensity along the superior cerebellar peduncle on MRI (T2 and FLAIR sequences) was observed in 75% of the cases.

Conclusion: POLR3A-related spastic ataxia is a distinct phenotype within the spectrum of POLR3A-related disorders and the c.1909+22G>A mutation would be its main phenotypic determinant. Specific MRI features such as hyperintensity along the superior cerebellar peduncle might be useful for guiding the genetic diagnosis.

References: Minnerop M, Kurzwelly D, Wagner H, et al. Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. Brain. 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095. Erratum in: Brain. 2017 Dec 9;:. PubMed PMID: 28459997. Gauquelin L, Tétreault M, Thiffault I, et al. POLR3A variants in hereditary spastic paraplegia and ataxia. Brain. 2018 Jan 1;141(1):e1. doi: 10.1093/brain/awx290. PubMed PMID: 29228109; PubMed Central PMCID: PMC5837469.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/polr3a-related-spastic-ataxia-new-mutations-and-a-look-into-the-clinical-and-mri-phenotype/